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WO2023201267A1 - Combination therapy for treating trop-2 expressing cancers - Google Patents

Combination therapy for treating trop-2 expressing cancers Download PDF

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Publication number
WO2023201267A1
WO2023201267A1 PCT/US2023/065682 US2023065682W WO2023201267A1 WO 2023201267 A1 WO2023201267 A1 WO 2023201267A1 US 2023065682 W US2023065682 W US 2023065682W WO 2023201267 A1 WO2023201267 A1 WO 2023201267A1
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WO
WIPO (PCT)
Prior art keywords
cancer
antibody
inhibitor
therapy
trop
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2023/065682
Other languages
French (fr)
Inventor
Oyewale ABIDOYE
Chih-Chien Chou
William J. GROSSMAN
Jessica N. ORF
Joseph Kwang PARK
Nathalie Scholler
Mitchell R. SIERECKI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Sciences Inc
Arcus Biosciences Inc
Original Assignee
Gilead Sciences Inc
Arcus Biosciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Sciences Inc, Arcus Biosciences Inc filed Critical Gilead Sciences Inc
Priority to CN202380033738.5A priority Critical patent/CN119173276A/en
Priority to CA3256033A priority patent/CA3256033A1/en
Priority to KR1020247037701A priority patent/KR20250004779A/en
Priority to JP2024560326A priority patent/JP2025512384A/en
Priority to AU2023252914A priority patent/AU2023252914A1/en
Priority to EP23721581.9A priority patent/EP4507736A1/en
Publication of WO2023201267A1 publication Critical patent/WO2023201267A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Definitions

  • the present disclosure relates to methods of treating, mitigating, or preventing or delaying the recurrence or metastasis of a Trop-2 expressing cancer (c.g., metastatic castrate resistant prostate cancer, non-small cell lung cancer) in a subject by administering an effective amount of: (a) an anti-Trop-2 antibody drug conjugate (ADC) (e.g., sacituzumab govitecan); and (b) an adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat) to the subject.
  • ADC anti-Trop-2 antibody drug conjugate
  • adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • the present disclosure further relates to methods of treating, mitigating, or preventing or delaying the recurrence or metastasis of a tumor antigen (TA) expressing cancer in a subject by administering an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (Topi ADC); and b) an adenosine pathway inhibitor.
  • ADC tumor antigen targeted antibody-drug conjugate
  • Topici ADC topoisomerase I inhibitor
  • Anti-Trop-2 antibody drug conjugates such as sacituzumab govitecan and datopotamab deruxtecan, are under clinical investigation for the treatment of a variety of Trop-2 expressing cancers. While evidence of clinical efficacy has been obtained in a monotherapy setting, further therapeutic benefits for patients are desired.
  • Trop-2 expression has been reported for a variety of epithelial cancers, including breast, bladder, lung, colorectal and prostate cancers.
  • Prostate cancer is the most commonly diagnosed cancer and the second most frequent cause of cancer-related mortality among men in the United States (US).
  • US United States
  • Adenocarcinoma comprises 95% of prostatic carcinomas (Lie AK. Histology of prostate cancer. Oncolex Oncology Encyclopedia. Accessed 25 February 2020 at oncolex.org/Prostate-cancer/Background/Histology.).
  • Most cases (90%) are diagnosed at a local or regional stage for which treatment options include active surveillance, surgery, or radiation.
  • the 5-ycar relative survival is 98% across all stages but is 30% for disease diagnosed at an advanced stage.
  • Metastatic or advanced prostate cancer has a more complex treatment algorithm. Patients with locally advanced disease initially receive androgen ablation with radiation or prostatectomy, whereas first-line therapy in the metastatic setting is androgen ablation plus systemic treatment (e.g., second-generation hormonal therapy or docetaxel-based chemotherapy).
  • Disease progression in the context of androgen deprivation is known as castrate resistant prostate cancer (CRPC).
  • PCWG2 Prostate Cancer Working Group 2
  • PCWG2 Prostate Cancer Working Group 2
  • PSA serum prostate-specific antigen
  • the progression of pre-existing local or metastatic disease and/or the appearance of new metastases in the setting of castrate levels of serum testosterone ( ⁇ 50 ng/dL; Scher HI, et al. J Clin Oncol. (2008) 26(7): 1148- 1159.).
  • Prognosis for CRPC is associated with several factors, including performance status, presence of bone pain, extent of disease on bone scan, and serum alkaline phosphatase (ALP) levels. Bone metastases will occur in approximately 80% of men with CRPC and can produce significant morbidity, including pain, pathologic fractures, spinal cord compression, and bone marrow failure. Paraneoplastic effects are also common, including anemia, weight loss, fatigue, hypercoagulability, and increased susceptibility to infection (Saad F and Hotte S. Can Urol Assoc J. (2010) 4(6):380-384).
  • Lung cancer is the leading cause of cancer-related mortality worldwide. It was estimated that in 2020, there were over 2 million new cases of lung cancer and approximately 1.8 million deaths worldwide. In the United States (US) in 2021, it is estimated that there will be over 235,000 new cases of lung cancer and over 131,000 deaths. Approximately 80% to 85% of all lung cancers are non-small cell lung cancer (NSCLC) (Ettinger et al. J Natl Compr Cane Netw (2019); 17(12): 1464-72) and more than half of these arc identified at an advanced stage (Siegel ct al. CA Cancer J Clin (2019);69 (l):7-34).
  • NSCLC non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • ROS1 ROS proto-oncogene 1
  • BRAF proto-oncogene B-raf
  • RET alterations neurotrophic tyrosine receptor kinase
  • NSRK neurotrophic tyrosine receptor kinase
  • Chemotherapy /immunotherapy regimens such as pembrolizumab/(carboplatin or cisplatin)/pemetrexed are recommended for patients with non-squamous NSCLC regardless of PD-L1 expression.
  • chemotherapy/immunotherapy regimens such as pembrolizumab/carboplatin/ (paclitaxel or albumin-bound paclitaxel) are recommended (Ettinger et al. J Natl Compr Cane Netw (2019);17 (12): 1464-72).
  • Immune checkpoint inhibitors have reinvigorated clinical development interest in anticancer immunotherapy. The latter relies on therapeutic modulation of the tumor microenvironment or other aspects of the immune system to overcome mechanisms of immune suppression that a tumor elicits on the host immune system. Despite their proven benefit in numerous tumor types as evidenced by the approvals of nivolumab, pembrolizumab, atezolizumab, and ipilimumab, checkpoint inhibition has not proven effective in the treatment of metastatic prostate cancer where response rates to monotherapy are less than 5% (Antonarakis ES, et al. J Clin Oncol. (2020) 38(5):395-405.).
  • ADCs Antibody-drug conjugates
  • ADCs are a fast-growing drug class in oncology with several different ADCs currently approved as cancer treatments and many more in preclinical and clinical development (e.g., Drago, J.Z. et al., Nat Rev Clin Oncol (2021) 18, 327-344).
  • ADCs are generally composed of monoclonal antibodies linked to cytotoxic drugs (payloads).
  • ADCs are designed to limit the delivery of cytotoxic drugs specifically to cells expressing the target antigen of the respective antibody (e.g., Trop-2, Her-2, Nectin-4) and immediately surrounding tumor tissue (bystander effect).
  • ADCs As a result of their tumor targeted delivery of cytotoxic agents ADCs often have much improved therapeutic windows compared to systemically administered cytotoxic agents.
  • ADCs that have obtained marketing approval by the U.S. Food and Drug Administration (US FDA) include gemtuzumab ozogamicin, brentuximab vedotin, ado- trastuzumab emtansine (T-DM1), inotuzumab ozogamicin, trastuzumab deruxtecan (T-DXd), polatuzumab vcdotin, sacituzumab deruxtecan, enfortumab vedotin, and bclantamab mafodotin.
  • Adenosine pathway mediates immunosuppressive effects in the tumor microenvironment (e.g., Allard, B., et al. Nat Rev Clin Oncol (2020) 17, 611-629).
  • Adenosine pathway inhibitors including various CD39 inhibitors, CD73 inhibitors, and adenosine receptor antagonists, are under clinical investigation as promising agents stimulating anti-cancer immune responses.
  • a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor.
  • ADC anti-Trop-2 antibody-drug conjugate
  • the methods provided herein are for treating a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor.
  • ADC anti-Trop-2 antibody-drug conjugate
  • the anti-Trop-2 ADC comprises a topoisomerase I inhibitor.
  • the topoisomerase I inhibitor is a camptothecin (CPT).
  • the topoisomerase I inhibitor is a topotecan, irinotecan, belotecan or exatecan.
  • the topoisomerase I inhibitor is SN38 or Dxd.
  • the topoisomerase I inhibitor is selected from the group consisting of irinotecan, topetecan, and SN-38.
  • the topoisomerase I inhibitor is SN38.
  • the anti-Trop-2 ADC has a structural formula of mAb-CL2A-SN- 38, with a structure represented by:
  • the anti-Trop-2 ADC comprises sacituzumab (hRS7; described, e.g., in W02003074566, Figures 3 and 4).
  • the anti-Trop-2 ADC is selected from the group consisting of sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02 and BAT-8003.
  • the anti-Trop-2 ADC is sacituzumab govitecan.
  • the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist.
  • the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors.
  • the plurality of adenosine pathway inhibitors comprises a CD73 inhibitor and an adenosine receptor antagonist.
  • the CD73 inhibitor is quemliclustat and the adenosine receptor antagonist is etrumadenant.
  • the adenosine pathway inhibitor is an adenosine receptor antagonist.
  • the adenosine pathway inhibitor is imaradenant, NIR178, ID11902, IN-A003, NTI-55, TT-10, TT-228, PBF-1129 (Palobiofarma), TT-702, etrumadenant, INCB 106385, M1069, HM87277, RVU-330, or TT-53.
  • the adenosine pathway inhibitor is a dual antagonist of adenosine A2A receptor (A2AR; ADORA2A) and A2B receptor (A2BR; ADORA2B).
  • A2AR adenosine A2A receptor
  • A2BR A2B receptor
  • the adenosine pathway inhibitor is etrumadenant (AB928; GS- 0928), taminadcnant, TT-10, TT-4, or M1069.
  • the adenosine pathway inhibitor is etrumadenant.
  • the adenosine pathway inhibitor is a CD73 inhibitor.
  • the CD73 inhibitor is oleclumab, B MS-986179, uliledlimab, AK119, quemliclustat, mupadolimab, HLX23, INCA00186, IB 1325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037.
  • the CD73 inhibitor is quemliclustat (AB680, GS-0680), uliledlimab, mupadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV93O, BMS-986179, or oleclumab.
  • the CD73 inhibitor is quemliclustat.
  • the method further comprises co-administering an additional therapeutic agent or therapeutic modality.
  • the additional therapeutic agent or therapeutic modality comprises one, two, three, or four additional therapeutic agents and/or therapeutic modalities.
  • the additional therapeutic agent comprises an anti-PD-(L)l antibody.
  • the anti-PD-(L)l antibody is pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, or zimberelimab.
  • the anti-PD-(L)l antibody is zimberelimab.
  • the additional therapeutic agent comprises an anti-TIGIT antibody.
  • the anti-TIGIT antibody is tiragolumab, vibostolimab, domvanalimab, AB3O8, AK127, BMS-986207, ralzapastotug, or etigilimab.
  • the anti-TTGTT antibody is domvanalimab.
  • the anti-TIGIT antibody is ralzapastotug.
  • the additional therapeutic agent comprises a) zimberelimab and domvanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vibostolimab, e) pembrolizumab and domvanalimab, f) pembrolizumab and AB308, g) MK- 7684A (pembrolizumab/vibostolimab coformulation), h) durvalumab and domvanalimab, i) zimberelimab and ralzapastotug, or j) pembrolizumab and ralzapastotug.
  • the additional therapeutic agent comprises zimberelimab and domvanalimab.
  • the Trop-2 positive cancer is a solid epithelial cancer.
  • the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC), HR + /Her2- breast cancer, HR + /Her2 low breast cancer), colorectal cancer, lung cancer, stomach cancer, urinary tract cancer, urothelial cancer, bladder cancer, renal cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer and prostatic cancer.
  • breast cancer e.g., triple negative breast cancer (TNBC), HR + /Her2- breast cancer, HR + /Her2 low breast cancer
  • colorectal cancer e.g., lung cancer, stomach cancer, urinary tract cancer, urothelial cancer, bladder cancer, renal cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer and prostatic cancer.
  • the breast cancer is triple negative breast cancer (TNBC), HR + /Her2’ breast cancer, or HR + /Her2 low breast cancer.
  • the prostatic cancer is castrate-resistant prostate cancer (CRPC).
  • CRPC castrate-resistant prostate cancer
  • the lung cancer is non-small lung cancer (NSCLC).
  • NSCLC non-small lung cancer
  • the lung cancer is (i) squamous NSCLC or (ii) non-squamous NSCLC.
  • the lung cancer is without EGFR, ALK, or other actionable genomic alterations.
  • the Trop-2 positive cancer is (i) unresectable, locally advanced or (ii) metastatic.
  • the cancer has progressed following at least one prior anti-cancer therapy.
  • Tn some embodiments, the cancer has progressed after prior new hormonal agent treatment (NHA; first- or second-generation non-steroidal antiandrogens, abiratcronc).
  • NHA first- or second-generation non-steroidal antiandrogens, abiratcronc
  • the cancer has progressed or recurred after platinum-based chemotherapy.
  • the cancer has progressed or recurred after checkpoint inhibitor therapy (CPI) therapy.
  • CPI checkpoint inhibitor therapy
  • the cancer has progressed or recurred after platinum-based chemotherapy and anti-PD-(L)l antibody therapy, received either in combination or sequentially in any order.
  • the cancer has progressed or recurred after a tyrosine kinase inhibitor therapy.
  • the subject is treatment naive.
  • the subject has not received a prior therapy selected from the group consisting of a taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.
  • a prior therapy selected from the group consisting of a taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.
  • the subject has not received a prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy.
  • taxane naive prior taxane therapy
  • CPI naive checkpoint inhibitor therapy
  • topoisomerase I inhibitor therapy topoisomerase I inhibitor therapy
  • the taxane therapy comprises paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel.
  • the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)l antibody.
  • the topoisomerase I inhibitor therapy comprises a topotecan, irinotecan, belotecan or exatecan.
  • the anti-Trop-2 ADC and the adenosine pathway inhibitor are coadministered concurrently.
  • the anti-Trop-2 ADC and the adenosine pathway inhibitor are coadministered sequentially.
  • the subject is human.
  • the anti-Trop-2 ADC is administered at one or more doses in the range of 8 mg/kg to 10 mg/kg.
  • the anti-Trop2 ADC is administered at one or more doses of 8 mg/kg or 10 mg/kg.
  • the anti-Trop2 ADC is administered at one or more doses of 10 mg/kg.
  • the anti-Trop-2 ADC is administered intravenously.
  • the anti-Trop-2 ADC is administered on days 1 and 8 of a 21-day cycle.
  • the adenosine pathway inhibitor is administered at one or more doses of 75 mg or 150 mg.
  • the adenosine pathway inhibitor is administered at one or more doses of 150 mg.
  • the adenosine pathway inhibitor is administered orally (PO).
  • the adenosine pathway inhibitor is administered once daily (QD).
  • the anti-PD(L)l antibody is administered at one or more doses of 360 mg.
  • the anti-PD(L)l antibody is administered intravenously (IV).
  • the anti-PD(L)l antibody is administered once every three weeks (Q3W).
  • sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on day 1 and day 8 of a 21 -day treatment cycle
  • etrumadenant is administered orally (PO) once a day (QD) at a dose of 150 mg on each day of the 21-day treatment cycle
  • zimberelimab is administered intravenously (IV) on day 1 of the 21-day treatment cycle (Q3W).
  • an anti-cancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof.
  • ORR objective response rate
  • DCR disease control rate
  • PFS progression free survival
  • DOR duration of response
  • OS overall survival
  • CR complete response
  • PR partial response
  • PSA response rate radiographic response rate
  • change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers or a combination thereof.
  • tumor response or progression is determined according to RECIST version 1.1.
  • a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of castrate-resistant prostate cancer comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; and b) etrumadenant.
  • CRPC castrate-resistant prostate cancer
  • Tn some embodiments, provided herein is a method of treating metastatic castrate-resistant prostate cancer (mCRPC) comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; and b) etrumadenant.
  • the method further comprises co-administering an anti-PD-(L)l antibody to the human patient.
  • the anti-PD-(L)l antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the method further comprises co-administering zimberelimab to the human patient.
  • the human mCRPC patient has previously progressed on ADT.
  • the human mCRPC patient has previously progressed on NHA.
  • the human mCRPC patient is CPI and taxane naive.
  • the human mCRPC patient has RECIST 1.1 measurable or non-measurable disease.
  • the CRPC is metastatic CRPC (mCRPC).
  • the CRPC is resistant or refractory to one or more anti-cancer therapies.
  • the CRPC has progressed following prior NHA therapy (first- or second-generation non-steroidal antiandrogens, abiraterone).
  • prior NHA therapy first- or second-generation non-steroidal antiandrogens, abiraterone.
  • the human patient has not received a prior therapy selected from taxanc therapy (taxanc naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.
  • the human patient has not received a prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy.
  • taxane naive prior taxane therapy
  • CPI naive checkpoint inhibitor therapy
  • topoisomerase I inhibitor therapy topoisomerase I inhibitor therapy
  • the taxane therapy comprises paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel.
  • the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)! antibody.
  • the topoisomerase I inhibitor therapy comprises a topotecan, irinotecan, belotecan or exatecan.
  • NSCLC non-small cell lung cancer
  • the anti-PD-(L)l antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the anti-PD-(L)l antibody is zimberelimab.
  • the NSCLC has progressed or recurred after platinum-based chemotherapy. In some embodiments, the NSCLC has progressed or recurred after checkpoint inhibitor therapy (CPI) therapy. In some embodiments, the NSCLC has progressed or recurred after platinum based chemotherapy and anti-PD-(L)l antibody therapy, received either in combination or sequentially in any order. In some embodiments, the NSCLC has progressed or recurred after a tyrosine kinase inhibitor therapy. In some embodiments, the NSCLC is (i) unresectable, locally advanced or (ii) metastatic.
  • sacituzumab govitecan is administered intravenously (IV) at a dose of 8 mg/kg or 10 mg/kg on day 1 and day 8 of a 21 -day treatment cycle and etrumadenant is administered orally (PO) once a day (QD) at a dose of 75 mg or 150 mg on each day of the 21 -day treatment cycle.
  • sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on day 1 and day 8 of a 21-day treatment cycle and etrumadenant is administered orally (PO) once a day (QD) at a dose of 150 mg on each day of the 21-day treatment cycle.
  • zimberelimab is administered intravenously (IV) on day 1 of the 21-day treatment cycle (Q3W).
  • an anti-cancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or combinations thereof.
  • an anti-cancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, or change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.
  • an anti-CD47 antibody e.g., magrolimab
  • an anti-CD47 antibody is not co-administered to the subject or human patient.
  • an MCL1 inhibitor e.g., GS-9716
  • GS-9716 is not co-administered to the subject or human patient.
  • a FLT3 agonist e.g., GS-3583, CDX-301
  • GS-3583, CDX-301 is not administered to the subject or human patient.
  • TA + tumor antigen positive
  • TA + tumor antigen positive
  • TA + tumor antigen positive
  • TA + tumor antigen positive
  • a tumor antigen targeted ADC comprising a topoisomerase I inhibitor (Topi ADC)
  • Topici ADC topoisomerase I inhibitor
  • adenosine pathway inhibitor an adenosine pathway inhibitor
  • optionally an anti-PD(L)l antibody optionally an anti-PD(L)l antibody.
  • an anti-Trop-2 ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)l antibody in a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of Trop-2 positive cancers, wherein the method comprises administering the anti-Trop-2 ADC, adenosine pathway inhibitor, and optionally the additional anti-PD(L) 1 antibody to a subject.
  • a Topi ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)l antibody in a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of tumor antigen positive (TA + ) cancers, wherein the method comprises administering the Topi ADC, adenosine pathway inhibitor, and optionally the anti-PD(L)l antibody to a subject.
  • arc combination therapies for treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of Trop-2 positive (Trop-2 + ) cancers by co-administering effective amounts of a) an anti-Trop-2 antibody-drug conjugate (anti-Trop-2 ADC) and b) an adenosine pathway inhibitor to a subject.
  • an anti-Trop-2 antibody-drug conjugate anti-Trop-2 ADC
  • combination therapies for treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of a tumor antigen positive (TA + ) cancer by co-administering an effective amount of a) a tumor antigen (TA) targeted ADC comprising a topoisomerase I inhibitor (Topi ADC) and b) an effective amount of an adenosine pathway inhibitor to a subject.
  • the combination therapies provided herein further comprise co-administering an additional therapeutic agent, such as a checkpoint inhibitor, or an additional therapeutic modality (e.g., surgery, radiation).
  • the anti-Trop-2 ADC is sacituzumab govitecan.
  • the Topi ADC is trastuzumab-deruxtecan (T-DXd).
  • the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quemliclustat, oleclumab), or an adenosine receptor antagonist (e.g., etrumadenant, imaradenant, NIR178).
  • the checkpoint inhibitor is an anti-PD(L)l antibody (e.g., zimberelimab, pembrolizumab, nivolumab, atezolizumab, durvalumab).
  • the Trop-2 positive cancer is castrate-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).
  • an anti-Trop-2 ADC e.g., sacituzumab govitecan
  • an adenosine pathway inhibitor e.g., etrumadenant
  • an additional therapeutic agent such as a checkpoint inhibitor (e.g., anti-PD(L)l antibody), or an additional therapeutic modality (e.g., surgery, radiation) in a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of Trop-2 positive cancers
  • the method comprises administering the anti-Trop-2 ADC, adenosine pathway inhibitor, and optionally the additional therapeutic agent or additional therapeutic modality to a subject (e.g., a human cancer patient).
  • the anti-Trop-2 ADC is sacituzumab govitecan.
  • the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quemliclustat, oleclumab), or an adenosine receptor antagonist (e.g., etrumadenant, imaradenant, NIR178).
  • the checkpoint inhibitor is an anti-PD(L)l antibody (e.g., zimberelimab, pembrolizumab, nivolumab, atezolizumab, durvalumab).
  • the Trop-2 positive cancer is castrate-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).
  • a Topi ADC for use in combination with an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, adenosine receptor antagonist) and optionally an additional therapeutic agent, such as a checkpoint inhibitor (e.g., anti-PD(L)l antibody), or an additional therapeutic modality (e.g., surgery, radiation) in a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of TA positive cancers, wherein the method comprises administering the Topi ADC, adenosine pathway inhibitor, and optionally the additional therapeutic agent or additional therapeutic modality to a subject (e.g., a human cancer patient).
  • an adenosine pathway inhibitor e.g., CD39 inhibitor, CD73 inhibitor, adenosine receptor antagonist
  • an additional therapeutic agent such as a checkpoint inhibitor (e.g., anti-PD(L)l antibody), or an additional therapeutic modality (e.g., surgery, radiation) in
  • the Topi ADC is trastuzumab-deruxtecan (T-DXd).
  • the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quemliclustat, oleclumab), or an adenosine receptor antagonist (e.g., etrumadenant, imaradenant, NIR178).
  • the checkpoint inhibitor is an anti-PD(L)l antibody (e.g., zimberelimab, pembrolizumab, nivolumab, atezolizumab, durvalumab).
  • the Trop-2 positive cancer is castrate-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).
  • This disclosure is based, at least in part, on the realization that a combination therapy comprising co-administration of a) an anti-Trop2 ADC or a Topi ADC and b) an adenosine pathway inhibitor can have improved anticancer effects compared to single-agent therapies with one of the combined agents a) and b).
  • Improved anti-cancer effects can include, for example, improved overall response rates (ORR), improved partial response rates (PR), improved complete response rates (CR), improved durations of response (DOR), improved overall survival (OS), improved progression free survival (PFS), improved quality of life (QoL) indicators, or the like.
  • the combination therapies described herein generally have tolerable safety profiles, c.g., as determined by the incidence and/or severity of observed adverse events (AEs) or serious adverse events (SAEs).
  • the combination therapies described herein have improved safety profiles, e.g., as compared to monotherapies involving the co-administered agents, or relative to a standard of care for a given indication (e.g., a chemotherapy regimen of physician’s choice).
  • the term “antibody” refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen (e.g., a heavy chain variable domain, a light chain variable domain, and/or one or more CDRs sufficient to confer specific binding to a particular target antigen).
  • a particular target antigen e.g., a heavy chain variable domain, a light chain variable domain, and/or one or more CDRs sufficient to confer specific binding to a particular target antigen.
  • the term antibody includes, for example, and without limitation, human antibodies, non-human antibodies, antibody fragments, and antigen-binding agents that include antibody fragments, inclusive of synthetic, engineered, and modified forms thereof.
  • the term antibody includes, by way of example, both naturally occurring and non-naturally occurring antibodies.
  • an antibody may comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding molecule thereof.
  • Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region comprises three constant domains, CHI, CH2 and CH3.
  • Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region comprises one constant domain, CL.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • Each VH and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies (Abs) may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • Naturally -produced antibodies are glycosylated, typically on the CH2 domain.
  • antibodies include monoclonal antibodies, monospecific antibodies, polyclonal antibodies, multispecific antibodies (including bispecific antibodies), engineered antibodies, rccombinantly produced antibodies, wholly synthetic antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain- antibody heavy chain pairs, intrabodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelized antibodies, affybodies, Fab fragments, Fab' fragments, F(ab’)2 fragments, Fd' fragments, Fd fragments, isolated CDRs, single chain Fvs, polypeptide-Fc fusions, single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); came
  • the term “antibody-drug conjugate” generally refers to a compound comprising an antibody targeting a tumor antigen and an anticancer agent payload, optionally connected by a linker.
  • the tumor antigen is tumor- associated calcium signal transducer 2 (Trop-2; NCBI Gene ID: 4070).
  • the tumor antigen targeted antibody is an anti-Trop-2 antibody (e.g., sacituzumab or datopotamab).
  • the payload is a topoisomerase I inhibitor (e.g., SN38 or Dxd).
  • ADC linker chemistries are known to a skilled artisan and referenced herein (e.g., CL2A).
  • topoisomerase I inhibitor refers to small molecule compounds capable of inhibiting the activity of a DNA topoisomerase type I enzyme.
  • Type I topoisomerases can catalyze changes in DNA topology via transient single-stranded breaks in DNA.
  • Type I topoisomerases can be further classified as Type 1 A and a Type IB subtypes.
  • a description of type I topoisomerases can be found, for example, in Baker et al. (2009) Nucleic Acids Res 37(3), 693- 701.
  • Topoisomerase inhibitors that can be used as payloads in the ADCs described herein include camptothecin (CPT) and non-camptothecin based inhibitors.
  • Useful camptothecins include, for example, topotecan, irinotecan, belotecan, exatecan, and derivatives thereof.
  • Useful non- camptothccins include, for example, indcnosinoquinolincs (c.g., indcno[l,2-c]isoquinolinc, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)), phenanthridines (e.g., topovale (ARC- 111), and indolocarbazoles (e.g., BE-13793C).
  • the topoisomerase I inhibitor is a camptothecin (e.g., an irinotecan, topotecan, belotecan, or exatecan derivative, such as SN38 or Dxd). In some embodiments, the topoisomerase I inhibitor is SN38. In some embodiments, the topoisomerase I inhibitor is Dxd.
  • camptothecin e.g., an irinotecan, topotecan, belotecan, or exatecan derivative, such as SN38 or Dxd.
  • the topoisomerase I inhibitor is SN38. In some embodiments, the topoisomerase I inhibitor is Dxd.
  • anti-PD(L)l antibody refers to antibodies that a) bind to programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 5133) or programmed deathligand 1 (PD-L1 , CD274; NCBI Gene ID: 29126); and b) inhibit the PD-1/PD-L1 interaction and PD-1/PD-L1 pathway.
  • PD-1, CD279; NCBI Gene ID: 5133 programmed cell death protein 1
  • PD-L1 , CD274 NCBI Gene ID: 29126
  • the PD-1/PD-L1 pathway and its role in cancer immunotherapy is described, for example, in Salmaninejad etal, J. Cell Physiol (2019) 234 (10): 16824-16837.
  • Anti- PD(L)1 antibodies that can be used in the methods provided herein include, for example, pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the anti-PD(L)l antibody is zimberelimab.
  • the terms “effective amount” or “therapeutically effective amount” refer to that amount of a therapeutic agent administered in the methods provided herein (e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor) that, when administered alone or in combination with another therapeutic agent to a cell, tissue, or subject is sufficient to effect treatment or a beneficial result in the subject.
  • the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.
  • an effective amount further refers to that amount of the therapeutic agent, which when used in the context of the combination therapies provided herein, is sufficient to treat, prevent, alleviate, ameliorate or mitigate a disease condition, or delay or slow the progression of a disease, and that amount sufficient to effect an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • an effective amount refers to that active ingredient alone.
  • a therapeutically effective amount refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • an effective amount or therapeutically effective amount of a therapeutic agent e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor
  • a therapeutic agent e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor
  • the amount is sufficient to ameliorate, palliate, lessen, and/or delay one or more of symptoms of cancer.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.
  • the methods provided herein refer to the treatment of a subject having cancer (e.g., a human cancer patient).
  • treating a subject having cancer comprises inhibiting cancer or cancer cell proliferation in the treated subject.
  • treating a human cancer patient using the methods provided herein results in the observation of anti-tumor effects or anti-cancer effects in the treated patient.
  • the terms “inhibition of cancer” and “inhibition of cancer cell proliferation” refer to the inhibition of the growth, division, maturation or viability of cancer cells, and/or causing the death of cancer cells, individually or in aggregate with other cancer cells, by cytotoxicity, nutrient depletion, or the induction of apoptosis.
  • anti-tumor effect refers to a biological effect that can present as a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, a decrease in the number of metastases, an increase in overall or progression-free survival, an increase in life expectancy, or amelioration of various physiological symptoms associated with the tumor.
  • anti-cancer effects are measured using one or more of the endpoint criteria applied in the clinical studies described herein (e.g., primary, secondary, or exploratory endpoints).
  • Exemplary clinical endpoint criteria that can be used to measure anti-cancer effects in connection with the methods provided herein include objective response rate (ORR), complete response (CR) rate, partial response (PR) rate, disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), biomarker-based signals, e.g., of intratumoral immune activation or induction of cancer cell death (e.g., tumor tissue or blood based biomarkers), patient quality of life (QoL) indicators (e.g., based on patient surveys), and others.
  • anti-tumor effects e.g., tumor responses or progression
  • RECIST version 1.1 Eisenhauer et al. Eur J Cancer (2009);45 (2):228-47.
  • Anti-cancer effects can be observed using any diagnostic methods known to a skilled artisan, such as computed tomography (CT), magnetic resonance imaging (MRI), radiography, or the like.
  • an “increased” or “enhanced” amount is typically a “statistically significant” amount (e.g., with respect to tumor size, cancer cell proliferation or growth), and may include an increase that is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50 or more times (e.g., 100, 500, 1000 times) (including all integers and decimal points in between and above 1, e.g., 2.1, 2.2, 2.3, 2.4, etc.) an amount or level described herein.
  • It may also include an increase of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 500%, or at least 1000% of an amount or level described herein.
  • a “decreased” or “reduced” or “lesser” amount refers to a decrease that is about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6
  • an amount or level described herein may also include a decrease of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, at least 100%, at least 150%, at least 200%, at least 500%, or at least 1000% of an amount or level described herein.
  • AE adverse event
  • Adverse event refers to any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment.
  • An AE can therefore be any unfavorable and/or unintended sign (including clinically significant abnormal laboratory findings), symptom, or disease temporally associated with the use of a study drug, whether or not the AE is considered related to the study drug.
  • Adverse events may also include pretreatment or posttreatment complications that occur as a result of protocol-specified procedures or special situations.
  • preexisting events that increase in severity or change in nature after study drug initiation or during or as a consequence of participation in the clinical study are also considered AEs.
  • the term “serious adverse event” refers to a) death; b) a lifethreatening situation; c) in-participant hospitalization or prologation of existing hospitalization; d) persistent or significant disability or incapacity; e) a congenital anomaly or birth defect; or f) a medically important event or reaction as determined by an attending physician.
  • medically important events include intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; and development of drug dependency or drug abuse.
  • tumor antigen expressing cancer or “tumor antigen positive cancer” are used interchangeably to refer to cancers having detectable levels of tumor antigen (TA) expression.
  • the tumor antigen is Trop-2.
  • Tumor antigen expression in a cancer tissue or cancer cell can be detected in a sample from a subject having cancer (e.g., a human cancer patient) by any method known to a skilled artisan, e.g., as a protein, mRNA, or cell-surface expression level.
  • tumor antigen expression can be determined by methods such as immunohistochemistry (IHC), western blot, fluorescence in-situ hybridization (FISH), polymerase chain reaction (PCR), next-generation exome sequencing, or fluorescence associated cell sorting (FACS).
  • IHC immunohistochemistry
  • FISH fluorescence in-situ hybridization
  • PCR polymerase chain reaction
  • FACS fluorescence associated cell sorting
  • TA expressing cancer or “TA positive cancer”
  • less than 99%, less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of cells in a tumor or tumor sample have detectable levels of tumor antigen expression.
  • 99% or more, 95% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more of cells in a tumor or tumor sample have detectable levels of tumor antigen expression.
  • TA expressing cancer or “TA positive cancer” refers to a cancer for which treatment with a certain anti-Trop-2 ADC or Topi ADC is indicated either as a single-agent therapy or in a combination.
  • TA positive cancer indications of anti-Trop-2 ADCs or Topi ADCs that have received a marketing authorization from a regulatory health agency e.g., FDA, EMA are listed, for example, on agency approved drug product labels.
  • a TA positive (e.g., Trop-2 + ) cancer is a cancer in which an anti-Trop-2 ADC or Topi ADC has demonstrated an anti-cancer effect that is attributable to the anti-Trop-2 ADC or Topi ADC.
  • Such anti-cancer effects can be demonstrated in a preclinical model (e.g., a mouse xenograft or syngeneic cancer model) or in a clinical trial conducted with human cancer patients.
  • the TA expressing cancer or TA positive cancer does not express detectable levels of Trop-2, e.g., as determined by IHC and/or FISH analysis.
  • the term “tumor antigen targeted antibody-drug conjugate (ADC)” generally refers to an ADC comprising a tumor antigen binding antibody.
  • ADC tumor antigen targeted antibody-drug conjugate
  • Such TA binding antibodies can generally direct an ADC to TA expressing cancer cells in a tumor tissue.
  • the TA binding antibody is a neutralizing or blocking antibody (competing with the binding of another binding partner to the TA).
  • the TA binding antibody can modulate TA associated molecular or cellular signaling events.
  • the TA binding antibody has antagonistic or agonistic activity relative to the TA.
  • TA targeted ADCs that can be used in the methods provided herein include, without limitation, gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine (T-DM1), inotuzumab ozogamicin, trastuzumab deruxtecan (T-DXD), datopotamab deruxtecan (DATO-DXD), polatuzumab vedotin, sacituzumab govitecan, labetuzumab govitecan, enfortumab vedotin, and belantamab mafodotin.
  • the TA targeted ADC does not bind to Trop-2.
  • ADCs Antibody-Drug-Conjugates
  • the treatment methods provided herein comprise co-administering an antibody-drug- conjugate (ADC) to a subject, such as a human cancer patient.
  • ADC antibody-drug- conjugate
  • the ADC comprises an anti-Trop-2 antibody, an anti-cancer agent payload, and an optional linker connecting the anti-Trop-2 antibody and payload (anti-Trop-2 ADC).
  • the anti-cancer agent payload in the anti-Trop-2 ADC is a topoisomerase I inhibitor (e.g., SN38, Dxd).
  • the anti-cancer agent payload in the anti-Trop-2 ADC does not include a topoisomerase I inhibitor.
  • the ADC comprises a tumor antigen (TA) targeted antibody, a topoisomerase I inhibitor payload, and an optional linker connecting the TA targeted antibody and payload (Topi ADC).
  • TA targeted antibody in the Topi ADC is an anti-Trop-2 antibody.
  • the TA targeted antibody in the TropI ADC does not include an anti-Trop-2 antibody.
  • ADCs that can be used in the methods provided herein can comprise antibodies or antigen- binding fragments thereof of any format.
  • the ADC can include, without limitation, a monospecific or multispecific (e.g., bispecific, trispecific) antibody, or an antigenbinding fragment thereof, in any format, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, or Fab derivative.
  • the ADC comprises a non-immunoglobulin antibody mimetic (e.g., including adnectin, affibody, affilin, affimer, affitin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein (DARPin®), fynomer, knottin, Kunitz domain peptide, monobody, and nanoCLAMPs).
  • a non-immunoglobulin antibody mimetic e.g., including adnectin, affibody, affilin, affimer, affitin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein (DARPin®), fynomer, knottin, Kunitz domain peptide, monobody, and nanoCLAMPs).
  • the ADC antibody is a blocking antibody. In some embodiments, the ADC antibody is a neutralizing antibody. In some embodiments, the ADC antibody is an agonistic or activating antibody. Tn some embodiments, the ADC antibody is an antagonistic or inhibitory antibody.
  • the ADC comprises an IgG antibody or antigen-binding fragment thereof.
  • the IgG antibody or antigen-binding fragment thereof can be of various isotypes, such as IgGl, IgG2, IgG3 or IgG4.
  • the ADC antibody comprises human IgGl hinge and constant region sequences.
  • the ADC antibody can be a chimeric human-mouse, a chimeric human-primate, a humanized (human framework and murine hypervariable (CDR) regions), or a fully human antibody, as well as a variation thereof.
  • the ADC antibody is a half-IgG4 antibody (referred to as “unibody”), as described, e.g., by van der Neut Kolfschoten et al. (Science 2007; 317:1554-1557).
  • the ADC antibody or antigen-binding fragment thereof is designed or selected to comprise human constant region sequences that belong to specific allotypes, which may result in reduced immunogenicity when the antibody or ADC is administered to a human subject.
  • the ADC antibody or antigen-binding fragment thereof is of a non-Glml allotype (nGlml), such as Glm3, Glm3,l, Glm3,2 or Glm3,l,2.
  • the allotype is selected from the group consisting of the nGlml, Glm3, nGlml, 2 and Km3 allotypes.
  • the ADCs that can be used in the methods provided herein comprise an anti-Trop-2 antibody, an anti-cancer agent payload, and an optional linker connecting the anti-Trop-2 antibody and payload (Anti-Trop-2 ADC).
  • the pay load is a topoisomerase I inhibitor. In some embodiments, the payload does not include a toposisomerase I inhibitor.
  • anti-Trop-2 antibodies that can be used in anti-Trop-2 ADCs to perform the methods provided herein include, but are not limited to, those described in W02020016662 (Abmart), W02020249063 (Bio-Thera Solutions), US20190048095 (Bio-Thera Solutions), WO2013077458 (LivTech/Chiome), EP20110783675 (Chiome), W02015098099 (Daiichi Sankyo), WG2017002776 (Daiichi Sankyo), W02020130125 (Daiichi Sankyo), W02020240467 (Daiichi Sankyo), US2021093730 (Daiichi Sankyo), US9850312 (Daiichi Sankyo), CN112321715 (Biosion), US2006193865 (Immunomedics/Gilead), WO2011068845 (Immunomedic s/Gilead), US2016296633 (
  • WO2020257648 (Gilead), US2013039861 (Gilead), WO2014163684 (Gilead), US9427464 (LivTech/Chiome), US10501555 (Abruzzo Theranostic/Oncoxx), WO2018036428 (Sichuan Kelun Pharma), WO2013068946 (Pfizer), W02007095749 (Roche), and W02020094670 (SynAffix).
  • the anti-Trop-2 ADC comprises an antibody selected from sacituzumab (hRS7), datopotamab (hTINA HILI), and a Trop-2 binding fragment thereof.
  • the anti-Trop-2 ADC is sacituzumab (hRS7).
  • the anti-Trop-2 antibody is datopotamab (hTINA HILI).
  • the anti-Trop-2 ADC comprises a VH-CDR1, a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2 and a VL-CDR3 selected from one of Tables 1 to 4.
  • the anti-Trop-2 ADC comprises the following VH- CDR1 , a VH-CDR2, a VH-CDR3, a VL-CDR1 , a VL-CDR2 and a VL-CDR3 amino acid sequences (according to Kabat), respectively:
  • the anti-Trop-2 ADC comprise variable domains (VH and VL) selected from Table 5.
  • the anti-Trop-2 ADC comprises the following VH and VL amino acid sequences, respectively:
  • the anti-Trop-2 ADC comprises an anti-Trop-2 antibody, an anti-cancer agent payload, and an optional linker connecting antibody and pay load.
  • the linker is non-cleavable (e.g., a maleimidocaproyl or maleimidomethyl cyclohexane- 1 -carboxylate linker).
  • the linker is cleavable.
  • the linker is acid cleavable (e.g., a hydrazone linker).
  • the cleavable linker is reducible (e.g., a disulphide linker).
  • the linker is protease cleavable (e.g., a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from linkers disclosed in USPN 7,999,083 (e.g., CL2A, CL6, CL7, CLX, or CLY). In some embodiments, the linker is CL2A.
  • Exemplary anti-cancer agent payloads that can be used in anti-Trop-2 ADCs in the methods provided herein include, for example, microtubule inhibitors, DNA cleavage agents, and topoisomerase I inhibitors.
  • the microtubule inhibitor is an auristatin (e.g., monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF), a taxane, a vinca alkaloid, an epothilone) or maytansinoid (e.g., mertansine (DM1) or ravtansine (DM4)).
  • auristatin e.g., monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF)
  • MMAE monomethyl auristatin E
  • MMAF monomethyl auristatin F
  • DM1 mertansine
  • DM4 mertansine
  • the DNA cleavage agent is a calicheamicin (e.g., ozogamicin).
  • the topoisomerase I inhibitor is a camptothecin (e.g., an irinotecan, topotecan, belotecan, or exatecan derivative, such as SN38 or Dxd).
  • the topoisomerase I inhibitor is SN38.
  • the topoisomerase I inhibitor is Dxd.
  • the topoisomerase I inhibitor is not a camptothecin (i.e. non-camptothecin topoisomerase 1 inhibitor).
  • the non-camptothecin topoisomerase 1 inhibitor is selected from an indenosinoquinoline (e.g., indeno[l,2-c]isoquinoline, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)), a phenanthridine (e.g., topovale (ARC-111), and a indolocarbazole (e.g., BE-13793C).
  • indenosinoquinoline e.g., indeno[l,2-c]isoquinoline, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)
  • a phenanthridine e.g., topovale (ARC-111)
  • a indolocarbazole e.g., BE-13793C
  • Additional illustrative anti-cancer agent payloads that can be conjugated to anti-Trop-2 ADCs include without limitation anthracyline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD), or dimer thereof, DNA cross-linking agent SC-DR002 (D6.5), duocarmycin, a duocarmycin (A, B l, B2, Cl, C2, D, SA, CC-1065), tubulysin B and analogs thereof (e.g., Tubl96), and other anti-cancer agents described herein.
  • anthracyline e.g., doxorubicin, daunorubicin, epirubicin, idarubicin
  • PBD pyrrolobenzodiazepine
  • SC-DR002 DNA cross-linking agent SC-DR002 (D6.5)
  • duocarmycin a duocarmycin (A, B
  • Exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), W022010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), W015098099 (Daiichi Sankyo; datopotamab deruxtecan), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Baili Pharmaceutical; BL-M02D1 ).
  • the anti-Trop-2 ADC is selected from sacituzumab govitecan (Immunomedic s/Gilead), datopotamab deruxtecan (DS- 1062, Dato- Dxd; Daiichi Snakyo/AstraZeneca), SKB-264 (KL-A264; Klus Pharma, Sichuan Kelun Pharma), ESG-401 (Shanghai Escugen Bio technology/Le vena Biopharma), JS-108 (DAC-002; Junshi Bio/Hangzhou DAC), FDA018-ADC (Shanghai Fudan Zhangjiang Bio Pharma), STI-3258 (Sorrento), OXG-64 (Oncoxx), BD1-4702 (OBI Pharma), BL-M02D1 (Systimmune), Anti-Trop- 2 Ab (Mediterrania Theranostic/Legochem), KD-065 (Nanjing KAEDI Bio
  • the anti-Trop-2 ADC is sacituzumab govitecan (Immunomedics/Gilead). In some embodiments, the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02 and BAT-8003. In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan. In some embodiments, the anti-Trop-2 ADC is datopotamab deruxtecan (DS-1062, Dato-Dxd; Daiichi Snakyo/AstraZeneca). Further examples of useful anti-Trop-2 therapeutics include, but are not limited to, those described in W02016201300 (Gilead), and CN108440674 (Hangzhou Lonzymc Biological Technology).
  • anti-Trop-2 ADCs that can be used in the methods provided herein are described, for example, in USPN 7,999,083 and USPN 9,028,833, which are hereby incorporated herein by reference in their entireties.
  • the anti-Trop-2 ADC comprises a topoisomerase I inhibitor.
  • the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38.
  • the anti-Trop-2 ADC has a structural formula of mAb-CL2A-SN-38, with a structure represented by:
  • the anti-Trop-2 ADC comprises sacituzumab (hRS7; described, e.g., in W02003074566, Figures 3 and 4).
  • the anti-Trop-2 ADC is sacituzumab govitecan (IMMU-132). Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) composed of the following 3 components:
  • the humanized monoclonal antibody hRS7 IgGlK which binds to trophoblast cellsurface antigen 2 (Trop-2; TACSTD2; EGP-1; NCBI Gene ID: 4070), a transmembrane calcium signal transducer that is overexpressed in many epithelial cancers, including triple-negative breast cancer (TNBC).
  • camptothecin-derived agent SN-38 a topoisomerase I inhibitor.
  • a hydrolyzable linker that links the humanized monoclonal antibody to SN-38.
  • CL2A hydrolyzable linker
  • Additional exemplary anti-Trop-2 ADCs that can be used in the methods provided herein arc described in WO21225892 (Shanghai Escugcn Biotechnology).
  • the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hRS7).
  • the anti-Trop-2 ADC has a DAR of between 1 and 8.
  • the anti-Trop-2 ADC has a DAR of between 7.0 and 8.0.
  • the anti-Trop-2 ADC is ESG-401 (STI-3258).
  • the anti-Trop-2 ADC comprises a linker-payload conjugate (TL035) having a structure represented by:
  • the anti-Trop-2 ADC has a DAR of between 1 and 8. In some embodiments, the anti-Trop-2 ADC has a DAR of between 7.0 and 8.0. In some embodiments, the anti-Trop-2 ADC has a DAR of about 7.0. In some embodiments, the anti-Trop-2 ADC is KL-A264.
  • anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by:
  • the anti-Trop-2 ADC has a DAR of between 1 and 8. In some embodiments, the anti-Trop-2 ADC has a DAR of ⁇ 7.0. In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is datopotamab deruxtecan.
  • the ADCs that can be co-administered in the methods provided herein comprise a tumor antigen (TA) targeted antibody, a topoisomerase I inhibitor payload, and an optional linker connecting the TA targeted antibody and payload (Topi ADC).
  • TA tumor antigen
  • Topici ADC topoisomerase I inhibitor
  • the TA targeted antibody in the Topi ADC is an anti-Trop-2 antibody.
  • the TA targeted antibody in the Topi ADC does not comprise an anti-Trop-2 antibody.
  • the Topi ADCs that can be co-administered in the methods provided herein comprise an antibody that binds a tumor antigen selected from carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2/neu, BrE3, CD1, CDla, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, ED-B fibronectin, EGP-1, EGP
  • the Topi ADCs that can be co-administered in the methods provided herein comprise an antibody that binds a tumor antigen selected from CEACAM5 (NCBI Gene ID: 1048), CEACAM6 (NCBI Gene ID: 4680), CD74 (NCBI Gene ID: 972), CD19 (NCBI Gene ID: 930), CD20 (NCBI Gene ID: 931), CD22 (NCBI Gene ID: 933), CSAp (NCBI Gene ID: 126731), HLA-DR, HLA-G, MUC5ac (NCBI Gene ID: 4586), and AFP (NCBI Gene ID: 174).
  • a tumor antigen selected from CEACAM5 (NCBI Gene ID: 1048), CEACAM6 (NCBI Gene ID: 4680), CD74 (NCBI Gene ID: 972), CD19 (NCBI Gene ID: 930), CD20 (NCBI Gene ID: 931), CD22 (NCBI Gene ID: 933), CSAp (NCBI Gene ID: 126731), HLA-
  • the Topi ADCs that can be used to perform the methods provided herein comprise an antibody selected from gemtuzumab, brentuximab, belantamab, camidanlumab. trastuzumab, inotuzumab, glembatumumab, anetumab, mirvetuximab, depatuxizumab, vadastuximab, labetuzumab, ladiratuzumab, loncastuximab, patritumab, lifastuzumab, indusatumab, polatuzumab, pinatuzumab, coltuximab, upifitamab, indatuximab, milatuzumab, rovalpituzumab, enfortumab, tisotumab, tusamitamab. disitamab, telisotuzumab, and antigen-
  • the Topi ADC that can be used in the methods provided herein comprise an antibody selected from hLLl (anti-CD74; USPN 7,312,318), 11LL2 (anti-CD22; USPN 7,074,403), hRFB4 (anti-CD22), hPAM4 (anti-MUC5ac; USPN 7,282,567), hMN-3 (anti- NOTCH3; USPN 7,541,440), hMN-14 (labetuzumab; anti-CEAC AM5 ; USPN 6,676,924); hMN15 (anti-CEACAM6; USPN 7,541,440); hA19 (anti-CD19; USPN 7,109,304), hA20 (anti- CD22; USPN 7,251,164), hMu-9 (anti-CSAp; USPN 7,387,773), hL243 (anti-HLA-DR; USPN 7,612,180), and hIMMU-31 (anti- AFP; USPN 7,
  • the Topi ADC comprises a linker connecting a topoisomerase I inhibitor payload with a tumor antigen targeted antibody.
  • the linker is non-cleavable (e.g., a maleimidocaproyl or maleimidomethyl cyclohexane- 1 -carboxylate linker).
  • the linker is cleavable.
  • the linker is acid clcav blc (c.g., a hydrazone linker).
  • the cleavable linker is reducible (e.g., a disulphide linker).
  • the linker is protease cleavable (e.g., a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from linkers disclosed in USPN 7,999,083 (e.g., CL2A, CL6, CL7, CLX, or CLY). In some embodiments, the linker is CL2A.
  • the Topi ADC comprises a topoisomerase I inhibitor that is a camptothecin (e.g., an irinotecan, topotecan, belotecan, or exatecan derivative, such as Dxd or SN38).
  • a camptothecin e.g., an irinotecan, topotecan, belotecan, or exatecan derivative, such as Dxd or SN38.
  • the topoisomerase I inhibitor in the Topi ADC is Dxd.
  • the topoisomerase I inhibitor in the Topi ADC is SN38.
  • the topoisomerase I inhibitor in the Topi ADC is not a camptothecin.
  • the non-camptothecin topoisomerase I inhibitor is selected from an indenosinoquinoline (e.g., indeno[l,2-c]isoquinoline, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)), a phenanthridine (e.g., topovale (ARC-111), and a indolocarbazole (e.g., BE-13793C).
  • indenosinoquinoline e.g., indeno[l,2-c]isoquinoline, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)
  • a phenanthridine e.g., topovale (ARC-111)
  • a indolocarbazole e.g., BE-13793C
  • the Topi ADC has a structural formula of mAb-CL2A-SN-38, with a structure represented by:
  • the Topi ADC that can be used in a method provided herein includes an antibody targeting carcinocmbryonic antigen-related cell adhesion molecule 5 (CEACAM5; CD66e; NCBI Gene ID: 1048).
  • CEACAM5 an antibody targeting carcinocmbryonic antigen-related cell adhesion molecule 5
  • the CEACAM5 antibody is hMN-14 (e.g., as described in WO1996011013).
  • the anti-CEACAM5 ADC is as described in W02010093395 (anti-CEACAM5-CL2A-SN38).
  • the Topi ADC is labetuzumab govitecan (IMMU-130).
  • the Topi ADC that can be used in a method provided herein comprises an antibody targeting MHC class II cell surface receptor encoded by the human leukocyte antigen complex (HLA-DR).
  • HLA-DR antibody is hL243 (e.g., as described in W02006094192).
  • the HLA-DR-ADC is as described in W02010093395 (anti-HLA-DR-CL2A-SN38).
  • the antibody and/or fusion protein provided herein is administered with the HLA-DR-ADC IMMU-140.
  • Topi ADCs that can be co-administered in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology).
  • the Topi ADC comprises a linker-payload conjugate having a structure represented by: attached to a tumor antigen targeted antibody.
  • Topi ADCs that can be co-administered in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical).
  • the Topi ADC comprises a linker-payload conjugate (TLO35) having a structure represented by: attached to a tumor antigen targeting antibody.
  • TLO35 linker-payload conjugate
  • Topi ADCs that can be co-administered in the methods provided herein are described in US2016297890 (Daiichi Sankyo).
  • the Topi ADC comprises a linker-payload conjugate having a structure represented by: attached to a tumor antigen targeting antibody (e.g., trastuzumab).
  • a tumor antigen targeting antibody e.g., trastuzumab
  • the Topi ADC has a DAR of about 4.
  • the Topi ADC is trastuzumab-deruxtecan (T- DXd).
  • the adenosine pathway is one of several pathways that can promote tumor immune evasion in the tumor microenvironment. It is believed that the conversion of pro-inflammatory extracellular ATP into immunosuppressive adenosine (eADO) can favor tumor progression and escape from antitumor immunity.
  • eADO immunosuppressive adenosine
  • the role of the adenosine pathway in immuno-oncology is described, for example, in Allard et al., (2020) Nat Rev Clin Oncol 17, 611-629.
  • Adenosine pathway inhibitors that can be co-administered in the methods provided herein can include, for example, inhibitors of CD39 (cctonuclcosidc triphosphate diphospohydrolasc-1; ENTPD1; NCBI Gene ID: 953); inhibitors of CD73 (exto-5’ -nucleotidase; NT5E; NCBI Gene ID: 4907), or antagonists of adenosine receptors, such as adenosine A 2A receptor (AD0RA2A; NCBI Gene ID: 135) or adenosine AIB receptor (AD0RA2B; NCBI Gene ID: 136).
  • the adenosine pathway inhibitors that can be co-administered in the methods provided herein include Inhibitors of CD38 (cyclic ADP ribose hydrolase; NCBI Gene ID: 952).
  • CD39 inhibitors that can be co-administered in the methods provided herein include small molecule inhibitors and large molecule inhibitors (e.g., anti-CD39 antibodies) of CD39.
  • Exemplary CD39 inhibitors are described, for example in WO09095478, WO12085132, WO16073845, WO17157948, WO18049145, WO18065552, WO18065622, WO19027935, WO19178269, W021056610, WG21037037, WO21055329, WO21088838, and WO22111576.
  • the CD39 inhibitor is selected from TTX-030 (AbbVie/Trishula), IPH5201 (AstraZeneca/Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secama Pharmaceuticals), JS-019 (Shanghai Junshi Biosciences); anti-CD39 (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPDl (Biotheus).
  • CD73 inhibitors that can be co-administered in the methods provided herein include small molecule inhibitors and large molecule inhibitors (e.g., anti-CD73 antibodies) of CD73.
  • CD73 inhibitors that can be used in the methods provided herein are described, for example, in US Patent No. 11,001,603, the compounds of which are hereby incorporated by reference herein. Additional illustrative CD73 inhibitors that can be co-administered in the methods provided herein are described, for example in WO15164573, W016055609, W016075099, WO16081746, WO16081748, W017064043, WO17098421, W017100670, WO17118613, WO17153952, WO18013611, WO18067424, WO18065627, WO18094148, WO18110555, WO18119284, WO18137598, WO18183635, W018208980, WO18208727, WO18215535, WO18237173, WO18237157, WO19053617, W019090111, WO19129059, WO19168744, WO
  • the CD73 inhibitor is quemliclustat (AB680, GS-0680), uliledlimab, mupadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV93O, BMS-986179, or oleclumab.
  • the CD73 inhibitor is oleclumab or quemliclustat. In some embodiments, the CD73 inhibitor is quemliclustat.
  • the adenosine receptor antagonists that can be co-administered in the methods provided herein can be selective antagonists of adenosine A2A receptor (A2AR; ADORA2A) or A2B receptor (A2BR; ADORA2B), or dual A2A/2BR antagonists.
  • the adenosine receptor antagonist is a selective A2aR antagonist.
  • the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist selected from imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarns Therapeutics), and TT-228 (Teon Therapeutics).
  • the adenosine receptor antagonist is a selective A2BR antagonist.
  • the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) selective antagonist selected from PBF-1129 (Palobiofarma) and TT-702 (Toon Therapeutics).
  • A2BR adenosine A2B receptor
  • ADORA2B adenosine A2B receptor
  • the adenosine receptor antagonist is a dual A2A/2BR antagonist.
  • the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist selected from etrumadenant (AB928, Arcus Biosciences), INCB 106385 (Incyte), M1069 (Merck KGaA), A2aR/A2bR (Domain/Merck KgaA), HM87277 (Al/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), and TT-53 (Tarns Therapeutics).
  • the adenosine receptor antagonist is etrumadenant.
  • the adenosine receptor antagonists can be small molecule antagonists or large molecule antagonists.
  • adenosine receptor antagonists that can be co-administered in the methods provided herein are described, for example, in WO07103776, WO07134958, W008086201, W009009178, WG09033161, WO09037463, WO09037468, WO09037467, WO09055548, W009055308, W010008775, WO11027805, WO11050160, WO11055391, WO12135084, W014101120, WO14101113, WO14106861, WO15027431, W016081290, WO16126570, W016200717, WO16209787, W017008205, WO18013951, W019086074, WO2019118313, WO20053263, W020106558, W020103930, W020103939, W020106560, W020112706, W020112700, WO20216152
  • adenosine receptor antagonists that can be used in the methods provided herein are described, for example, in US Patent No. 10,399,962, the compounds of which are hereby incorporated by reference.
  • the adenosine pathway inhibitor is a dual antagonist of adenosine A2A receptor (A2AR; ADORA2A) and A2B receptor (A2BR; ADORA2B).
  • the adenosine pathway inhibitor is etrumadenant (AB928; GS-0928), taminadenant, TT-10, TT-4, or M 1069.
  • the adenosine pathway inhibitor is etrumadenant.
  • Etrumadenant is a small molecule dual antagonist of both A2AR and A2BR that can inhibit the adcnosinc-drivcn impairment of tumor-infiltrating lymphocytes (mainly through A2AR on CD8+ T cells and NK cells) and myeloid cells (through A2BR on dendritic cells and macrophages) in the absence of any agonist activity.
  • Etrumadenant can achieve high penetration of tumor tissue, robust potency in the presence of high adenosine concentrations, and shows low nonspecific protein binding.
  • the combination treatment methods provided herein comprise coadministering a PD(L)1 inhibitor.
  • PD(L)1 inhibitors that can be co-administered can include small molecule PD(L)1 inhibitors and large molecule PD(L)1 inhibitors (e.g., anti-PD(L)-l antibodies).
  • Exemplary small molecule PD(L)1 inhibitors that can be co-administered in the methods provided herein include, for example, CA-170, GS-4224, GS-4416 and lazertinib (GNS-1480; PD- Ll/EGFR). Additional illustrative small molecule PD(L)1 inhibitors are described, for example, in Guzik et al. (2019) Molecules 24(11), 2071.
  • anti-PD-(L)l antibodies that can be co-administered in the method provided herein include, for example, pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the anti-PD-(L)! antibody is zimberelimab.
  • Additional illustrative anti-PD-(L)l antibodies that can be co-administered in the methods provided herein include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP- 224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP- 3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, retifanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-637232
  • anti-TIGIT antibodies that can be co-administered in the methods provided herein include, for example, tiragolumab, vibostolimab, domvanalimab, AB3O8, AK127, BMS- 986207, ralzapastotug, and etigilimab.
  • the anti-TIGIT antibody is domvanalimab.
  • the anti-TIGIT antibody is AB308.
  • the anti-TIGIT antibody is ralzapastotug.
  • the anti-TIGIT antibody is an Fc-silent antibody. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent, or eliminate binding to an Fc receptor. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyRIV.
  • the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent, or eliminate ADCC, ADCP, and/or CDC. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region to reduce, prevent, or eliminate binding to Fc receptors, wherein the one or more substitutions occur at EU index positions 228, 233, 234, 235, 235, 235, 236, 237, 265, 297, 322, 327, 328, 330, 331, and any combination thereof.
  • the anti-TIGIT antibody comprises one or more substitutions in the Fc region to reduce, prevent, or eliminate binding to Fc receptors, wherein the one or more substitutions comprise S228P, E233P, E234A, L235A, E235E, E235F, G236R, G237A, D265A, N297A, K322A, A327G, E328R, A330S, P331S, and any combination thereof. Additional mutations in the Fc region that reduce, prevent, or eliminate binding to Fc receptors and alternative strategies for reducing, preventing, or eliminating binding to Fc receptors are described in, e.g., Saunders, Front Immunol.
  • the anti-TIGIT antibody is an Fc-enabled antibody. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable or enhance binding to an Fc receptor. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable or enhance binding to FcyR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enable or enhance binding to FcyRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enable or enhance binding to FcyRIV.
  • the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable or enhance ADCC, ADCP, and/or CDC.
  • the anti-PD- (E)l antibody comprises one or more substitutions in Fc region to enhance or enable binding to Fc receptors, wherein the one or more substitutions occur at EU index positions 234, 235, 236, 239, 243, 247, 267, 268, 292, 298, 300, 305, 324, 326, 330, 332, 333, 334, 339, 345, 396, 430, and any combination thereof.
  • the anti-TIGIT antibody comprises one or more substitutions in the Fc region to enhance or enable binding to Fc receptors, wherein the one or more substitutions comprise F234L, L235V, G236A, S239D, F243L, P247I, S267E, H268E, R292P, S298A, Y300L, V305I, S324T, K326W, A33OE, I332E, E333A, E333S, K334A, A339Q, E345G, P396L, E430G, and any combination thereof.
  • substitutions comprise F234L, L235V, G236A, S239D, F243L, P247I, S267E, H268E, R292P, S298A, Y300L, V305I, S324T, K326W, A33OE, I332E, E333A, E333S, K334A, A339Q, E345G
  • the Fc-enabled antibody comprises a modified IgGl domain characterized by substitutions at S239D, A33OL, and I332E (Eu numbering).
  • the anti-TIGIT antibody contains or has a glycoform perturbation.
  • the anti-TIGIT antibody contains or has an N-linked Fc glycosylation.
  • the anti-TTGTT antibody contains or has sialylation, galactosylation, bisecting sugars, fucosylation, or any combination thereof. Additional mutations in the Fc region that enhance or enable binding to Fc receptors and alternative strategies for enhancing or enabling binding to Fc receptors are described in Saunders, 2019.
  • adenosine pathway inhibitor e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor
  • the methods provided herein include treating a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
  • the methods provided herein include treating the recurrence or metastasis of a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
  • the methods provided herein include preventing or delaying the recurrence or metastasis of a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
  • ADC anti-Trop-2 antibody-drug conjugate
  • the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors.
  • the plurality of adenosine pathway inhibitors comprises a CD73 inhibitor and an adenosine receptor antagonist.
  • the CD73 inhibitor is quemliclustat and the adenosine receptor antagonist is etrumadenant.
  • the methods provided herein are for treating a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
  • ADC anti-Trop-2 antibody-drug conjugate
  • adenosine pathway inhibitor e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor
  • TA + tumor antigen positive
  • methods of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of a tumor antigen positive (TA + ) cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen (TA) targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (Topi ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
  • TA tumor antigen
  • ADC targeted antibody-drug conjugate
  • Topici ADC topoisomerase I inhibitor
  • an adenosine pathway inhibitor e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor
  • the methods provided herein include treating a tumor antigen positive (TA+) cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
  • ADC tumor antigen targeted antibody-drug conjugate
  • adenosine pathway inhibitor e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor
  • the methods provided herein include treating the recurrence or metastasis of a tumor antigen positive cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
  • ADC tumor antigen targeted antibody-drug conjugate
  • an adenosine pathway inhibitor e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor.
  • the methods provided herein include preventing or delaying the recurrence or metastasis of a tumor antigen positive cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
  • ADC tumor antigen targeted antibody-drug conjugate
  • an adenosine pathway inhibitor e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor.
  • the methods provided herein are for treating a tumor antigen positive cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
  • ADC tumor antigen targeted antibody-drug conjugate
  • adenosine pathway inhibitor e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor
  • provided herein are methods of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of a tumor antigen (e.g., Trop-2) positive cancer comprising co-administering to a subject the combinations provided herein.
  • the treatment methods provided herein mitigate the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering the combinations provided herein.
  • the treatment methods provided herein reduce the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering the combinations provided herein.
  • the treatment methods provided herein prevent the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering the combinations provided herein. In some embodiments, the treatment methods provided herein delay the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering the combinations provided herein.
  • a tumor antigen e.g., Trop-2
  • the treatment methods provided herein delay the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering the combinations provided herein.
  • the methods provided herein further comprise co-administering an additional therapeutic agent or therapeutic modality, or a combination thereof.
  • the methods provided herein comprise co-administering one, two, or three additional therapeutic agents or therapeutic modalities, or combinations thereof.
  • the additional therapeutic agent comprises chemotherapy (e.g., a chemotherapy treatment of physician’s choice, or an indicated standard of care for a specific therapeutic setting).
  • the additional therapeutic agent comprises an immune checkpoint inhibitor (CPI; e.g., anti-CTLA4 antibody, anti-PD(L)! antibody, anti-TTGTT antibody).
  • CPI immune checkpoint inhibitor
  • the additional therapeutic agent comprises an anti-PD(L)l antibody (e.g., an anti- PD-1 antibody or an anti-PD-Ll antibody), and optionally an anti-TIGIT antibody.
  • the additional therapeutic agent comprises an anti-PD-(L)l antibody.
  • the additional therapeutic agent comprises an anti-TIGIT antibody.
  • the additional therapeutic agent comprises an anti-PD-(Ll) antibody and an anti- TIGIT antibody.
  • the additional therapeutic agent comprises a) zimberelimab and domvanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vibostolimab, e) pembrolizumab and domvanalimab, f) pembrolizumab and AB3O8, g) MK-7684A (pembrolizumab/vibostolimab coformulation), h) durvalumab and domvanalimab, i) zimberelimab and ralzapastotug, or j) pembrolizumab and ralzapastotug.
  • the additional therapeutic agent comprises zimberelimab and domvanalimab. In some embodiments, the additional therapeutic agent comprises zimberelimab and ralzapastotug. In some embodiments, the additional therapeutic modality comprises surgery or radiation therapy.
  • the subject is a cancer patient.
  • the subject is a human cancer patient.
  • the subject is treatment naive.
  • the subject e.g., human cancer patient
  • has not received a taxane e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel
  • a checkpoint inhibitor therapy e.g., anti-CTLA4 antibody, anti-PD(L)l antibody
  • the subject e.g. human cancer patient
  • a topoisomerase I inhibitor therapy e.g., irinotecan
  • the subject has received one or more lines of previous anti-cancer therapy before administration of a combination provided herein.
  • the subject e.g., human (m)CRPC patient
  • a new hormonal agent NHA; first- or second-generation nonsteroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof
  • NHA new hormonal agent
  • first- or second-generation nonsteroidal antiandrogens e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof
  • the subject e.g., human (m)CRPC patient
  • has shown disease progression after prior NHA treatment first- or second-generation non-steroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof
  • first- or second-generation non-steroidal antiandrogens e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof
  • the subject has received a prior anticancer therapy selected from surgery, radiation therapy, chemotherapy (including NHA therapy), checkpoint inhibitor therapy (e.g. anti-PD(L)l antibody).
  • the subject has a cancer that is resistant or refractory to one or more anti-cancer therapies.
  • the cancer is resistant or refractory to one or more anti-cancer therapies selected from radiation therapy, chemotherapy (including NHA therapy), and checkpoint inhibitor therapy (e.g., anti- PD(L)1 antibody).
  • the subject e.g., human (m)CRPC patient
  • first- or second-generation non-steroidal antiandrogens e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof
  • a taxane e.g., docetaxel, cabazitaxel
  • checkpoint inhibitor e.g., anti-CTLA-4 antibody; anti-PD(L)l antibody
  • a topoisomerase I inhibitor e.g., irinotecan
  • the subject e.g., human (m)NSCLC patient
  • the subject e.g., human (m)NSCLC patient
  • has shown disease progression after checkpoint inhibitor therapy e.g., anti-PD-(L)l antibody or anti-CTLA4 antibody therapy.
  • the subject has progressed after platinum-based chemotherapy and checkpoint inhibitor therapy (e.g., anti-PD-(L)l antibody or anti-CTLA4 antibody therapy), received either in combination or sequentially in any order.
  • the subject e.g., human (m)NSCLC patient
  • a tyrosine kinase inhibitor therapy targeting specific genomic alterations in a cancer.
  • Exemplary tyrosine kinase inhibitors that are useful to address specific genomic alterations in lung cancer include gefitinib, erlotinib, afatinib, dacomitinib, neratinib, osimertinib, rociletinib, olmutinib, ASP8273 (Astellas), moninib, PF-06747775 (Pfizer), avitinib, and HS- 10296 (Jiangsu Hansoh).
  • the subject e.g., human (m)CRPC or (m)NSCLC patient
  • tumor antigen e.g., Trop-2
  • tumor antigen expression levels e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing.
  • the subject is a human prostate cancer patient.
  • the human patient has castrate resistant prostate cancer (CRPC).
  • the human patient has metastatic CRPC (mCRPC).
  • the human patient with CRPC or mCRPC ((m)CRPC) is treatment naive.
  • the human patient with (m)CRPC has not received a taxane (e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel) therapy before administration of a combination therapy provided herein.
  • a taxane e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel
  • the human patient with (m)CRPC has not received a checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)l antibody) before administration of a combination therapy provided herein.
  • a checkpoint inhibitor therapy e.g., anti-CTLA4 antibody, anti-PD(L)l antibody
  • the human patient with (m)CRPC has not received a topoisomerase I inhibitor therapy (e.g., irinotecan) before administration of a combination therapy provided herein.
  • the human patient with (m)CRPC has received one or more lines of anti-cancer therapy before administration of a combination provided herein.
  • the human patient with (m)CRPC has shown disease progression on one or more lines of anti-cancer therapy before administration of a combination provided herein.
  • the human patient with (m)CRPC has received a new hormonal agent (NHA; first- or second-generation non-steroidal antiandrogens, abiraterone) (NHA experienced) prior to administration of a combination therapy provided herein.
  • NHA new hormonal agent
  • the human patient with (m)CRPC has shown disease progression after prior NHA treatment (first- or second-generation non-steroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) before administration of a combination therapy provided herein
  • the human patient with (m)CRPC has received a prior anti-cancer therapy selected from surgery, radiation therapy, chemotherapy (including NHA therapy), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)l antibody).
  • the human patient with (m)CRPC has a cancer that is resistant or refractory to one or more anti-cancer therapies.
  • the cancer is resistant or refractory to one or more anti-cancer therapies selected from radiation therapy, chemotherapy (including NHA therapy), and checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti- PD(L)1 antibody).
  • the human patient with (m)CRPC has received a prior NHA treatment (first- or second-generation non-steroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) (NHA experienced) and has not received a taxane (e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel) or checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)l antibody) (taxane and CPI naive) before administration of a combination therapy provided herein.
  • first- or second-generation non-steroidal antiandrogens e.
  • the human patient with (m)CRPC has received a prior NHA treatment (first- or second-generation nonsteroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) (NHA experienced) and has not received a taxane (e.g., paclitaxel, nab- paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)l antibody), or topoisomerase I inhibitor (e.g., irinotecan) before administration of a combination therapy provided herein.
  • first- or second-generation nonsteroidal antiandrogens e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof
  • NHA experienced and has not received a taxane (e.g., pac
  • the human patient with (m)CRPC has shown disease progression after prior NHA treatment (first- or second- generation non-steroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) and has not received a taxane (e.g., paclitaxel, nab- paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)l antibody), or a topoisomerase I inhibitor (e.g., irinotecan) before administration of a combination therapy provided herein.
  • first- or second- generation non-steroidal antiandrogens e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof
  • a taxane e.g., paclitaxel, na
  • the human patient with (m)CRPC has histologically confirmed adenocarcinoma of the prostate and metastatic castrate resistant with tumor progression while on androgen deprivation therapy (ADT; including orchiectomy) with castrate levels of serum (total) testosterone ( ⁇ 1.7 nmol/L or 50 ng/dL) defined by PSA and/or radiographic criteria according to PCWG3.
  • ADT on androgen deprivation therapy
  • the human patient (m)CRPC has metastatic castrate resistant adenocarcinoma of the prostate with tumor progression while on androgen deprivation therapy (e.g., including orchiectomy) with castrate levels of serum (total) testosterone ( ⁇ 1.7 nmol/L or 50 ng/dL) defined by prostate specific antigen (PSA) and/or radiographic criteria according to The Prostate Cancer Working Group 3 (PCWG3) and measurable or non-measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1.
  • the human patient with (m)CRPC has Eastern Cooperative Oncology Group performance status 0 or 1 with a life expectancy >3 months.
  • the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing).
  • tumor antigen e.g., Trop-2
  • expression levels e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing.
  • the subject is a human lung cancer patient.
  • the human patient has non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the NSCLC is squamous.
  • the NSCLC is non-squamous.
  • the lung cancer does not have an actionable genomic alteration (e.g., an EGFR or ALK mutation, insertion, deletion, or the like) for which treatment with a targeted therapy (e.g., a targeted tyrosine kinase inhibitor therapy) is indicated (actionable genomic alteration).
  • a targeted therapy e.g., a targeted tyrosine kinase inhibitor therapy
  • Exemplary actionable genomic alterations and targeted tyrosine kinase inhibitor therapies are described, e.g., in Sullivan and Planchard Front.
  • the human NSCLC patient has shown disease progression after platinum-based chemotherapy. In some embodiments, the human NSCLC patient has shown disease progression after checkpoint inhibitor therapy (e.g., anti-PD- (L)l antibody or anti-CTLA4 antibody therapy). In some embodiments, the human NSCLC patient has progressed after platinum-based chemotherapy and checkpoint inhibitor therapy (e.g., anti-PD-(L)! antibody or anti-CTLA4 antibody therapy), received either in combination or sequentially in any order. In some embodiments, the human NSCLC patient has progressed after a tyrosine kinase inhibitor therapy targeting specific genomic alterations in a cancer.
  • checkpoint inhibitor therapy e.g., anti-PD- (L)l antibody or anti-CTLA4 antibody therapy
  • checkpoint inhibitor therapy e.g., anti-PD-(L)! antibody or anti-CTLA4 antibody therapy
  • Exemplary tyrosine kinase inhibitors that are useful to address specific genomic alterations in lung cancer (e.g., EGFR mutations or deletions) include gefitinib, erlotinib, afatinib, dacomitinib, neratinib, osimertinib, rociletinib, olmutinib, ASP8273 (Astellas), Feliartinib, PF-06747775 (Pfizer), avitinib, and HS- 10296 (Jiangsu Hansoh).
  • the combinations provided herein are administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy).
  • the combinations provided herein are administered in an adjuvant setting (e.g., following a primary treatment such as surgery or radiation therapy).
  • the combinations provided herein are administered in a therapeutic setting (e.g., as the primary therapy).
  • the combinations provided herein are administered in a maintenance setting.
  • the cancer is a hematological cancer.
  • the cancer includes a solid tumor.
  • the cancer includes a malignant tumor.
  • the cancer includes a metastatic cancer.
  • the cancer is resistant or refractory to one or more anticanccr therapies.
  • greater than about 50% of the cancer cells delectably express one or more cell surface immune checkpoint receptors (e.g., so-called “hot” cancer or tumor).
  • greater than about 1% and less than about 50% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so called “warm” cancer or tumor).
  • less than about 1% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so called “cold” cancer or tumor).
  • the cancer is a hematological cancer, e.g., a leukemia (e.g., Acute Myelogenous Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), B-cell ALL, Myelodysplastic Syndrome (MDS), myeloproliferative disease (MPD), Chronic Myelogenous Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), undifferentiated leukemia), a lymphoma (e.g., small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), Waldestrom’s macroglobulinemia (WM)) and/or a myeloma (e.g., multiple myeloma (e.g., multiple mye
  • the cancer is an epithelial tumor (e.g., a carcinoma, a squamous cell carcinoma, a basal cell carcinoma, a squamous intraepithelial neoplasia), a glandular tumor (e.g., an adenocarcinoma, an adenoma, an adenomyoma), a mesenchymal or soft tissue tumor (e.g., a sarcoma, a rhabdomyosarcoma, a leiomyosarcoma, a liposarcoma, a fibrosarcoma, a dermatofibrosarcoma, a neurofibrosarcoma, a fibrous histiocytoma, an angiosarcoma, an angiomyxoma, a leiomyoma, a chondroma, a chondrosarcoma, an alve
  • a glandular tumor e.g., an
  • the cancer includes a solid tumor in or arising from a tissue or organ, such as:
  • bone e.g., adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of the bone, giant cell tumour of bone, haemangiomas and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, Desmoid tumor, Ewing sarcoma);
  • bone e.g., adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chord
  • lips and oral cavity e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma
  • salivary glands e.g., pleomorphic salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumors
  • esophagus e.g., Barrett's esophagus, dysplasia and adenocarcinoma
  • stomach e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumors (GISTs), metastatic deposits, gastric carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, anus;
  • stomach e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumors (GISTs), metastatic deposits, gastric carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g
  • pancreas e.g., serous neoplasms, including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)-associated serous cystic neoplasm, serous cystadenocarcinoma; mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), intraductal oncocytic papillary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, including acinar cell cystadenoma, acinar cell cystadcnocarcinoma, pancreatic adenocarcinoma, invasive pancreatic ductal adenocarcinomas, including tubular adenocarcinoma, adenosquamous carcinoma, colloid carcinoma, medullary carcinoma, he
  • neuro-endocrine e.g., adrenal cortical carcinoma, carcinoid tumors, phaeochromocytoma, pituitary adenomas
  • thyroid e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumors, papillary carcinoma, adenocarcinoma);
  • liver e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, York sac tumor, carcinosarcoma, rhabdoid tumor);
  • kidney e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wilms tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma);
  • ALK-rearranged renal cell carcinoma e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wil
  • breast e.g. , invasive ductal carcinoma, including without limitation, acinic cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich/clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including without limitation, pleomorphic carcinoma, signet ring cell carcinoma);
  • peritoneum e.g., mesothelioma; primary peritoneal cancer
  • female sex organ tissues including ovary (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Mullerian tumors, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., carcinoma of the cervix, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial carcinoma (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma
  • male sex organ tissues including prostate, testis (e.g., germ cell tumors, spermatocytic seminoma), penis;
  • bladder e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma
  • brain e.g., gliomas (e.g., astrocytomas, including non-infiltrating, low-grade, anaplastic, glioblastomas; oligodendrogliomas, ependymomas)), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, Non-Hodgkin lymphomas (NHLs), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, pituitary tumors;
  • gliomas e.g., astrocytomas, including non-infiltrating, low-grade, anaplastic, glioblastomas; oligodendrogliomas, ependymomas
  • Meningiomas e.g., astrocytomas, including non-infiltrating, low-grade, anaplastic, glioblastomas;
  • eye e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris hamartoma
  • eye e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris hamartoma
  • head and neck e.g., nasopharyngeal carcinoma, Endolymphatic Sac Tumor (ELST), epidermoid carcinoma, laryngeal cancers including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, transglottic carcinoma), carcinoma in situ, verrucous, spindle cell and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinomas, laryngeal sarcoma), head and neck paragangliomas (e.g., carotid body, jugulotympanic, vagal); thymus (e.g., thymoma);
  • heart e.g., cardiac myxoma
  • lung e.g., small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant cell carcinomas, spindle cell carcinomas, pleuropulmonary blastoma);
  • SCLC small cell carcinoma
  • NSCLC non-small cell lung carcinoma
  • SCC squamous cell carcinoma
  • carcinoids typically or atypical
  • carcinosarcomas pulmonary blastomas
  • giant cell carcinomas e.g., giant cell carcinomas, spindle cell carcinomas, pleuropulmonary blastoma
  • pleuropulmonary blastoma e.g., small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoids (typical or atypical), carcino
  • lymphomas including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (NHL), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, Epstein-Barr virus (EBV)-associatcd lymphoproliferative diseases, including B cell lymphomas and T cell lymphomas e.g., Burkitt lymphoma; large B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low grade B cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK/T cell lymphoma, nasal type; peripheral T cell lymphoma, cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma; follicular
  • central nervous system e.g., gliomas including astrocytic tumors (e.g., pilocytic astrocytoma, pilomyxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme) and gliomatosis cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, an astrocy
  • skin e.g., clear cell hidradenoma, cutaneous benign fibrous histiocytomas, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumors); and
  • soft tissues e.g. , aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid-type fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, Ewing's tumors/primitive neurectodermal tumors (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastoma, lipoma, chondroid lipoma, liposarcoma I malignant lipomatous tumors, lipo
  • the cancer is positive for a tumor antigen selected from carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2/neu, BrE3, CD1, CDla, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20 (e.g., C2B8, hA20, 1F5 MAbs), CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, fibronectin splice variant, ED-B fibronectin
  • a tumor antigen selected
  • the cancer is positive for a tumor antigen selected from CD74, CD22, Trop-2, CEA, CSAp Mu-9, AFP, CC49, and PSMA.
  • the cancer is Trop-2 positive.
  • the Trop-2 positive cancer is a solid epithelial cancer.
  • the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC); HR positive/Her-2 negative (HR + /Her-2 ) breast cancer; HR positive/Her-2 low breast cancer), colorectal cancer, lung cancer, stomach cancer, urinary tract cancer, urothelial cancer, bladder cancer, renal cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer, and prostatic cancer.
  • the prostatic cancer is castrate-resistant prostate cancer (CRPC).
  • the lung cancer is non-small lung cancer (NSCLC).
  • the Trop- 2 positive cancer is (i) unresectable, locally advanced or (ii) metastatic cancer (e.g., mCRPC or mNSCLC). In some embodiments, the Trop-2 positive cancer is resistant or refractive to one or more anti-cancer therapy.
  • the Trop-2 positive cancer is prostate cancer. In some embodiments, the Trop-2 positive cancer is metatstatic prostate cancer. In some embodiments, the Trop-2 positive cancer is castrate resistant prostate cancer (CRPC). In some embodiments, the Trop-2 positive cancer is metatstatic castrate resistant prostate cancer (mCRPC).
  • the Trop-2 positive cancer is metastatic castrate resistant adenocarcinoma of the prostate showing tumor progression on androgen deprivation therapy (e.g., including orchiectomy) with castrate levels of serum (total) testosterone ( ⁇ 1.7 nmol/L or 50 ng/dL) defined by prostate specific antigen (PSA) and/or radiographic criteria according to The Prostate Cancer Working Group 3 (PCWG3); measurable or non-measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l.
  • tumor progression on androgen deprivation therapy e.g., including orchiectomy
  • PSA prostate specific antigen
  • PCWG3 Prostate Cancer Working Group 3
  • RECIST Solid Tumors
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop2 antibody drug conjugate; and b) an adenosine pathway inhibitor.
  • the anti-Trop-2 ADC comprises a topoisomerase I inhibitor.
  • the topoisomerase inhibitor is a camptothecin analog.
  • the camptothecin analog is an irinotecan derivative, a topotecan derivative, or an exatecan derivative.
  • the camptothecin analog is SN38 or Dxd.
  • the camptothecin analog is SN38. In some embodiments, the camptothecin analog is connected to an anti-Trop-2 antibody via a hydrolyzable linker. In some embodiments, the hydrolyzable linker is CL2A (e.g., as described in US 7,999,083). In some embodiments, the camptothecin analog is connected to an anti-Trop-2 antibody via a protease cleavable linker. In some embodiments, the anti-Trop-2 ADC has a structure mAb-CL2A-SN-38, represented by:
  • the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0. In some embodiments, the DAR of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop-2 ADC is about 7.6. In some embodiments, the anti-Trop-2 ADC comprises the anti-Trop-2 antibody sacituzumab (hRS7, described, e.g., in W02003074566, Figures 3 and 4).
  • the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS- 1062), ESG-401, SKB-264, DAC-02 and BAT-8003. In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan. In some embodiments, the anti-Trop-2 ADC is datopotamab deruxtecan (DS- 1062). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist.
  • the CD39 inhibitor is selected from TTX-030 (AbbVie/Trishula), IPH5201 (AstraZeneca/Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secarna Pharmaceuticals), JS-019 (Shanghai Junshi Biosciences); AB598 (anti-CD39) (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPDl (Biotheus).
  • the CD73 inhibitor is selected from oleclumab (AstraZeneca), BMS-986179 (BMS), uliledlimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB680, Arcus Biosciences), mupadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Hcnlius Biotech), INCA00186 (Incytc), IBI325 (Innovcnt Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPD
  • the CD73 inhibitor is oleclumab or quemliclustat. In some embodiments, the CD73 inhibitor is quemliclustat.
  • the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), or TT- 228 (Teon Therapeutics).
  • A2AR adenosine A2A receptor
  • ADORA2A adenosine A2A receptor selective antagonist
  • the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics).
  • A2BR adenosine A2B receptor
  • ADORA2B adenosine A2B receptor
  • PBF-1129 Palobiofarma
  • TT-702 Teon Therapeutics
  • the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenant (AB928, Arcus Biosciences), INCB 106385 (Incyte), M1069 (Merck KgaA), A2aR/A2bR (Domain/Merck KgaA), HM87277 (Al/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), TT-53 (Tarus Therapeutics).
  • the adenosine receptor antagonist is etrumadenant.
  • the adenosine pathway inhibitor is quemliclustat or etrumadenant.
  • the adenosine pathway inhibitor is etrumadenant.
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from a CD39 inhibitor, a CD73 inhibitor, and an adenosine receptor antagonist.
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from a CD73 inhibitor and an adenosine receptor antagonist.
  • a subject e.g., a human cancer patient
  • an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd)
  • an adenosine pathway inhibitor selected from a CD73 inhibitor and an adenosine receptor antagonist.
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, ulilcdlimab, imaradenant, NIR178, and ctrumadcnant.
  • a subject e.g., a human cancer patient
  • an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd)
  • an adenosine pathway inhibitor selected from oleclumab, BMS-986179, ulilcdlimab, imaradenant, NIR178, and ctrumadcnant.
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC having a structure mAb-CL2A-SN-38, represented by: and b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uliledlimab, imaradenant, NIR178, and etrumadenant.
  • a subject e.g., a human cancer patient
  • an anti-Trop-2 ADC having a structure mAb-CL2A-SN-38, represented by: and b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uliledlimab, imaradenant, NIR178, and etrumadenant.
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan or datopotamab deruxtecan (DS-1062); and b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uliledlimab, imaradenant, NIR178, and etrumadenant.
  • a subject e.g., a human cancer patient
  • a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan or datopotamab deruxtecan (DS-1062); and b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uliledlimab, imaradenant, NIR178, and etrumadenant.
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan; and b) etrumadenant.
  • the methods provided herein further comprise co-administering an additional therapeutic agent or therapeutic modality, or a combination thereof.
  • the additional therapeutic agent comprises an immune checkpoint inhibitor (CPI).
  • the CPI comprises an anti-PD(L)l antibody (e.g., an anti-PD-1 antibody or an anti- PD-L1 antibody), and optionally an anti-TIGIT antibody.
  • the anti-PD(L)l antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the anti-PD(L)l antibody is zimberelimab.
  • the anti-TIGIT antibody is selected from tiragolumab, vibostolimab, domvanalimab, AB308, AK127, BMS- 986207, ralzapastotug, and etigilimab.
  • the anti-TIGIT antibody is domvanalimab.
  • the additional therapeutic agent comprises an anti-PD(L)! antibody and an anti-TIGIT antibody.
  • the additional therapeutic agent comprises a) zimberelimab and domvanalimab, b) zimberelimab and AB3O8, c) atezolizumab and tiragolumab, d) pembrolizumab and vibostolimab, e) MK-7684A (pembrolizumab/vibostolimab coformulation), f) durvalumab and domvanalimab, g) zimberelimab and ralzapastotug, or h) pembrolizumab and ralzapastotug.
  • the anti-PD(L)l antibody is zimberelimab and the anti-TIGIT antibody is domvanalimab.
  • the additional therapeutic modality comprises surgery or radiation therapy.
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); b) an adenosine pathway inhibitor selected from oleclumab, BMS- 986179, uliledlimab, imaradenant, NIR178, and etrumadenant, and c) an anti-PD(L)l antibody.
  • a subject e.g., a human cancer patient
  • a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dx
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC having a structure mAb-CL2A-SN-38, represented by: b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uliledlimab, imaradenant, NIR178, and etrumadenant, and c) an anti-PD(L)l antibody.
  • the methods provided herein comprise co-administering to a subject (e.g.
  • a human cancer patient having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan or datopotamab deruxtecan (DS- 1062); b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uliledlimab, imaradenant, NIR178, and etrumadenant; and c) and anti-PD(L)l antibody.
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan; b) etrumadenant; and c) an anti-PD(L)l antibody.
  • a subject e.g., a human cancer patient
  • a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan; b) etrumadenant; and c) an anti-PD(L)l antibody.
  • the anti-PD(L)l antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cctrclimab, gcnolimzumab, prolgolimab, lodapolimab, camrclizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the anti-PD(L)l antibody is zimberelimab.
  • the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan; b) etrumadenant; and c) zimberelimab.
  • the Trop-2 positive cancer is castrate resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).
  • the Trop-2 positive cancer is CRPC.
  • the Trop-2 positive cancer is metastatic (e.g., mCRPC, mNSCLC).
  • the Trop-2 positive cancer is resistant or refractive of one or more anti-cancer therapy (e.g., NHA resistant or refractive mCRPC).
  • the methods provided herein comprise co-administering to a subject e.g., a human cancer patient) having a tumor antigen positive (TA + ) cancer an effective amount of a) a Topi ADC; and b) an adenosine pathway inhibitor.
  • the Topi ADC comprises a camptothecin analog.
  • the camptothecin analog is an irinotecan derivative, a topotecan derivative, or an exatecan derivative.
  • the camptothecin analog is SN38 or Dxd.
  • the camptothecin analog is SN38.
  • the camptothecin analog is connected to a tumor antigen targeted antibody via a hydrolyzable linker.
  • the hydrolyzable linker is CL2A (e.g., as described in US 7,999,083).
  • the camptothecin analog is connected to a tumor antigen targeted antibody via a protease cleavable linker.
  • the Topi ADC has a structure mAb-CL2A-SN-38, represented by:
  • the tumor antigen targeted antibody in the Topi ADC is selected from gemtuzumab, brentuximab, belantamab, camidanlumah, trastuzumab, inotuzumab, glembatumumab, anetumab, mirvetuximab, dcpatuxizumab, vadastuximab, labctuzumab, ladiratuzumab, loncastuximab, patritumab, lifastuzumab, indusatumab, polatuzumab, pinatuzumab, coltuximab, upifitamab, indatuximab, milatuzumab, rovalpituzumab, enfortumab, tisotumab, tusamitamab, disitamab
  • the tumor antigen targeted antibody in the Topi ADC is selected from hLLl, hLL2, RFB4, hA19, hA20, hRS7, hPAM4, hMN-3, hMN-14, hMu-9, hRl, CC49, hL243, D2/B, hlmmu-31, and antigen binding fragments thereof.
  • the anti-Trop-2 ADC comprises the anti-Trop-2 antibody sacituzumab (hRS7, described, e.g., in W02003074566, Figures 3 and 4).
  • the Topi ADC is trastuzumab deruxtecan.
  • the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist.
  • the CD39 inhibitor is selected from TTX-030 (AbbVie/Trishula), IPH5201 (AstraZeneca/Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secama Pharmaceuticals), JS-O19 (Shanghai Junshi Biosciences); anti-CD39 (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPDl (Biotheus).
  • the CD73 inhibitor is selected from oleclumab (AstraZeneca), BMS-986179 (BMS), uliledlimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB68O, Arcus Biosciences), mupadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), TNCAOO186 (Tncyte), IBT325 (Tnnovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB- BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPDl
  • the CD73 inhibitor is oleclumab or quemliclustat. In some embodiments, the CD73 inhibitor is quemliclustat.
  • the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; AD0RA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarns Therapeutics), or TT-228 (Teon Therapeutics).
  • A2AR adenosine A2A receptor
  • AD0RA2A adenosine A2A receptor selective antagonist
  • the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; AD0RA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics).
  • A2BR adenosine A2B receptor
  • AD0RA2B adenosine A2B receptor
  • PBF-1129 Palobiofarma
  • TT-702 Teon Therapeutics
  • the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenant (AB928, Arcus Biosciences), INCB 106385 (Incyte), M1069 (Merck KGaA), A2aR/A2bR (Domain/Merck KGaA), HM87277 (Al/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), TT-53 (Tarns Therapeutics).
  • the methods provided herein further comprise co-administering an additional therapeutic agent or therapeutic modality, or a combination thereof.
  • the additional therapeutic agent comprises an immune checkpoint inhibitor.
  • the CPI comprises an anti-PD(L)l antibody (e.g., an anti-PD-1 antibody or an anti-PD-Ll antibody), and optionally an anti-TIGIT antibody.
  • the anti-PD(L)l antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the anti-PD(L)l antibody is zimberelimab.
  • the anti-TIGIT antibody is selected from tiragolumab, vibostolimab, domvanalimab, AB3O8, AK127, BMS-986207, ralzapastotug, and etigilimab.
  • the anti-TIGIT antibody is domvanalimab.
  • the additional therapeutic agent comprises an anti-PD(L)l antibody and an anti- TIGIT antibody.
  • the additional therapeutic agent comprises a) zimberelimab and domvanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vibostolimab, e) MK-7684A (pembrolizumab/vibostolimab coformulation), f) durvalumab and domvanalimab, g) zimberelimab and ralzapastotug, or h) pembrolizumab and ralzapastotug.
  • the anti-PD(L)l antibody is zimberelimab and the anti-TIGIT antibody is domvanalimab.
  • the additional therapeutic modality comprises surgery or radiation therapy.
  • the tumor antigen positive cancer is positive for a tumor antigen selected from carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2/neu, BrE3, CD1, CDla, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM5, CEACAM5, CEACAM5, CE
  • General dosing and administration regimens and pharmaceutical compositions for antibody-drug conjugates, adenosine pathway inhibitors, and additional therapeutic agents that can be used in the methods provide herein are known to a skilled artisan.
  • general dosing and administration regimens and pharmaceutical compositions are described in W02014/092804A1 for exemplary ADCs, including sacituzumab govitecan, in WO2017120508 for exemplary CD73 inhibitors, including quemliclustat, in W02018136700A1 for exemplary adenosine receptor antagonists, including etrumadenant, and in W02017025051A1 for exemplary anti-PD(L)l antibodies, including zimberelimab.
  • the ADC e.g., sacituzumab govitecan
  • adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • the anti-PD(L)l antibody e.g., zimberelimab
  • the ADC e.g., sacituzumab govitecan
  • adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • the anti-PD(Ll) antibody e.g., zimberelimab
  • the same day e.g., on day 1 of a 21-day treatment cycle.
  • the ADC e.g., sacituzumab govitecan
  • adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • the anti-PD(Ll) antibody e.g., zimberelimab
  • the ADC e.g., sacituzumab govitecan
  • adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • the anti-PD(Ll) antibody e.g., zimberelimab
  • the ADC e.g., sacituzumab govitecan
  • adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • the anti-PD(Ll) antibody e.g., zimberelimab
  • sacituzumab govitecan and etrumadenant are co-administered sequentially on day 1 of a 21 -day treatment cycle, wherein etrumadenant is co-administcrcd orally at least 30 minutes prior to the start of an intravenous infusion of sacituzumab govitecan.
  • sacituzumab govitecan, etrumadenant, and zimberelimab are co-administered sequentially on day 1 of a 21 -day treatment cycle, wherein etrumadenant is co-administered orally at least 30 minutes prior to the start of an intravenous infusion of zimberelimab, and sacituzumab govitecan is coadministered intravenously after completion of the zimberelimab infusion.
  • sacituzumab govitecan is coadministered on day 1 and day 8 of a 21 -day treatment cycle.
  • sacituzumab govitecan is co-administered intravenously (IV).
  • IV intravenously
  • sacituzumab govitecan is co-administered at a dose of 8 mg/kg to 10 mg/kg.
  • sacituzumab govitecan is co-administered at a dose of 8 mg/kg or 10 mg/kg.
  • sacituzumab govitecan is co-administered at a dose of 10 mg/kg.
  • sacituzumab govitecan is coadministered intravenously (IV) at a dose of 8 mg/kg or 10 mg/kg on day 1 and day 8 of a 21-day treatment cycle.
  • etrumadenant is co-administered once daily (QD). In some embodiments, etrumadenant is co-administered orally (PO). In some embodiments, etrumadenant is co-administered at a dose of 75 mg or 150 mg. In some embodiments, etrumadenant is co-administered at a dose of 150 mg. Tn some embodiments, etrumadenant is co-administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg. In some embodiments, etrumadenant is co-administered orally (PO) once daily (QD) at a dose of 150 mg.
  • an anti-PD(L)l antibody e.g., zimberelimab
  • Q3W once every three weeks
  • an anti-PD(L)1 antibody is co-administered intravenously (IV).
  • an anti-PD(L)l antibody is co-administered at a dose of 360 mg.
  • sacituzumab govitecan is coadministered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 8 mg/kg or 10 mg/kg; etrumadenant is co-administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21 -day treatment cycle, and, optionally, zimberelimab is coadministered on day 1 of the 21-day treatment cycle (Q3W) at a dose of 360 mg.
  • IV intravenously
  • etrumadenant is co-administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21 -day treatment cycle
  • Zmberelimab is coadministered on day 1 of the 21-day treatment cycle (Q3W) at a dose of 360 mg.
  • sacituzumab govitecan is coadministered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 10 mg/kg; etrumadenant is co-administered orally (PO) once daily (QD) at a dose of 150 mg on each day of the 21-day treatment cycle, and, optionally, zimberelimab is co-administered on day 1 of the 21-day treatment cycle (Q3W) at a dose of 360 mg.
  • IV intravenously
  • etrumadenant is co-administered orally (PO) once daily (QD) at a dose of 150 mg on each day of the 21-day treatment cycle
  • Zmberelimab is co-administered on day 1 of the 21-day treatment cycle (Q3W) at a dose of 360 mg.
  • the methods provided herein have anti-cancer effects as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.
  • ORR objective response rate
  • DCR disease control rate
  • PFS progression free survival
  • DOR duration of response
  • OS overall survival
  • CR complete response
  • PR partial response
  • PSA response rate radiographic response rate
  • tumor response or progression is determined according to RECIST version 1.1.
  • the ORR is defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response determined by the investigator according to the Prostate Cancer Working Group 3 (PCWG3) criteria.
  • PCWG3 Prostate Cancer Working Group 3
  • the PSA response is defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on 2 consecutive assessments measured at least 3 to 4 weeks apart.
  • the radiographic response defined as the proportion of participants with a best overall response of CR or PR according to RECIST v 1.1.
  • DCR is defined as the proportion of participants with a best overall RECIST response of CR, PR, or stable disease (SD).
  • SD stable disease
  • the DCR is at least 6 months.
  • PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiographic progression, bone scan progression, or other) or death, whichever occurs first. Depending on data availability, time to progression due to specific reasons (e.g., PSA progression or radiographic progression) may also be presented individually.
  • OS is defined as the time from treatment assignment until death due to any cause.
  • the methods provided herein further comprise determining tumor antigen (e.g., Trop-2) expression levels in a sample from the subject.
  • the determination of tumor antigen (e.g., Trop-2) expression levels can occur with any clinical analytics method known to a skilled artisan.
  • Samples can include liquid biopsy samples (e.g., blood samples) and solid tumor biopsy samples.
  • Tumor antigen (e.g., Trop-2) expression levels can be determined at the DNA, RNA, or protein level.
  • Illustrative methods for the determination of tumor antigen (e.g., Trop-2) expression levels include western blot, immunohistochemistry, QPCR, exome sequencing, FACS, and the like.
  • an anti-CD47 antibody is not coadministered to the subject or human patient (CD47; integrin associated protein; IAP; NCBI Gene ID: 961).
  • the subject or human patient is not co-administered an anti-CD47 antibody selected from magrolimab, lemzoparlimab, letaplimab, ligufalimab, AO- 176, IBI-322, ZL-1201, IMC-002, SRF-231, CC-90002 (a.k.a., INBRX-103), NI-1701 (a.k.a., TG-1801) and STI-6643.
  • the subject or human patient is not co-administered magrolimab.
  • an MCL1 inhibitor is not coadministered to the subject or human patient (MCL1; myeloid leukemia cell differentiation protein; NCBI Gene ID: 4170).
  • MCL1 myeloid leukemia cell differentiation protein
  • NCBI Gene ID: 4170 the subject or human patient is not coadministered an MCL1 inhibitor selected from GS-9716, AMG-397, AMG-176, PRT-1419, and S6431.
  • the subject or human patient is not co-administered GS-9716.
  • a FLT3 agonist is not coadministered to the subject or human patient (FLT3; fms like tyrosine kinase; CD135; NCBI Gene ID: 2322).
  • the FLT3 agonist is selected from GS-3583, CDX-301, TAK- 605, ONCR-177, Alb-Ftl3L, and SYM-027.
  • the FLT3 agonist is GS-3583.
  • kits for use as a medicament comprising a) TROP-2- targeted antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an adenosine pathway inhibitor; and c) optionally an anti-PD-(L)l antibody.
  • ADC TROP-2- targeted antibody-drug conjugate
  • kits for use as a medicament comprising a) a tumor antigen (TA) targeted ADC comprising a topoisomerase I inhibitor (Topi ADC); b) an adenosine pathway inhibitor; and c) optionally an anti-PD-(L)! antibody.
  • TA tumor antigen
  • Topici ADC topoisomerase I inhibitor
  • adenosine pathway inhibitor optionally an anti-PD-(L)! antibody.
  • kits comprising one or more unitary doses of the active agents, e.g., a) an anti-Trop-2 ADC (c.g., sacituzumab govitccan) or Topi ADC; b) an adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) an anti-PD(L)l antibody (e.g., zimberelimab), and formulations thereof, as described herein, and instructions for use.
  • an anti-Trop-2 ADC c.g., sacituzumab govitccan
  • Topi ADC adenosine pathway inhibitor
  • an anti-PD(L)l antibody e.g., zimberelimab
  • the a) anti-Trop-2 ADC e.g., sacituzumab govitecan
  • Topi ADC e.g., adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab)
  • the kit can further contain a least one additional reagent, e.g. an anti-TIGIT antibody.
  • Kits typically include a label indicating the intended use of the contents of the kit. The term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
  • one or more of the a) anti-Trop-2 ADC e.g., sacituzumab govitecan) or Topi ADC
  • adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • c) anti-PD(L)l antibody e.g., zimberelimab
  • a dosage form e.g., a therapeutically effective dosage form
  • one or more of the a) anti-Trop-2 ADC e.g., sacituzumab govitecan) or Topi ADC
  • b) adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • optionally c) anti-PD(L)l antibody e.g., zimberelimab
  • two or more different dosage forms e.g., two or more different therapeutically effective dosage forms.
  • one or more of the a) anti-Trop-2 ADC e.g., sacituzumab govitecan) or Topi ADC
  • b) adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • c) anti-PD(L)l antibody e.g., zimberelimab
  • any convenient packaging e.g., stick pack, dose pack, etc.
  • anti-Trop-2 ADC e.g., sacituzumab govitecan
  • Topi ADC e.g., adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab)
  • adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • anti-PD(L)l antibody e.g., zimberelimab
  • the a) anti-Trop-2 ADC e.g., sacituzumab govitecan
  • Topi ADC e.g., adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab) are provided in separate containers.
  • adenosine pathway inhibitor e.g., etrumadenant, quemliclustat
  • anti-PD(L)l antibody e.g., zimberelimab
  • compositions comprising one or more of the a) anti-Trop-2 ADC (e.g., sacituzumab govitecan) or Topi ADC; b) adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab) are provided in one or more containers, the containers having a label.
  • Suitable containers include, for example, bottles, vials, ampoules, syringes (including pre-loaded syringes), and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds a composition which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the active agent in one composition is a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or Topi ADC.
  • the active agent in a second composition is an adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat).
  • the active agent in an optional third composition is optionally c) anti-PD(L)l antibody (e.g., zimberelimab).
  • the label on, or associated with, the container indicates that the composition is used for treating the condition of choice.
  • the article of manufacture may further comprise one or more containers comprising a pharmaceutically- acceptable buffer, e.g., for use as diluent.
  • a pharmaceutically- acceptable buffer include without limitation phosphate -buffered saline, Ringer’s solution and/or dextrose solution.
  • the kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • the subject kits may further include (in certain embodiments) instructions for practicing the subject methods.
  • These instructions may be present in the subject kits in a variety of forms, one or more of which may be present in the kit.
  • One form in which these instructions may be present is as printed information on a suitable medium or substrate, e.g., a piece or pieces of paper on which the information is printed, in the packaging of the kit, in a package insert, and the like.
  • Yet another form of these instructions is a computer readable medium, e.g., diskette, compact disk (CD), flash drive, and the like, on which the information has been recorded.
  • Yet another form of these instructions that may be present is a website address which may be used via the internet to access the information at a removed site.
  • mCRPC metastatic castrateresistant prostate cancer
  • the method further comprises co-administering zimberelimab to the human patient.
  • the human mCRPC patient has previously progressed on androgen deprivation therapy (ADT).
  • ADT androgen deprivation therapy
  • the human mCRPC patient has previously progressed on one or more next generation hormonal agents (NHAs, e.g., abiraterone, enzalutamide, darolutamide, apalutamide).
  • NHAs next generation hormonal agents
  • the human mCRPC patient is checkpoint inhibitor (CPI) and taxanc naive.
  • the human mCRPC patient has RECIST 1.1 measurable or non-measurable disease.
  • a method of treating castrate resistant prostate cancer comprising co-administering to a human patient an effective amount of a) an anti- Trop-2 ADC; b) a CD73 inhibitor or adenosine receptor antagonist; and, optionally, c) an anti- PD(L)1 antibody.
  • the CRPC is metastatic CRPC (mCRPC).
  • the anti-Trop-2 ADC has a structural formula of mAb-CL2A-SN-38, with a structure represented by:
  • the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hRS7).
  • the anti-Trop-2 ADC comprises a linker-payload conjugate (TL035) having a structure represented by:
  • the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hTINAl-HILl).
  • the anti-Trop-2 ADC has a DAR of about 4.
  • the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02 and BAT-8003.
  • the anti-Trop-2 antibody is sacituzumab govitecan or datopotamab deruxtecan.
  • the anti-Trop-2 antibody is sacituzumab govitecan.
  • the CD73 inhibitor is selected from oleclumab (AstraZeneca), BMS-986179 (BMS), uliledlimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB680, Arcus Biosciences), mupadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3Sbio),
  • the CD73 inhibitor is selected from oleclumab and quemliclustat. In some embodiments, the CD73 inhibitor is quemliclustat.
  • the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; AD0RA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), or TT-228 (Teon Therapeutics).
  • A2AR adenosine A2A receptor
  • AD0RA2A adenosine A2A receptor selective antagonist
  • the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; AD0RA2B) antagonist, such as PBF- 1129 (Palobiofarma) or TT-702 (Teon Therapeutics).
  • A2BR adenosine A2B receptor
  • AD0RA2B adenosine A2B receptor
  • PBF- 1129 Palobiofarma
  • TT-702 Teon Therapeutics
  • the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenant (AB928, Arcus Biosciences), INCB 106385 (Incyte), M1069 (Merck KgaA), A2aR/A2bR (Domain/Merck KgaA), HM87277 (Al/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), and TT-53 (Tarus Therapeutics).
  • the adenosine receptor antagonist is etrumadenant.
  • the anti-PD(L)1 antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the anti-PD(L)l antibody is zimberelimab.
  • the human patient is not co-administered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
  • a method of treating castrate resistant prostate cancer comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; and b) etrumadenant.
  • the CRPC is metastatic CRPC (mCRPC).
  • the CRPC or mCRPC ((m)CRPC) is resistant or refractive to at least one anti-cancer therapy.
  • the human patient has shown disease progression after prior treatment with a new hormonal agent (NHA; first- or second- generation non-steroidal antiandrogens, abiraterone, enzalutamide, darolutamide, apalutamide).
  • the human patient has not received a prior taxane therapy (e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), checkpoint inhibitor therapy (e.g., anti- CTLA4 antibody, anti-PD(L)l antibody), topoisomerase I inhibitor therapy (e.g., irinotecan).
  • a prior taxane therapy e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel
  • checkpoint inhibitor therapy e.g., anti- CTLA4 antibody, anti-PD(L)l antibody
  • topoisomerase I inhibitor therapy e.g., irinotecan
  • the human patient with (m)CRPC has histologically confirmed adenocarcinoma of the prostate and metastatic castrate resistant with tumor progression while on androgen deprivation therapy (ADT ; including orchiectomy) with castrate levels of scrum (total) testosterone ( ⁇ 1.7 nmol/L or 50 ng/dL) defined by PSA and/or radiographic criteria according to PCWG3.
  • ADT on androgen deprivation therapy
  • the human patient (m)CRPC has metastatic castrate resistant adenocarcinoma of the prostate with tumor progression while on androgen deprivation therapy (e.g., including orchiectomy) with castrate levels of serum (total) testosterone ( ⁇ 1.7 nmol/L or 50 ng/dL) defined by prostate specific antigen (PSA) and/or radiographic criteria according to The Prostate Cancer Working Group 3 (PCWG3) and measurable or non-measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l.
  • the human patient with (m)CRPC has Eastern Cooperative Oncology Group performance status 0 or 1 with a life expectancy >3 months.
  • the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing).
  • tumor antigen e.g., Trop-2
  • sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 8 mg/kg or 10 mg/kg and etrumadenant is administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21-day treatment cycle.
  • sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 10 mg/kg and etrumadenant is administered orally (PO) once daily (QD) at a dose of 150 mg on each day of the 21-day treatment cycle.
  • the methods provided herein have anti-cancer effects as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.
  • the ORR is defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response determined by the investigator according to the Prostate Cancer Working Group 3 (PCWG3) criteria.
  • the PSA response is defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on 2 consecutive assessments measured at least 3 to 4 weeks apart.
  • the radiographic response defined as the proportion of participants with a best overall response of CR or PR according to RECIST vl.l.
  • DCR is defined as the proportion of participants with a best overall RECTST response of CR, PR, or stable disease (SD). Tn some embodiments, the DCR is at least 6 months.
  • PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiographic progression, bone scan progression, or other) or death, whichever occurs first. Depending on data availability, time to progression due to specific reasons (e.g., PSA progression or radiographic progression) may also be presented individually.
  • OS is defined as the time from treatment assignment until death due to any cause.
  • the human patient is not coadministered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
  • a method of treating castrate resistant prostate cancer comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; b) etrumadenant and c) zimberelimab.
  • the CRPC is metastatic CRPC (mCRPC).
  • the CRPC or mCRPC ((m)CRPC) is resistant or refractive to at least one anti-cancer therapy.
  • the human patient has shown disease progression after prior treatment with a new hormonal agent (NHA; first- or second-generation non-steroidal antiandrogens, e.g, abiraterone, enzalutamide, darolutamide, apalutamide).
  • NHA new hormonal agent
  • the human patient has not received a prior taxane therapy (e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)l antibody), topoisomerase I inhibitor therapy (e.g., irinotecan).
  • a prior taxane therapy e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel
  • checkpoint inhibitor therapy e.g., anti-CTLA4 antibody, anti-PD(L)l antibody
  • the human patient with (m)CRPC has histologically confirmed adenocarcinoma of the prostate and metastatic castrate resistant with tumor progression while on androgen deprivation therapy (ADT ; including orchiectomy) with castrate levels of serum (total) testosterone ( ⁇ 1.7 nmol/L or 50 ng/dL) defined by PSA and/or radiographic criteria according to PCWG3.
  • ADT on androgen deprivation therapy
  • the human patient (m)CRPC has metastatic castrate resistant adenocarcinoma of the prostate with tumor progression while on androgen deprivation therapy (e.g., including orchiectomy) with castrate levels of serum (total) testosterone ( ⁇ 1.7 nmol/L or 50 ng/dL) defined by prostate specific antigen (PSA) and/or radiographic criteria according to The Prostate Cancer Working Group 3 (PCWG3) and measurable or non-measurable disease per the Response Evaluation Criteria in Solid Tumors (RECTST) vl .l . Tn some embodiments, the human patient with (m)CRPC has Eastern Cooperative Oncology Group performance status 0 or 1 with a life expectancy >3 months.
  • the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or nextgeneration DNA sequencing).
  • tumor antigen e.g., Trop-2
  • sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 8 mg/kg or 10 mg/kg
  • etrumadenant is administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21-day treatment cycle
  • zimberelimab is administered on day 1 of the 21- day treatment cycle (Q3W) at a dose of 360 mg.
  • sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 10 mg/kg
  • etrumadenant is administered orally (PO) once daily (QD) at a dose of 150 mg on each day of the 21-day treatment cycle
  • zimberelimab is administered on day 1 of the 21-day treatment cycle (Q3W) at a dose of 360 mg.
  • the methods provided herein have anticancer effects as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, hr some embodiments, the ORR is defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response determined by the investigator according to the Prostate Cancer Working Group 3 (PCWG3) criteria.
  • PCWG3 Prostate Cancer Working Group 3
  • the PSA response is defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on 2 consecutive assessments measured at least 3 to 4 weeks apart.
  • the radiographic response defined as the proportion of participants with a best overall response of CR or PR according to RECIST vl.l.
  • DCR is defined as the proportion of participants with a best overall RECIST response of CR, PR, or stable disease (SD).
  • the DCR is at least 6 months.
  • PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiographic progression, bone scan progression, or other) or death, whichever occurs first.
  • time to progression due to specific reasons may also be presented individually.
  • OS is defined as the time from treatment assignment until death due to any cause.
  • the human patient is not co-administered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
  • Tn some embodiments, provided herein is a method of treating metastatic non-small cell lung cancer (mNSCLC) comprising co-administcring to a human mNSCLC patient an effective amount of a) sacituzumab govitecan; b) etrumadenant; and c) an anti-PD-(L)l antibody.
  • mNSCLC metastatic non-small cell lung cancer
  • the anti-PD-(L)l antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the anti-PD-(L)l antibody is zimberelimab.
  • the human mNSCLC patient has progressed after platinumbased chemotherapy.
  • the human mNSCLC patient has progressed after checkpoint inhibitor therapy (e.g., anti-PD-(L)l antibody or anti-CTLA4 antibody therapy).
  • the human mNSCLC patient has progressed after platinum-based chemotherapy and anti-PD-(L)l antibody therapy, received either in combination or sequentially (in any order).
  • the human mNSCLC patient is treatment naive.
  • NSCLC non-small cell lung cancer
  • a method of treating non-small cell lung cancer comprising co-administering to a human patient an effective amount of a) an anti-Trop- 2 ADC; b) a CD73 inhibitor or adenosine receptor antagonist; and, optionally, c) an anti-PD(L)l antibody.
  • the NSCLC is metastatic NSCLC (mNSCLC).
  • the anti-Trop-2 ADC has a structural formula of mAb-CL2A-SN-38, with a structure represented by:
  • the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by:
  • the anti-Trop-2 ADC comprises a linker-payload conjugate (TL035) having a structure represented by:
  • the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hTINAl-HILl).
  • the anti-Trop-2 ADC has a DAR of about 4.
  • the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02 and BAT-8003.
  • the anti-Trop-2 antibody is sacituzumab govitecan or datopotamab deruxtecan. In some embodiments, the anti-Trop-2 antibody is sacituzumab govitecan.
  • the CD73 inhibitor is selected from oleclumab (AstraZeneca), B MS-986179 (BMS), ulilcdlimab (I-MAB Biopharma), AK119 (Akcso Biopharma), quemliclustat (AB680, Arcus Biosciences), mupadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio),
  • the CD73 inhibitor is selected from oleclumab and quemliclustat. In some embodiments, the CD73 inhibitor is quemliclustat.
  • the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), or TT-228 (Teon Therapeutics).
  • A2AR adenosine A2A receptor
  • ADORA2A adenosine A2A receptor selective antagonist
  • the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF- 1129 (Palobiofarma) or TT-702 (Teon Therapeutics).
  • A2BR adenosine A2B receptor
  • ADORA2B adenosine A2B receptor
  • PBF- 1129 Palobiofarma
  • TT-702 Teon Therapeutics
  • the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenant (AB928, Arcus Biosciences), INCB 106385 (Incyte), M1069 (Merck KGaA), A2aR/A2bR (Domain/Merck KGaA), HM87277 (Al/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), and TT-53 (Tarus Therapeutics).
  • the adenosine receptor antagonist is etrumadenant.
  • the anti-PD-(L)l antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the anti-PD-(L)l antibody is zimberelimab.
  • the human patient is not co-administered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
  • NSCLC non-small cell lung cancer
  • the anti-PD- (L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atczolizumab, avclumab, durvalumab, cosibclimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the anti-PD-(L)l antibody is zimberelimab.
  • the NSCLC is metastatic NSCLC (mNSCLC).
  • the NSCLC or mNSCLC ((m)NSCLC) is resistant or refractive to at least one anti-cancer therapy.
  • the human mNSCLC patient has progressed after platinum-based chemotherapy.
  • the human mNSCLC patient has progressed after checkpoint inhibitor therapy (e.g., anti-PD-(L)l antibody or anti-CTLA4 antibody therapy).
  • the human mNSCLC patient has progressed after platinum-based chemotherapy and anti-PD-(L)l antibody therapy, received either in combination or sequentially (in any order).
  • the human mNSCLC patient is treatment naive.
  • the human patient with (m)NSCLC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing).
  • tumor antigen e.g., Trop-2
  • tumor antigen expression levels e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing.
  • sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21 -day treatment cycle at a dose of 8 mg/kg or 10 mg/kg and etrumadenant is administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21-day treatment cycle.
  • sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 10 mg/kg and etrumadenant is administered orally (PO) once daily (QD) at a dose of 150 mg on each day of the 21-day treatment cycle.
  • the methods provided herein have anti-cancer effects as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.
  • efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.
  • tumor response or progression is determined according to RECIST version 1.1.
  • the human patient is not co-administered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
  • [0215] Disclosed herein are methods of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of breast cancer comprising co-administering to a human patient an effective amount of: (a) sacituzumab govitecan; and (b) a CD73 inhibitor.
  • the CD73 inhibitor is olcclumab, BMS-986179, ulilcdlimab, AK119, qucmliclustat, mupadolimab, HLX23, INCA00186, IB 1325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037.
  • the CD73 inhibitor is quemliclustat (AB680, GS- 0680), uliledlimab, mupadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS- 986179, or oleclumab. In some embodiments, the CD73 inhibitor is quemliclustat (AB680, GS- 0680). In some embodiments, the method further comprises co-administering an anti-PD-(L)l antibody to the human patient.
  • the anti-PD-(L)l antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.
  • the method further comprises co-administering zimberelimab to the human patient.
  • the breast cancer is metastatic breast cancer.
  • the breast cancer is resistant or refractory to one or more anti-cancer therapies.
  • the breast has progressed following prior anti-cancer therapy (first- or second-generation anti-cancer therapy, e.g., hormone therapy).
  • the human patient has not received a prior therapy selected from taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.
  • the human patient has not received a prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy.
  • taxane therapy comprises paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel.
  • the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti- PD(L)1 antibody.
  • the topoisomerase I inhibitor therapy comprises a topotecan, irinotecan, belotecan, or exatecan.
  • the methods provided herein have anti-cancer effects as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.
  • efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.
  • tumor response or progression is determined according to RECTST version 1.1.
  • the human patient is not co-administcrcd an additional therapeutic agent selected from an MCL- 1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
  • a clinical study is conducted administering human patients with metastatic castrate resistant prostate cancer (mCRPC) with a combination of an anti-Trop-2 antibody and an adenosine receptor antagonist.
  • mCRPC metastatic castrate resistant prostate cancer
  • a subgroup of patients is treated with a combination of an anti-Trop-2 antibody, an adenosine receptor antagonist, and an anti-PD-(L)l antibody.
  • human mCRPC patients are treated with a combination of sacituzumab govitecan and etrumadenant.
  • human mCRPC patients are treated with a combination of sacituzumab govitecan (SG), etrumadenant, and zimberelimab.
  • the patient population in this study can include previously treated mCRPC patients who have progressed on androgen deprivation therapy (ADT) and/or next generation hormonal agents (NHAs). mCRPC patients who are CPI and taxane naive can also be included. Additional patients can have RECIST 1.1 measurable or non-measurable disease.
  • ADT androgen deprivation therapy
  • NHAs next generation hormonal agents
  • Primary endpoints in the study can include composite overall response rate (ORR; PSA/RECIST Response) and safety.
  • Secondary endpoints can include ORR per RECIST 1.1, PSA response rate per PCWG3, disease control rate (DCR), or pharmacokinetics (PK).
  • ORR per RECIST 1.1 PSA response rate per PCWG3, disease control rate (DCR), or pharmacokinetics (PK).
  • DCR disease control rate
  • PK pharmacokinetics
  • Exploratory endpoints can include progression free survival, overall survival, or certain biomarkers. Investigational Products
  • Sacituzumab govitecan is an antibody-drug conjugate (ADC) composed of the following 3 components: o The humanized monoclonal antibody hRS7 IgGlK, which binds to trophoblast cellsurface antigen 2 (Trop-2), a transmembrane calcium signal transducer that is overexpressed in many epithelial cancers, including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). o The camptothecin-derived agent SN-38, a topoisomerase I inhibitor. o A hydrolyzable linker CL2A that links the humanized monoclonal antibody to SN-38.
  • ADC antibody-drug conjugate
  • SG delivers significantly greater amounts of SN 38 to a Trop 2-cxprcssing tumor than conventional irinotecan chemotherapy (Sharkey RM, et al. Clinical Cancer Research (2015) 21(22):5131-8).
  • the extracellular release of SN 38 from SG also allows for bystander killing of Trop 2 negative tumor cells (Lopez S, et al. Oncotarget (2020) l l(5):560;Perrone E, et al. Frontiers in Oncology (2020): 118; Zeybek B, et al. Scientific Reports (2020) 10(l):973)Thus
  • SG can deliver cytotoxic chemotherapy to tumors, including adjacent cancer cells, in concentrations that are higher than those with standard chemotherapy and may reduce toxic effects in normal tissues that do not express the target.
  • sacituzumab govitecan is generally administered at 10 mg/kg as an IV infusion on Days 1 and 8 of a 21-day cycle.
  • Etrumadenant is generally administered at 10 mg/kg as an IV infusion on Days 1 and 8 of a 21-day cycle.
  • Etrumadenant also known as AB928, GS-0928
  • Etrumadenant is a low-molecular-weight, orally bioavailable, selective dual antagonist of adenosine receptors adenosine 2a receptor (A2aR) and adenosine 2b receptor (A2b ).
  • A2aR adenosine 2a receptor
  • A2b adenosine 2b receptor
  • etrumadenant has been shown to selectively reverse the immunosuppressive effects caused by high concentrations of adenosine, without causing any immune activation effects on its own.
  • Tn prostate cancer, A2bR is upregulated and the activity of prostatic acid phosphatase (PAP) produces additional adenosine, suggesting this tumor type may be more susceptible than others to adenosine-mediated immunosuppression.
  • PAP prostatic acid phosphatase
  • Etrumadenant can achieve high penetration of tumor tissue, robust potency in the presence of high adenosine concentrations, and only small shift in potency from nonspecific protein binding.
  • Etrumadenant exhibits PK/pharmacodynamics consistent with once-daily dosing and has been well tolerated in dose escalation studies as a single agent and in Phase lb/2 studies administered in combination with chemo/immunotherapy across multiple advanced solid tumor indications.
  • Tn the clinical studies described herein, etrumadenant is generally administered orally at a dose of 75 mg or 150 mg QD.
  • Zimberelimab is a fully human IgG4 monoclonal antibody targeting human PD- 1.
  • PD- 1 is a type I transmembrane protein that is part of the immunoglobulin gene superfamily and the CD28 family of cell surface receptors.
  • the structure of PD-1 consists of 1 immunoglobulin variable-like extracellular domain and 1 cytoplasmic domain containing an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif.
  • PD-1 has 2 known ligands, PD-L1 (B7 Hl and CD274) and programmed cell death ligand 2 (PD-L2; B7 DC and CD73), which are members of the B7 family and are expressed on the plasma membrane of cancer cells and tumor-infiltrating leukocytes. Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1, but they do not bind to other CD28 family members. [0229] PD-1 is an inhibitory immune checkpoint protein that is expressed on activated B cells, T cells, and myeloid cells, and it plays a key role in limiting the activity of effector T cells. It also provides a major resistance mechanism by which tumor cells can escape immune surveillance.
  • PD-1 When activated by its ligands, PD-1 induces a state of anergy or unresponsiveness in T cells, and the cells are unable to produce optimal levels of effector cytokines or carry out other effector T- cell functions. PD-1 may also induce apoptosis in T cells via its ability to inhibit survival signals. Under normal circumstances, PD-1 is important for limiting the extent of T cell-mediated immune responses. PD- 1 -deficient animals develop various autoimmune phenotypes, including autoimmune cardiomyopathy and a lupus-like syndrome with arthritis and nephritis.
  • PD-1/PD-L1 The interaction of PD-1 expressed on activated T cells and PD-L1 expressed on tumor cells negatively regulates immune response and dampens anticancer immunity.
  • PD-L1 is abundantly expressed on a variety of human tumors, and its expression correlates with reduced patient survival in esophageal, pancreatic, and other types of cancers. Therefore, the PD-1/PD-L1 pathway is an important target for tumor immunotherapy.
  • Activation of the PD-1/PD-L1 signaling pathway results in a decrease in tumor-infiltrating lymphocytes, a decrease in T cell proliferation, and an increase in immune evasion by cancerous cells.
  • Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is also blocked.
  • the selected dose of zimberelimab is generally 360 mg administered IV Q3W.
  • the treatment arms will be conducted in 2 stages: Stage 1 and Stage 2. Depending on the treatment arm and stage, enrollment may or may not involve randomization. The decision to begin randomized enrollment in a specific treatment arm will be made by the sponsor for each combination therapy. Stage 1
  • Stage 1 approximately 15 participants will be enrolled and will receive investigational products at the single agent recommended dose for expansion; standard of care therapies will be administered according to label instructions. The decision to begin enrollment in a specific treatment arm in Stage 1 will be made by the sponsor. The study includes the following anus:
  • Etrumadenant Sacituzumab govitecan 10 mg/kg on Days 1 and 8 of a 21-day cycle + Etrumadenant 150 mg QD.
  • SG+ Etrumadenant + Zimberelimab Sacituzumab govitecan 10 mg/kg on Days 1 and 8 of a 21-day cycle + Etrumadenant 150 mg QD + Zimberelimab 360 mg Q3W.
  • CPI checkpoint inhibitor
  • NHA new hormonal agent
  • SG sacituzumab govitecan
  • Safety assessments will consist of monitoring and recording AEs, including SAEs and AEs of special interest (AESI), performing protocol- specified safety laboratory assessments, measuring protocol- specified vital signs, and conducting other protocol- specified tests that are deemed critical to the safety evaluation of the study. All AEs and laboratory abnormalities will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Objectives and Endpoints
  • ORR Objective response rate
  • PCWG3 Prostate Cancer Working Group 3
  • ORR defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response determined by PCWG3 criteria.
  • Participants for biopsy should have at least 2 measurable lesions at baseline: 1 for tissue sampling and 1 for radiographic response assessment.
  • HIV Negative human immunodeficiency virus
  • HBsAg hepatitis B surface antigen
  • HBcAb total hepatitis B core antibody
  • HCV hepatitis C virus
  • Prior anticancer treatment for the disease under study including approved agents, systemic radiotherapy, or investigational therapy, within 4 weeks (or 5 half-lives) prior to initiation of study treatment.
  • Prior focal radiotherapy must be completed at least 2 weeks prior to the initiation of study treatment
  • systemic immunostimulatory agents including, but not limited to, interferon and interleukin-2
  • systemic immunostimulatory agents including, but not limited to, interferon and interleukin-2
  • systemic immunosuppressive medication including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor-a agents
  • systemic immunosuppressive medication including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor-a agents
  • a Patients who received low dose ( ⁇ 10 mg/day prednisone or equivalent), systemic immunosuppressant medications or a 1-time pulse dose of systemic immunosuppressant medication (eg, 48 hours of corticosteroids for a contrast allergy) are eligible for the study after medical monitor approval has been obtained.
  • CNS metastases a. Patients with a history of treated CNS metastases arc eligible, if all of the following criteria are met: i. The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. ii. Metastases are limited to the cerebellum or the supratentorial region (ie, no metastases to the midbrain, pons, medulla, or spinal cord). iii. There is no evidence of interim progression between completion of CNS directed therapy and the screening brain scan. iv. The patient has not received stereotactic radiotherapy within 7 days prior to initiation of study treatment or whole brain radiotherapy within 14 days prior to initiation of study treatment.
  • IV intravenous
  • Severe infection within 4 weeks prior to initiation of study treatment including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Known allergy or hypersensitivity to any of the study drugs or their excipients may affect the interpretation of the results, or may render the patient at high risk from treatment complications 22.
  • autoimmune disease or immune deficiency including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain Barre syndrome, or multiple sclerosis with the following exceptions: a. Patients with a history of autoimmune related hypothyroidism who are on thyroid replacement hormone are eligible for the study. b. Patients with controlled Type 1 diabetes mellitus who, in the judgment of the investigator, arc on a stable insulin regimen arc eligible for the study. c.
  • Treatment with known strong CYP3A4 inducers eg, rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort
  • strong CYP3A4 inhibitors eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole
  • Sacituzumab govitecan 10 mg/kg, IV, on Days 1 and 8 of a 21-day cycle
  • Etrumadenant 150 mg, oral, once daily continuous dosing (21-day cycle)
  • Table 7 provides study intervention details: Table 7: Etrumadenant + sacituzumab govitecan with or without zimberelimab
  • a participant may receive etrumadenant as a capsule or tablet but cannot receive both formulations.
  • the dose of SG will be calculated based on actual weight at randomization (using weight obtained either at screening or on Cycle 1 Day 1) and remains constant throughout the study, unless there is a > 10% change in body weight from baseline. Modifications to the study drug doses administered should be made for a > 10% change in body weight from baseline and according to local and regional prescribing standards. Dose modifications for changes in body weight ⁇ 10% may be made according to local institutional guidelines. Sacituzumab govitecan is administered via IV infusion.
  • Sacituzumab govitecan will be administered in 21-day cycles on Days 1 and 8; the next cycle should start a minimum 14 days after the Day 8 dose (i.e., the Day 8 infusion will be counted as the first day of that 14-day period).
  • Etrumadenant should be taken at least 30 minutes prior to the start of IV infusion of SG. Sacituzumab govitecan is administered via IV infusion. The first infusion is administered over 3 hours. Subsequent infusions may be administered over 1 to 2 hours if previous infusions were well tolerated.
  • Etrumadenant should be taken at least 30 minutes prior to the start of IV infusion of zimberelimab. Administer zimberelimab over a 60-minute ( ⁇ 5 min) IV infusion followed by a 30- minute observation (+15 min) interval. Following the zimberelimab observation period, sacituzumab govitecan should be administered as described above.
  • Table 8 provides the study treatment administration schedule.
  • 1 experimental treatment cycle is 21 days in duration (Cl, C2, C3, C4).
  • Concomitant medications or treatments may be prescribed if considered necessary for adequate prophylactic or supportive care except for those medications identified as prohibited further below.
  • Anticoagulant therapy including low-molecular-weight heparins, are allowed as clinically indicated. Applicable participants should undergo routine monitoring of coagulation parameters, including INR, according to institutional guidelines.
  • Premedication is permitted for treatment with SG.
  • Guidance for premedication for prevention of toxicities associated with SG is presented in Table 9.
  • ANC absolute neutrophil count
  • ASCO American Society of Clinical Oncology
  • ESMO European Society for Medical Oncology
  • IV intravenous
  • PO orally
  • SG Sacituzumab govitecan
  • Systemic immuno stimulatory agents including but not limited to interferons and interleukin-2.
  • Systemic immunosuppressive medications including but not limited to corticosteroids, cyclophosphamide, azathioprinc, methotrexate, thalidomide, and antitumor necrosis factor-a agents
  • Systemic immunosuppressive medications including but not limited to corticosteroids, cyclophosphamide, azathioprinc, methotrexate, thalidomide, and antitumor necrosis factor-a agents
  • acute, low dose ⁇ 10 mg/day prednisone or equivalent
  • systemic immunosuppressant medications for management of AEs are allowed after medical monitor approval has been obtained.
  • UGT1A1 inducers that should be avoided while receiving SG include: Carbamazepine, efavirenz, ethinylestradiol, lamotrigine, phenobarbital, phenytoin, primidone, rifampicin, ritonavir, and tipranavir.
  • Stage 1 Participants will be enrolled into various treatment arms based on their prior cancer history. Enrollment may be paused after the accrual of approximately 6 participants in a treatment arm to allow for safety evaluation. A rate of toxicity of ⁇ 33% will be targeted, with toxicity being defined as the occurrence of either a treatment-related Grade 4 AE or a treatment- related Grade 3 AE that is not responsive to supportive care during Cycle 1. If 2 or more such events are observed, enrollment in that arm may not continue.
  • Radiographic response is defined as either a CR or PR by RECIST vl.l
  • PSA response is defined as percent change from baseline PSA of > 50%.
  • At least 1 radiographic CR or PR or 2 PSA responses out of 15 evaluable participants must be observed in order to consider opening Stage 2. In this case, across a range of prior beta distributions, observing 1 or fewer PSA responses would provide greater than 80% posterior probability confidence that the PSA response rate is less than 20%.
  • Participants must have at least 1 postbaseline radiographic disease evaluation or consecutive postbaseline PSA assessments measured at least 3 to 4 weeks apart to be considered evaluable for Stage 1 decision gating.
  • Stage 2 up to 25 additional participants may be enrolled either onto an experimental arm or a standard of care control arm. The goal of this stage is to better characterize potential treatment differences between experimental arms and standard of care among concurrently enrolled participants. Representative estimates of 90% confidence intervals for potential differences in response between treatment arms are provided. Safety Endpoints
  • Safety analyses will be conducted in the safety-evaluable population, defined as all participants who are enrolled and receive any amount of study treatment. Safety will be assessed through summaries of AEs, as well as relevant changes in laboratory test results, vital signs, and electrocardiograms. Verbatim AE terms will be mapped and coded using the Medical Dictionary for Regulatory Activities. All AEs will be assessed for severity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • Treatment-emergent adverse events defined as AEs with onset date on or after initiation of study treatment or as AEs present at baseline but which worsened after initiation of study treatment, will be summarized. Adverse events will be summarized on the participant-level using the maximum severity or grade reported. All TEAEs, SAEs, AEs leading to study treatment discontinuation, Grade 3 or higher AEs, and deaths will be listed and summarized by treatment arm with the mapped preferred terms, thesaurus level and NCI CTCAE grade, as appropriate.
  • Efficacy analyses will be primarily conducted in the efficacy-evaluable population, defined as all participants who are enrolled and receive at least 1 dose of each drug of their assigned treatment regimen. The following prioritized efficacy endpoints will be analyzed according to PCWG3 and based on the investigator’s assessment:
  • ORR defined as the composite proportion of participants with a PSA response or a radiographic CR or PR (defined below).
  • PSA response defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on 2 consecutive assessments measured at least 3 to 4 weeks apart.
  • Radiographic response defined as the proportion of participants with a best overall response of CR or PR according to RECIST vl.l.
  • DCR is defined as the proportion of participants with a best overall RECIST response of CR, PR, or stable disease (SD).
  • PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiographic progression, bone scan progression, or other) or death, whichever occurs first. Depending on data availability, time to progression due to specific reasons (e.g., PSA progression or radiographic progression) may also be presented individually.
  • OS is defined as the time from treatment assignment until death due to any cause.
  • the primary efficacy endpoint is the ORR, defined as the composite proportion of participants with a PSA response or a radiographic complete or partial response determined by the investigator according to the PCWG3 criteria. PSA response and radiographic complete or partial response may be reported individually. For clarity, PSA response is defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on 2 consecutive assessments measured 3 to 4 weeks apart. Radiographic response is defined as the percentage of participants with measurable disease at baseline who achieve a best overall response of CR or PR according to RECIST vl.l.
  • tumor assessments every 12 weeks ( ⁇ 7 days) from start of study treatment until disease progression (regardless of whether the participant is still receiving treatment), the start of new anticancer therapy, withdrawal of consent, death, or the end of the study.
  • tumor assessments may be repeated at any time if disease progression is suspected. All participants who discontinue study treatment for reasons other than disease progression (e.g., AEs) will continue tumor assessments until death, disease progression, initiation of another systemic anticancer therapy, lost to follow-up, withdrawal of consent, or study termination, whichever occurs first.
  • Measurable and evaluable lesions should be assessed and documented at screening. Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to enrollment do not have to be repeated at screening.
  • Baseline disease assessments for all participants will include: CT scan with contrast of the chest and abdomen/pelvis, Full-body bone scan (technetium-99m [TC-99m]), and MRI scan of the brain.
  • Postbaseline disease assessments for all participants will include:
  • All scans should be performed in accordance with RECIST vl.l and with contrast. If contrast is medically contraindicated, a chest CT without contrast and an abdomen/pelvis MRI without contrast may be performed. If a brain MRI is contraindicated, a brain CT with contrast should be performed. If a CT scan for tumor assessment is performed in a positron emission tomography (PET)/CT scanner, the CT acquisition must be consistent with standard for a full contrast diagnostic CT scan.
  • PET positron emission tomography
  • All measurable and evaluable lesions identified at baseline should be reassessed at each subsequent postbaseline tumor evaluation.
  • the same radiographic procedures used to assess disease sites at screening should be used for subsequent tumor assessments (e.g., same contrast protocol for CT scans). Response will be assessed by the investigator using PCWG3. Assessments should be performed by the same evaluator, if possible, to ensure internal consistency across disease evaluations. Results must be reviewed by the investigator before dosing at the next planned study treatment cycle.
  • An adverse event is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product regardless of causal attribution.
  • An AE can therefore be any of the following: Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product
  • a serious adverse event is any AE that meets any of the following criteria:
  • Severity refers to the intensity of an AE (e.g., rated as mild, moderate, or severe, or according to the National Cancer Institute [NCI] CTCAE); the event itself may be of relatively minor medical significance (such as severe headache without any further findings). Assessment of Severity
  • CTCAE Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
  • Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the toilet, and taking medications, as performed by patients who are not bedridden.
  • c If an event is assessed as a “significant medical event”, it must be reported as an SAE d Grade 4 and 5 events must be reported as SAEs should the event meet the SAE definition.
  • This study will evaluate the efficacy and safety of combination treatment regimens for patients with advanced or metastatic NSCLC with progression on or recurrence after platinumbased chemotherapy and PD-1/PD-L1 immunotherapy, received either in combination or sequentially.
  • Participants must have a diagnosis of advanced or metastatic squamous or non-squamous NSCLC.
  • Participants with EGFR, ALK, or any other known actionable genomic alterations must have also received treatment with at least 1 approved tyrosine kinase inhibitor appropriate to the genomic alteration.
  • participants will be randomly assigned to an experimental arm. Randomization will be stratified by histology (squamous versus non-squamous) and prior therapy for an actionable genomic alteration (yes versus no).
  • participant will be randomly assigned to the comparator arm or an experimental arm. Participants in the comparator arm will receive either sacituzumab govitecan or docetaxel, with the comparator arm choice based on the treatment landscape at the time of initiation of the expansion stage.
  • ORR Objective response rate
  • PFS Progression-free survival
  • DOR Duration of response
  • OS overall survival
  • Tumor biopsy must have been performed on or after progression on prior line of therapy and before enrollment with no anticancer treatment between collection of tissue and enrollment.
  • Topoisomerase 1 inhibitors Any agent including an ADC containing a chemotherapeutic agent targeting topoisomerase 1.
  • Trop-2-targeted therapy c) Docetaxel as monotherapy or in combination with other agents.
  • Docetaxel as monotherapy or in combination with other agents.
  • Sacituzumab govitecan, etrumadenant, and zimberelimab are as described in Example 1.
  • Etrumadenant is administered orally, followed by zimberelimab IV, followed by sacituzumab govitecan IV.
  • the comparator arm during the expansion phase of the study will be either docetaxel or sacituzumab govitecan monotherapy (Table 12).
  • EGFR testing will be performed using the Cobas® EGFR Mutation Test (Roche).
  • ALK the Vysis ALK Break Apart FISH probe test (Abbott) will be used.
  • Additional biomarkers in blood and tissue may include, but are not limited to, protein expression, analyses of specific immune and tumor signatures (RNA), as well as tumor mutational burden and tumor mutations (DNA). Tumor and blood samples will be collected to measure biomarkers of response and resistance and to better understand molecular attributes predictive of treatment in lung cancer. Examples may include, but will not be limited to, PD-L1 and Trop-2 - expression, other proteins as well as mutations/gene expression (WES/RNAseq) related to any of the study treatments or related to lung cancer, tumor mutational burden, oncogenic mutations, composition of immune subsets in tumor microenvironment, and pathological features of the tumor.
  • WES/RNAseq mutations/gene expression
  • hRS7 mAb, SG, Rab64 Ab and surrogate SG to Trop-2 was characterized by surface plasmon resonance (SPR, Table 13) and demonstrated that surrogate SG bound to both mouse and human Trop-2 in the low nanomolar range (1 .37 nM to mTrop-2 and 1.1 nM to hTrop-2).
  • a mouse isotype antibody control (mMAB1129/mG2a/mKap) was used as control ADC and coupled to CL2A linker/SN-38 payload in the same condition that Rab64 mAb.
  • Table 14 summarizes the ADC constructs.
  • the purpose of this study is to determine the in vivo efficacy of murinized SG combined to anti-mouse PD1 and/or quemliclustat in an immunocompetent mouse model of orthotopic breast cancer expressing human Trop-2.
  • mice were acquired from Biocytogen. Female (5-7 weeks old) are injected into the left fourth mammary fat pad with huTrop-2 transduced EO771 tumor cells. When the tumor volume reaches a mean volume of 100 mm 3 , mice are randomized into 12 groups (10 mice per group) and treated for four weeks with
  • Murinized SG ADC was produced as described in Example 3.
  • the anti-mouse PD1 antibody RMP1.14 mlgGl D265A is a commercially available antibody that can be purchased, for example, from Invivogen (cat. code mpdl-mabl5-l).
  • Palpable tumors are measured with calipers. Mice are sacrificed when tumor sizes reached -2000 mm 3 . It is contemplated that the group treated with triple combinations (group 8) will survive the longest due to the combination of the anti-tumor effect of murinized SG to the activation of the tumor infiltrate via IO drugs.

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Abstract

The present disclosure relates to methods of treating, mitigating, or preventing or delaying the recurrence or metastasis of, a Trop-2 expressing cancer (e.g., metastatic castrate resistant prostate cancer, non-small cell lung cancer) in a subject by administering an effective amount of: (a) an anti-Trop-2 antibody drug conjugate (ADC) (e.g., sacituzumab govitecan); and (b) an adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat) to the subject. The present disclosure further relates to methods of treating, mitigating, or preventing or delaying the recurrence or metastasis of a tumor antigen (TA) expressing cancer in a subject by administering an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); and b) an adenosine pathway inhibitor.

Description

COMBINATION THERAPY FOR TREATING TROP-2 EXPRESSING CANCERS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application No. 63/330,700, filed April 13, 2022, United States Provisional Application No. 63/370,228, filed August 2, 2022, and United States Provisional Application No. 63/377,918, filed September 30, 2022, each of which is hereby incorporated by reference in its entirety.
FIELD
[0002] The present disclosure relates to methods of treating, mitigating, or preventing or delaying the recurrence or metastasis of a Trop-2 expressing cancer (c.g., metastatic castrate resistant prostate cancer, non-small cell lung cancer) in a subject by administering an effective amount of: (a) an anti-Trop-2 antibody drug conjugate (ADC) (e.g., sacituzumab govitecan); and (b) an adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat) to the subject. The present disclosure further relates to methods of treating, mitigating, or preventing or delaying the recurrence or metastasis of a tumor antigen (TA) expressing cancer in a subject by administering an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (Topi ADC); and b) an adenosine pathway inhibitor.
BACKGROUND
[0003] Anti-Trop-2 antibody drug conjugates, such as sacituzumab govitecan and datopotamab deruxtecan, are under clinical investigation for the treatment of a variety of Trop-2 expressing cancers. While evidence of clinical efficacy has been obtained in a monotherapy setting, further therapeutic benefits for patients are desired.
[0004] Trop-2 expression has been reported for a variety of epithelial cancers, including breast, bladder, lung, colorectal and prostate cancers. Prostate cancer is the most commonly diagnosed cancer and the second most frequent cause of cancer-related mortality among men in the United States (US). An estimated 174,650 new cases were diagnosed in 2019 with 31,620 related deaths (National Cancer Institute. SEER Cancer Stat Facts: Prostate Cancer. Accessed 25 February 2020 at seer.cancer.gov/statfacts/html/prost.html.). Adenocarcinoma comprises 95% of prostatic carcinomas (Lie AK. Histology of prostate cancer. Oncolex Oncology Encyclopedia. Accessed 25 February 2020 at oncolex.org/Prostate-cancer/Background/Histology.). Most cases (90%) are diagnosed at a local or regional stage for which treatment options include active surveillance, surgery, or radiation. The 5-ycar relative survival is 98% across all stages but is 30% for disease diagnosed at an advanced stage.
[0005] Metastatic or advanced prostate cancer has a more complex treatment algorithm. Patients with locally advanced disease initially receive androgen ablation with radiation or prostatectomy, whereas first-line therapy in the metastatic setting is androgen ablation plus systemic treatment (e.g., second-generation hormonal therapy or docetaxel-based chemotherapy). Disease progression in the context of androgen deprivation is known as castrate resistant prostate cancer (CRPC). Specifically, the Prostate Cancer Working Group 2 (PCWG2) defined CRPC as a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing local or metastatic disease, and/or the appearance of new metastases in the setting of castrate levels of serum testosterone (< 50 ng/dL; Scher HI, et al. J Clin Oncol. (2008) 26(7): 1148- 1159.).
[0006] Prognosis for CRPC is associated with several factors, including performance status, presence of bone pain, extent of disease on bone scan, and serum alkaline phosphatase (ALP) levels. Bone metastases will occur in approximately 80% of men with CRPC and can produce significant morbidity, including pain, pathologic fractures, spinal cord compression, and bone marrow failure. Paraneoplastic effects are also common, including anemia, weight loss, fatigue, hypercoagulability, and increased susceptibility to infection (Saad F and Hotte S. Can Urol Assoc J. (2010) 4(6):380-384).
[0007] During the last decade, 6 new agents have received US Food and Drug Administration (FDA) approval for the treatment of metastatic CRPC (mCRPC) resulting in significant improvements in overall survival (OS; Fay AP and Antonarakis ES. Ann Transl Med. (2019) 7(Suppl 1):S7.). However, the clinical benefit with each individual agent is rarely durable with a median overall survival (OS) of approximately 2 to 3 years. Due to the complexity of the disease and the challenges of successful treatment, mCRPC continues to be an area of high unmet medical need where novel therapeutic development is being actively explored.
[0008] Lung cancer is the leading cause of cancer-related mortality worldwide. It was estimated that in 2020, there were over 2 million new cases of lung cancer and approximately 1.8 million deaths worldwide. In the United States (US) in 2021, it is estimated that there will be over 235,000 new cases of lung cancer and over 131,000 deaths. Approximately 80% to 85% of all lung cancers are non-small cell lung cancer (NSCLC) (Ettinger et al. J Natl Compr Cane Netw (2019); 17(12): 1464-72) and more than half of these arc identified at an advanced stage (Siegel ct al. CA Cancer J Clin (2019);69 (l):7-34).
[0009] Several genomic alterations have been identified in NSCLC that have an impact on therapy selection and molecular testing is part of the standard of care in the evaluation of NSCLC. Among these, epidermal growth factor receptor (EGFR) gene mutations (10% to 50% of NSCLC mutations) and anaplastic lymphoma kinase (ALK) gene rearrangements (5%) are most common and are associated with response to EGFR and ALK tyrosine kinase inhibitors, which are widely approved and in clinical use as first-line agents in these subtypes. Other genomic alterations such as ROS proto-oncogene 1 (ROS1 ) gene rearrangements, proto-oncogene B-raf (BRAF) point mutations, MET exon 14 skipping, RET alterations, and neurotrophic tyrosine receptor kinase (NTRK) mutations occur more rarely but have approved therapies targeting such alterations. Unfortunately, only a minority of new cases of NSCLC harbor actionable genomic alterations although the list of actionable genomic alterations being identified is growing.
[0010] Recent advances with immune checkpoint inhibitor (CPI) therapy have dramatically improved the prognosis of advanced lung cancer and these immune CPI therapies, as monotherapy (programmed cell death ligand 1 [PD-L1] tumor proportion score [TPS] > 1%) or in combination with platinum-doublet chemotherapy (regardless of PD-L1 expression), are mainly used in the frontline metastatic setting based on results of KEYNOTE-024, KEYNOTE-042, KEYNOTE- 189, and KEYNOTE-407 and similar studies for participants who do not have actionable genomic alterations. Chemotherapy /immunotherapy regimens such as pembrolizumab/(carboplatin or cisplatin)/pemetrexed are recommended for patients with non-squamous NSCLC regardless of PD-L1 expression. For patients with metastatic squamous cell NSCLC, chemotherapy/immunotherapy regimens such as pembrolizumab/carboplatin/ (paclitaxel or albumin-bound paclitaxel) are recommended (Ettinger et al. J Natl Compr Cane Netw (2019);17 (12): 1464-72).
[0011] After failure of immune checkpoint inhibitor therapy and platinum-based chemotherapy, there are limited treatment options for most patients. According to National Comprehensive Cancer Network guidelines, the use of single-agent chemotherapy (including taxanes) is the standard of care for patients with recurrent or metastatic NSCLC after failure of platinum-based therapy and/or immune checkpoint therapy regardless of presence of genomic alterations and PD- L1 status (Ettinger ct al. J Natl Compr Cane Netw (2019);17 (12):1464-72). The main options for single-agent chemotherapy in this setting generally include docetaxel (with or without ramucirumab) and pemetrexed (for non-squamous tumors, if not previously used). In a study of docetaxel versus best supportive care in relapsed NSCLC, the median progression-free survival (PFS) was approximately 3 months with a median overall survival (OS) of approximately 6 to 8 months (Shepherd et al. J Clin Oncol (2000);18 (10):2095-103). These numbers have been borne out in more contemporaneous studies with docetaxel following failure of platinum-based regimens in NSCLC (Hom et al. J Clin Oncol (2017);35 (35):3924-33; Mazieres et al. Journal of Thoracic Oncology (2021); 16 (1): 140-50). Although docetaxel is considered standard of care in patients failing platinum-based regimens and checkpoint inhibitors, novel agents remain a significant unmet medical need in subsequent treatment of advanced or metastatic NSCLC.
[0012] Immune checkpoint inhibitors have reinvigorated clinical development interest in anticancer immunotherapy. The latter relies on therapeutic modulation of the tumor microenvironment or other aspects of the immune system to overcome mechanisms of immune suppression that a tumor elicits on the host immune system. Despite their proven benefit in numerous tumor types as evidenced by the approvals of nivolumab, pembrolizumab, atezolizumab, and ipilimumab, checkpoint inhibition has not proven effective in the treatment of metastatic prostate cancer where response rates to monotherapy are less than 5% (Antonarakis ES, et al. J Clin Oncol. (2020) 38(5):395-405.).
[0013] Antibody-drug conjugates (ADCs) are a fast-growing drug class in oncology with several different ADCs currently approved as cancer treatments and many more in preclinical and clinical development (e.g., Drago, J.Z. et al., Nat Rev Clin Oncol (2021) 18, 327-344). ADCs are generally composed of monoclonal antibodies linked to cytotoxic drugs (payloads). ADCs are designed to limit the delivery of cytotoxic drugs specifically to cells expressing the target antigen of the respective antibody (e.g., Trop-2, Her-2, Nectin-4) and immediately surrounding tumor tissue (bystander effect). As a result of their tumor targeted delivery of cytotoxic agents ADCs often have much improved therapeutic windows compared to systemically administered cytotoxic agents. Examples of ADCs that have obtained marketing approval by the U.S. Food and Drug Administration (US FDA) include gemtuzumab ozogamicin, brentuximab vedotin, ado- trastuzumab emtansine (T-DM1), inotuzumab ozogamicin, trastuzumab deruxtecan (T-DXd), polatuzumab vcdotin, sacituzumab deruxtecan, enfortumab vedotin, and bclantamab mafodotin.
[0014] The adenosine pathway mediates immunosuppressive effects in the tumor microenvironment (e.g., Allard, B., et al. Nat Rev Clin Oncol (2020) 17, 611-629). Adenosine pathway inhibitors, including various CD39 inhibitors, CD73 inhibitors, and adenosine receptor antagonists, are under clinical investigation as promising agents stimulating anti-cancer immune responses.
[0015] Despite advances in the treatment of cancer, many patients either remain refractory to currently available therapy, or relapse following a response to available therapy, resulting in a need for the development of novel agents and combinations of agents for the treatment of many types cancers, including mCRPC.
SUMMARY
[0016] In one aspect, provided herein are methods of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of, a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor.
[0017] In some embodiment, the methods provided herein are for treating a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor.
[0018] In some embodiments, the anti-Trop-2 ADC comprises a topoisomerase I inhibitor.
[0019] In some embodiments, the topoisomerase I inhibitor is a camptothecin (CPT).
[0020] In some embodiments, the topoisomerase I inhibitor is a topotecan, irinotecan, belotecan or exatecan.
[0021] In some embodiments, the topoisomerase I inhibitor is SN38 or Dxd.
[0022] In some embodiments, the topoisomerase I inhibitor is selected from the group consisting of irinotecan, topetecan, and SN-38.
[0023] In some embodiments, the topoisomerase I inhibitor is SN38. [0024] Tn some embodiments, the anti-Trop-2 ADC has a structural formula of mAb-CL2A-SN- 38, with a structure represented by:
Figure imgf000007_0001
(described, e.g., in U.S. Patent No. 7,999,083).
[0025] In some embodiments, the anti-Trop-2 ADC comprises sacituzumab (hRS7; described, e.g., in W02003074566, Figures 3 and 4).
[0026] In some embodiments, the anti-Trop-2 ADC is selected from the group consisting of sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02 and BAT-8003.
[0027] In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan.
[0028] In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist.
[0029] In some embodiments, the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors. In some embodiments, the plurality of adenosine pathway inhibitors comprises a CD73 inhibitor and an adenosine receptor antagonist. In some embodiments, the CD73 inhibitor is quemliclustat and the adenosine receptor antagonist is etrumadenant.
[0030] In some embodiments, the adenosine pathway inhibitor is an adenosine receptor antagonist.
[0031] In some embodiments, the adenosine pathway inhibitor is imaradenant, NIR178, ID11902, IN-A003, NTI-55, TT-10, TT-228, PBF-1129 (Palobiofarma), TT-702, etrumadenant, INCB 106385, M1069, HM87277, RVU-330, or TT-53.
[0032] In some embodiments, the adenosine pathway inhibitor is a dual antagonist of adenosine A2A receptor (A2AR; ADORA2A) and A2B receptor (A2BR; ADORA2B). [0033] Tn some embodiments, the adenosine pathway inhibitor is etrumadenant (AB928; GS- 0928), taminadcnant, TT-10, TT-4, or M1069.
[0034] In some embodiments, the adenosine pathway inhibitor is etrumadenant.
[0035] In some embodiments, the adenosine pathway inhibitor is a CD73 inhibitor.
[0036] In some embodiments, the CD73 inhibitor is oleclumab, B MS-986179, uliledlimab, AK119, quemliclustat, mupadolimab, HLX23, INCA00186, IB 1325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037.
[0037] In some embodiments, the CD73 inhibitor is quemliclustat (AB680, GS-0680), uliledlimab, mupadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV93O, BMS-986179, or oleclumab.
[0038] In some embodiments, the CD73 inhibitor is quemliclustat.
[0039] In some embodiments, the method further comprises co-administering an additional therapeutic agent or therapeutic modality.
[0040] In some embodiments, the additional therapeutic agent or therapeutic modality comprises one, two, three, or four additional therapeutic agents and/or therapeutic modalities.
[0041] In some embodiments, the additional therapeutic agent comprises an anti-PD-(L)l antibody.
[0042] In some embodiment, the anti-PD-(L)l antibody is pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, or zimberelimab.
[0043] In some embodiments, the anti-PD-(L)l antibody is zimberelimab.
[0044] In some embodiments, the additional therapeutic agent comprises an anti-TIGIT antibody.
[0045] In some embodiments, the anti-TIGIT antibody is tiragolumab, vibostolimab, domvanalimab, AB3O8, AK127, BMS-986207, ralzapastotug, or etigilimab. [0046] Tn some embodiments, the anti-TTGTT antibody is domvanalimab. Tn some embodiments, the anti-TIGIT antibody is ralzapastotug.
[0047] In some embodiments, the additional therapeutic agent comprises an anti-PD-(LI) antibody and an anti-TIGIT antibody.
[0048] In some embodiments, the additional therapeutic agent comprises a) zimberelimab and domvanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vibostolimab, e) pembrolizumab and domvanalimab, f) pembrolizumab and AB308, g) MK- 7684A (pembrolizumab/vibostolimab coformulation), h) durvalumab and domvanalimab, i) zimberelimab and ralzapastotug, or j) pembrolizumab and ralzapastotug.
[0049] In some embodiments, the additional therapeutic agent comprises zimberelimab and domvanalimab.
[0050] In some embodiments, the Trop-2 positive cancer is a solid epithelial cancer.
[0051] In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC), HR+/Her2- breast cancer, HR+/Her2low breast cancer), colorectal cancer, lung cancer, stomach cancer, urinary tract cancer, urothelial cancer, bladder cancer, renal cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer and prostatic cancer. In some embodiments, the breast cancer is triple negative breast cancer (TNBC), HR+/Her2’ breast cancer, or HR+/Her2low breast cancer.
[0052] In some embodiments, the prostatic cancer is castrate-resistant prostate cancer (CRPC).
[0053] In some embodiments, the lung cancer is non-small lung cancer (NSCLC).
[0054] In some embodiments, the lung cancer is (i) squamous NSCLC or (ii) non-squamous NSCLC.
[0055] In some embodiments, the lung cancer is without EGFR, ALK, or other actionable genomic alterations.
[0056] In some embodiments, the Trop-2 positive cancer is (i) unresectable, locally advanced or (ii) metastatic.
[0057] In some embodiments, the cancer has progressed following at least one prior anti-cancer therapy. [0058] Tn some embodiments, the cancer has progressed after prior new hormonal agent treatment (NHA; first- or second-generation non-steroidal antiandrogens, abiratcronc).
[0059] In some embodiments, the cancer has progressed or recurred after platinum-based chemotherapy.
[0060] In some embodiments, the cancer has progressed or recurred after checkpoint inhibitor therapy (CPI) therapy.
[0061] In some embodiments, the cancer has progressed or recurred after platinum-based chemotherapy and anti-PD-(L)l antibody therapy, received either in combination or sequentially in any order.
[0062] In some embodiments, the cancer has progressed or recurred after a tyrosine kinase inhibitor therapy.
[0063] In some embodiments, the subject is treatment naive.
[0064] In some embodiments, the subject has not received a prior therapy selected from the group consisting of a taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.
[0065] In some embodiments, the subject has not received a prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy.
[0066] In some embodiments, the taxane therapy comprises paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel.
[0067] In some embodiments, the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)l antibody.
[0068] In some embodiments, the topoisomerase I inhibitor therapy comprises a topotecan, irinotecan, belotecan or exatecan.
[0069] Tn some embodiments, the anti-Trop-2 ADC and the adenosine pathway inhibitor are coadministered concurrently.
[0070] In some embodiments, the anti-Trop-2 ADC and the adenosine pathway inhibitor are coadministered sequentially. [0071] Tn some embodiments, the subject is human.
[0072] In some embodiments, the anti-Trop-2 ADC is administered at one or more doses in the range of 8 mg/kg to 10 mg/kg.
[0073] In some embodiments, the anti-Trop2 ADC is administered at one or more doses of 8 mg/kg or 10 mg/kg.
[0074] In some embodiments, the anti-Trop2 ADC is administered at one or more doses of 10 mg/kg.
[0075] In some embodiments, the anti-Trop-2 ADC is administered intravenously.
[0076] In some embodiments, the anti-Trop-2 ADC is administered on days 1 and 8 of a 21-day cycle.
[0077] In some embodiments, the adenosine pathway inhibitor is administered at one or more doses of 75 mg or 150 mg.
[0078] In some embodiments, the adenosine pathway inhibitor is administered at one or more doses of 150 mg.
[0079] In some embodiments, the adenosine pathway inhibitor is administered orally (PO).
[0080] In some embodiments, the adenosine pathway inhibitor is administered once daily (QD).
[0081] In some embodiments, the anti-PD(L)l antibody is administered at one or more doses of 360 mg.
[0082] In some embodiments, the anti-PD(L)l antibody is administered intravenously (IV).
[0083] In some embodiments, the anti-PD(L)l antibody is administered once every three weeks (Q3W).
[0084] In some embodiment, sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on day 1 and day 8 of a 21 -day treatment cycle, etrumadenant is administered orally (PO) once a day (QD) at a dose of 150 mg on each day of the 21-day treatment cycle, and, optionally, zimberelimab is administered intravenously (IV) on day 1 of the 21-day treatment cycle (Q3W). [0085] In some embodiments, an anti-cancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof. In some embodiments, tumor response or progression is determined according to RECIST version 1.1.
[0086] In some embodiments, provided herein is a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of castrate-resistant prostate cancer (CRPC) comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; and b) etrumadenant. Tn some embodiments, provided herein is a method of treating metastatic castrate-resistant prostate cancer (mCRPC) comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; and b) etrumadenant. In some embodiments, the method further comprises co-administering an anti-PD-(L)l antibody to the human patient. In some embodiments, the anti-PD-(L)l antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the method further comprises co-administering zimberelimab to the human patient. In some embodiments, the human mCRPC patient has previously progressed on ADT. In some embodiments, the human mCRPC patient has previously progressed on NHA. In some embodiments, the human mCRPC patient is CPI and taxane naive. In some embodiments, the human mCRPC patient has RECIST 1.1 measurable or non-measurable disease.
[0087] In some embodiments, the CRPC is metastatic CRPC (mCRPC).
[0088] In some embodiments, the CRPC is resistant or refractory to one or more anti-cancer therapies.
[0089] In some embodiments, the CRPC has progressed following prior NHA therapy (first- or second-generation non-steroidal antiandrogens, abiraterone). [0090] Tn some embodiments, the human patient has not received a prior therapy selected from taxanc therapy (taxanc naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.
[0091] In some embodiments, the human patient has not received a prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy.
[0092] In some embodiments, the taxane therapy comprises paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel.
[0093] In some embodiments, the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)! antibody.
[0094] In some embodiments, the topoisomerase I inhibitor therapy comprises a topotecan, irinotecan, belotecan or exatecan.
[0095] In some embodiments, provided herein are methods of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of non-small cell lung cancer (NSCLC) comprising co-administering to a human patient an effective amount of: a) sacituzumab govitecan; b) etrumadenant; and c) an anti-PD-(L)l antibody. In some embodiments, the anti-PD-(L)l antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)l antibody is zimberelimab. In some embodiments, the NSCLC has progressed or recurred after platinum-based chemotherapy. In some embodiments, the NSCLC has progressed or recurred after checkpoint inhibitor therapy (CPI) therapy. In some embodiments, the NSCLC has progressed or recurred after platinum based chemotherapy and anti-PD-(L)l antibody therapy, received either in combination or sequentially in any order. In some embodiments, the NSCLC has progressed or recurred after a tyrosine kinase inhibitor therapy. In some embodiments, the NSCLC is (i) unresectable, locally advanced or (ii) metastatic.
[0096] In some embodiments, sacituzumab govitecan is administered intravenously (IV) at a dose of 8 mg/kg or 10 mg/kg on day 1 and day 8 of a 21 -day treatment cycle and etrumadenant is administered orally (PO) once a day (QD) at a dose of 75 mg or 150 mg on each day of the 21 -day treatment cycle.
[0097] In some embodiments, sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on day 1 and day 8 of a 21-day treatment cycle and etrumadenant is administered orally (PO) once a day (QD) at a dose of 150 mg on each day of the 21-day treatment cycle.
[0098] In some embodiments, zimberelimab is administered intravenously (IV) on day 1 of the 21-day treatment cycle (Q3W).
[0099] In some embodiments, an anti-cancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or combinations thereof. In some embodiments, an anti-cancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, or change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.
[0100] In some embodiments of the methods provided herein, an anti-CD47 antibody (e.g., magrolimab) is not co-administered to the subject or human patient.
[0101] In some embodiments of the methods provided herein, an MCL1 inhibitor (e.g., GS-9716) is not co-administered to the subject or human patient.
[0102] In some embodiments of the methods provided herein, a FLT3 agonist (e.g., GS-3583, CDX-301) is not administered to the subject or human patient.
[0103] In another aspect, provided herein is a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of, a tumor antigen positive (TA+) cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen (TA) targeted ADC comprising a topoisomerase I inhibitor (Topi ADC); b) an adenosine pathway inhibitor; and c) optionally an anti-PD(L)l antibody.
[0104] In another aspect, provided herein is an anti-Trop-2 ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)l antibody in a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of Trop-2 positive cancers, wherein the method comprises administering the anti-Trop-2 ADC, adenosine pathway inhibitor, and optionally the additional anti-PD(L) 1 antibody to a subject.
[0105] In another aspect, provided herein is a Topi ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)l antibody in a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of tumor antigen positive (TA+) cancers, wherein the method comprises administering the Topi ADC, adenosine pathway inhibitor, and optionally the anti-PD(L)l antibody to a subject.
DETAILED DESCRIPTION
[0106] Provided herein arc combination therapies for treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of Trop-2 positive (Trop-2+) cancers by co-administering effective amounts of a) an anti-Trop-2 antibody-drug conjugate (anti-Trop-2 ADC) and b) an adenosine pathway inhibitor to a subject. Also provided herein are combination therapies for treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of a tumor antigen positive (TA+) cancer by co-administering an effective amount of a) a tumor antigen (TA) targeted ADC comprising a topoisomerase I inhibitor (Topi ADC) and b) an effective amount of an adenosine pathway inhibitor to a subject. In some embodiments, the combination therapies provided herein further comprise co-administering an additional therapeutic agent, such as a checkpoint inhibitor, or an additional therapeutic modality (e.g., surgery, radiation). In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan. In some embodiments, the Topi ADC is trastuzumab-deruxtecan (T-DXd). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quemliclustat, oleclumab), or an adenosine receptor antagonist (e.g., etrumadenant, imaradenant, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)l antibody (e.g., zimberelimab, pembrolizumab, nivolumab, atezolizumab, durvalumab). In some embodiments, the Trop-2 positive cancer is castrate-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).
[0107] In another aspect provided herein is an anti-Trop-2 ADC (e.g., sacituzumab govitecan) for use in combination with an adenosine pathway inhibitor (e.g., etrumadenant) and optionally an additional therapeutic agent, such as a checkpoint inhibitor (e.g., anti-PD(L)l antibody), or an additional therapeutic modality (e.g., surgery, radiation) in a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of Trop-2 positive cancers, wherein the method comprises administering the anti-Trop-2 ADC, adenosine pathway inhibitor, and optionally the additional therapeutic agent or additional therapeutic modality to a subject (e.g., a human cancer patient). In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan. In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quemliclustat, oleclumab), or an adenosine receptor antagonist (e.g., etrumadenant, imaradenant, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)l antibody (e.g., zimberelimab, pembrolizumab, nivolumab, atezolizumab, durvalumab). In some embodiments, the Trop-2 positive cancer is castrate-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).
[0108] In another aspect, provided herein is a Topi ADC for use in combination with an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, adenosine receptor antagonist) and optionally an additional therapeutic agent, such as a checkpoint inhibitor (e.g., anti-PD(L)l antibody), or an additional therapeutic modality (e.g., surgery, radiation) in a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of TA positive cancers, wherein the method comprises administering the Topi ADC, adenosine pathway inhibitor, and optionally the additional therapeutic agent or additional therapeutic modality to a subject (e.g., a human cancer patient). In some embodiments, the Topi ADC is trastuzumab-deruxtecan (T-DXd). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quemliclustat, oleclumab), or an adenosine receptor antagonist (e.g., etrumadenant, imaradenant, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)l antibody (e.g., zimberelimab, pembrolizumab, nivolumab, atezolizumab, durvalumab). In some embodiments, the Trop-2 positive cancer is castrate-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).
[0109] This disclosure is based, at least in part, on the realization that a combination therapy comprising co-administration of a) an anti-Trop2 ADC or a Topi ADC and b) an adenosine pathway inhibitor can have improved anticancer effects compared to single-agent therapies with one of the combined agents a) and b). Improved anti-cancer effects can include, for example, improved overall response rates (ORR), improved partial response rates (PR), improved complete response rates (CR), improved durations of response (DOR), improved overall survival (OS), improved progression free survival (PFS), improved quality of life (QoL) indicators, or the like. The combination therapies described herein generally have tolerable safety profiles, c.g., as determined by the incidence and/or severity of observed adverse events (AEs) or serious adverse events (SAEs). In some embodiments, the combination therapies described herein have improved safety profiles, e.g., as compared to monotherapies involving the co-administered agents, or relative to a standard of care for a given indication (e.g., a chemotherapy regimen of physician’s choice).
Definitions
[0110] As used herein, the term “antibody” refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen (e.g., a heavy chain variable domain, a light chain variable domain, and/or one or more CDRs sufficient to confer specific binding to a particular target antigen). Thus, the term antibody includes, for example, and without limitation, human antibodies, non-human antibodies, antibody fragments, and antigen-binding agents that include antibody fragments, inclusive of synthetic, engineered, and modified forms thereof. The term antibody includes, by way of example, both naturally occurring and non-naturally occurring antibodies. In general, an antibody may comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding molecule thereof. Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, CHI, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one constant domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies (Abs) may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. Naturally -produced antibodies are glycosylated, typically on the CH2 domain. Examples of antibodies include monoclonal antibodies, monospecific antibodies, polyclonal antibodies, multispecific antibodies (including bispecific antibodies), engineered antibodies, rccombinantly produced antibodies, wholly synthetic antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain- antibody heavy chain pairs, intrabodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelized antibodies, affybodies, Fab fragments, Fab' fragments, F(ab’)2 fragments, Fd' fragments, Fd fragments, isolated CDRs, single chain Fvs, polypeptide-Fc fusions, single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; disulfide- linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimetics”), single chain or Tandem diabodies (TandAb®), Anticalins®, Nanobodies®, minibodies, BiTE®s, ankyrin repeat proteins or DARPINs®, Avimers®, DARTs, TCR-like antibodies, Adnectins®, Affilins®, Trans-bodies®, Affibodies®, TrimerX®, MicroProteins, Fynomers®, Centyrins®, KALBITOR®s, and antigen-binding fragments of any of the above.
[0111] As used herein, the term “antibody-drug conjugate” generally refers to a compound comprising an antibody targeting a tumor antigen and an anticancer agent payload, optionally connected by a linker. In some embodiments, the tumor antigen is tumor- associated calcium signal transducer 2 (Trop-2; NCBI Gene ID: 4070). In some embodiments, the tumor antigen targeted antibody is an anti-Trop-2 antibody (e.g., sacituzumab or datopotamab). In some embodiments, the payload is a topoisomerase I inhibitor (e.g., SN38 or Dxd). Many ADC linker chemistries are known to a skilled artisan and referenced herein (e.g., CL2A).
[0112] As used herein, the term “topoisomerase I inhibitor” refers to small molecule compounds capable of inhibiting the activity of a DNA topoisomerase type I enzyme. Type I topoisomerases can catalyze changes in DNA topology via transient single-stranded breaks in DNA. Type I topoisomerases can be further classified as Type 1 A and a Type IB subtypes. A description of type I topoisomerases can be found, for example, in Baker et al. (2009) Nucleic Acids Res 37(3), 693- 701. Topoisomerase inhibitors that can be used as payloads in the ADCs described herein include camptothecin (CPT) and non-camptothecin based inhibitors. Useful camptothecins include, for example, topotecan, irinotecan, belotecan, exatecan, and derivatives thereof. Useful non- camptothccins include, for example, indcnosinoquinolincs (c.g., indcno[l,2-c]isoquinolinc, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)), phenanthridines (e.g., topovale (ARC- 111), and indolocarbazoles (e.g., BE-13793C). In some embodiments, the topoisomerase I inhibitor is a camptothecin (e.g., an irinotecan, topotecan, belotecan, or exatecan derivative, such as SN38 or Dxd). In some embodiments, the topoisomerase I inhibitor is SN38. In some embodiments, the topoisomerase I inhibitor is Dxd.
[0113] As used herein, the term “anti-PD(L)l antibody” refers to antibodies that a) bind to programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 5133) or programmed deathligand 1 (PD-L1 , CD274; NCBI Gene ID: 29126); and b) inhibit the PD-1/PD-L1 interaction and PD-1/PD-L1 pathway. The PD-1/PD-L1 pathway and its role in cancer immunotherapy is described, for example, in Salmaninejad etal, J. Cell Physiol (2019) 234 (10): 16824-16837. Anti- PD(L)1 antibodies that can be used in the methods provided herein include, for example, pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD(L)l antibody is zimberelimab.
[0114] As used herein, the terms “effective amount” or “therapeutically effective amount” refer to that amount of a therapeutic agent administered in the methods provided herein (e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor) that, when administered alone or in combination with another therapeutic agent to a cell, tissue, or subject is sufficient to effect treatment or a beneficial result in the subject. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art. An effective amount further refers to that amount of the therapeutic agent, which when used in the context of the combination therapies provided herein, is sufficient to treat, prevent, alleviate, ameliorate or mitigate a disease condition, or delay or slow the progression of a disease, and that amount sufficient to effect an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual therapeutic agent administered alone, an effective amount refers to that active ingredient alone. When applied to a combination, a therapeutically effective amount refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. In some embodiments, an effective amount or therapeutically effective amount of a therapeutic agent (e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor) administered to a subject in the methods provided herein with one or more additional therapeutic agents, as described herein, can (i) reduce the number of diseased cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent, and preferably stop the diseased cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of a tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with cancer. In various embodiments, the amount is sufficient to ameliorate, palliate, lessen, and/or delay one or more of symptoms of cancer.
[0115] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence. In some embodiments, the methods provided herein refer to the treatment of a subject having cancer (e.g., a human cancer patient). In some embodiments, treating a subject having cancer (e.g., a human cancer patient) comprises inhibiting cancer or cancer cell proliferation in the treated subject. In some embodiments, treating a human cancer patient using the methods provided herein results in the observation of anti-tumor effects or anti-cancer effects in the treated patient.
[0116] As used herein, the terms “inhibition of cancer” and “inhibition of cancer cell proliferation” refer to the inhibition of the growth, division, maturation or viability of cancer cells, and/or causing the death of cancer cells, individually or in aggregate with other cancer cells, by cytotoxicity, nutrient depletion, or the induction of apoptosis. [0117] As used herein, the terms “anti-tumor effect,” “anti-cancer effect,” or “anti-cancer efficacy” refer to a biological effect that can present as a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, a decrease in the number of metastases, an increase in overall or progression-free survival, an increase in life expectancy, or amelioration of various physiological symptoms associated with the tumor. In some embodiments, anti-cancer effects are measured using one or more of the endpoint criteria applied in the clinical studies described herein (e.g., primary, secondary, or exploratory endpoints). Exemplary clinical endpoint criteria that can be used to measure anti-cancer effects in connection with the methods provided herein include objective response rate (ORR), complete response (CR) rate, partial response (PR) rate, disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), biomarker-based signals, e.g., of intratumoral immune activation or induction of cancer cell death (e.g., tumor tissue or blood based biomarkers), patient quality of life (QoL) indicators (e.g., based on patient surveys), and others. In some embodiments, anti-tumor effects (e.g., tumor responses or progression) are determined according to RECIST version 1.1 (Eisenhauer et al. Eur J Cancer (2009);45 (2):228-47). Anti-cancer effects can be observed using any diagnostic methods known to a skilled artisan, such as computed tomography (CT), magnetic resonance imaging (MRI), radiography, or the like.
[0118] As used herein, an “increased” or “enhanced” amount is typically a “statistically significant” amount (e.g., with respect to tumor size, cancer cell proliferation or growth), and may include an increase that is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50 or more times (e.g., 100, 500, 1000 times) (including all integers and decimal points in between and above 1, e.g., 2.1, 2.2, 2.3, 2.4, etc.) an amount or level described herein. It may also include an increase of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 500%, or at least 1000% of an amount or level described herein.
[0119] As used herein, a “decreased” or “reduced” or “lesser” amount (e.g., with respect to tumor size, cancer cell proliferation or growth) refers to a decrease that is about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6
1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50 or more times (e.g., 100, 500, 1000 times) (including all integers and decimal points in between and above 1, e.g., 1.5, 1.6,
1.7. 1.8, etc.) an amount or level described herein. It may also include a decrease of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, at least 100%, at least 150%, at least 200%, at least 500%, or at least 1000% of an amount or level described herein.
[0120] As used herein, the term “adverse event” (AE) refers to any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign (including clinically significant abnormal laboratory findings), symptom, or disease temporally associated with the use of a study drug, whether or not the AE is considered related to the study drug. Adverse events may also include pretreatment or posttreatment complications that occur as a result of protocol-specified procedures or special situations. In some embodiments, preexisting events that increase in severity or change in nature after study drug initiation or during or as a consequence of participation in the clinical study are also considered AEs.
[0121] As used herein, the term “serious adverse event” (SAE) refers to a) death; b) a lifethreatening situation; c) in-participant hospitalization or prologation of existing hospitalization; d) persistent or significant disability or incapacity; e) a congenital anomaly or birth defect; or f) a medically important event or reaction as determined by an attending physician. Examples of medically important events include intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; and development of drug dependency or drug abuse.
[0122] As used herein, the terms “tumor antigen expressing cancer” or “tumor antigen positive cancer” are used interchangeably to refer to cancers having detectable levels of tumor antigen (TA) expression. In some embodiments, the tumor antigen is Trop-2. Tumor antigen expression in a cancer tissue or cancer cell can be detected in a sample from a subject having cancer (e.g., a human cancer patient) by any method known to a skilled artisan, e.g., as a protein, mRNA, or cell-surface expression level. For example, tumor antigen expression can be determined by methods such as immunohistochemistry (IHC), western blot, fluorescence in-situ hybridization (FISH), polymerase chain reaction (PCR), next-generation exome sequencing, or fluorescence associated cell sorting (FACS). As used herein, to be considered TA positive (e.g., Trop-2 positive) it is not required that every cell in a tumor or tumor sample have detectable levels of tumor antigen expression. In some embodiments in the “TA expressing cancer” or “TA positive cancer,” less than 99%, less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of cells in a tumor or tumor sample have detectable levels of tumor antigen expression. In some embodiments in the “TA expressing cancer” or “TA positive cancer,” 99% or more, 95% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more of cells in a tumor or tumor sample have detectable levels of tumor antigen expression. In some embodiments, “TA expressing cancer” or “TA positive cancer” (e.g., Trop-2 positive cancer) refers to a cancer for which treatment with a certain anti-Trop-2 ADC or Topi ADC is indicated either as a single-agent therapy or in a combination. TA positive cancer indications of anti-Trop-2 ADCs or Topi ADCs that have received a marketing authorization from a regulatory health agency (e.g., FDA, EMA) are listed, for example, on agency approved drug product labels. In some embodiments, a TA positive (e.g., Trop-2+) cancer, as used herein, is a cancer in which an anti-Trop-2 ADC or Topi ADC has demonstrated an anti-cancer effect that is attributable to the anti-Trop-2 ADC or Topi ADC. Such anti-cancer effects can be demonstrated in a preclinical model (e.g., a mouse xenograft or syngeneic cancer model) or in a clinical trial conducted with human cancer patients. In some embodiments, the TA expressing cancer or TA positive cancer does not express detectable levels of Trop-2, e.g., as determined by IHC and/or FISH analysis.
[0123] As used herein, the term “tumor antigen targeted antibody-drug conjugate (ADC)” generally refers to an ADC comprising a tumor antigen binding antibody. Such TA binding antibodies can generally direct an ADC to TA expressing cancer cells in a tumor tissue. In some embodiments, the TA binding antibody is a neutralizing or blocking antibody (competing with the binding of another binding partner to the TA). In some embodiments, the TA binding antibody can modulate TA associated molecular or cellular signaling events. In some embodiments, the TA binding antibody has antagonistic or agonistic activity relative to the TA. TA targeted ADCs that can be used in the methods provided herein include, without limitation, gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine (T-DM1), inotuzumab ozogamicin, trastuzumab deruxtecan (T-DXD), datopotamab deruxtecan (DATO-DXD), polatuzumab vedotin, sacituzumab govitecan, labetuzumab govitecan, enfortumab vedotin, and belantamab mafodotin. In some embodiments, the TA targeted ADC does not bind to Trop-2.
List of Abbreviations and Acronyms
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Antibody-Drug-Conjugates (ADCs )
[0124] The treatment methods provided herein comprise co-administering an antibody-drug- conjugate (ADC) to a subject, such as a human cancer patient. In some embodiments, the ADC comprises an anti-Trop-2 antibody, an anti-cancer agent payload, and an optional linker connecting the anti-Trop-2 antibody and payload (anti-Trop-2 ADC). In some embodiments, the anti-cancer agent payload in the anti-Trop-2 ADC is a topoisomerase I inhibitor (e.g., SN38, Dxd). In some embodiments, the anti-cancer agent payload in the anti-Trop-2 ADC does not include a topoisomerase I inhibitor. In some embodiments, the ADC comprises a tumor antigen (TA) targeted antibody, a topoisomerase I inhibitor payload, and an optional linker connecting the TA targeted antibody and payload (Topi ADC). In some embodiments, the TA targeted antibody in the Topi ADC is an anti-Trop-2 antibody. In some embodiments, the TA targeted antibody in the TropI ADC does not include an anti-Trop-2 antibody.
[0125] ADCs that can be used in the methods provided herein can comprise antibodies or antigen- binding fragments thereof of any format. For example, the ADC can include, without limitation, a monospecific or multispecific (e.g., bispecific, trispecific) antibody, or an antigenbinding fragment thereof, in any format, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, or Fab derivative. In some embodiments, the ADC comprises a non-immunoglobulin antibody mimetic (e.g., including adnectin, affibody, affilin, affimer, affitin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein (DARPin®), fynomer, knottin, Kunitz domain peptide, monobody, and nanoCLAMPs).
[0126] In some embodiments, the ADC antibody is a blocking antibody. In some embodiments, the ADC antibody is a neutralizing antibody. In some embodiments, the ADC antibody is an agonistic or activating antibody. Tn some embodiments, the ADC antibody is an antagonistic or inhibitory antibody.
[0127] In some embodiments, the ADC comprises an IgG antibody or antigen-binding fragment thereof. The IgG antibody or antigen-binding fragment thereof can be of various isotypes, such as IgGl, IgG2, IgG3 or IgG4. In some embodiments, the ADC antibody comprises human IgGl hinge and constant region sequences. The ADC antibody can be a chimeric human-mouse, a chimeric human-primate, a humanized (human framework and murine hypervariable (CDR) regions), or a fully human antibody, as well as a variation thereof. In some embodiments, the ADC antibody is a half-IgG4 antibody (referred to as “unibody”), as described, e.g., by van der Neut Kolfschoten et al. (Science 2007; 317:1554-1557). Tn some embodiments, the ADC antibody or antigen-binding fragment thereof is designed or selected to comprise human constant region sequences that belong to specific allotypes, which may result in reduced immunogenicity when the antibody or ADC is administered to a human subject. In some embodiments, the ADC antibody or antigen-binding fragment thereof is of a non-Glml allotype (nGlml), such as Glm3, Glm3,l, Glm3,2 or Glm3,l,2. In some embodiments, the allotype is selected from the group consisting of the nGlml, Glm3, nGlml, 2 and Km3 allotypes.
Anti-TROP-2 ADCs
[0128] In some embodiments, the ADCs that can be used in the methods provided herein comprise an anti-Trop-2 antibody, an anti-cancer agent payload, and an optional linker connecting the anti-Trop-2 antibody and payload (Anti-Trop-2 ADC). In some embodiments, the pay load is a topoisomerase I inhibitor. In some embodiments, the payload does not include a toposisomerase I inhibitor.
[0129] Examples of anti-Trop-2 antibodies that can be used in anti-Trop-2 ADCs to perform the methods provided herein include, but are not limited to, those described in W02020016662 (Abmart), W02020249063 (Bio-Thera Solutions), US20190048095 (Bio-Thera Solutions), WO2013077458 (LivTech/Chiome), EP20110783675 (Chiome), W02015098099 (Daiichi Sankyo), WG2017002776 (Daiichi Sankyo), W02020130125 (Daiichi Sankyo), W02020240467 (Daiichi Sankyo), US2021093730 (Daiichi Sankyo), US9850312 (Daiichi Sankyo), CN112321715 (Biosion), US2006193865 (Immunomedics/Gilead), WO2011068845 (Immunomedic s/Gilead), US2016296633 (Immunomedics/Gilead), US2017021017 (Tmmunomedics/Gilead), US2017209594 (Tmmunomedics/Gilead), US2017274093
(Immunomcdic s/ Gilead) , US2018110772 (Immunomcdic s/Gilcad) , US 2018185351
(Immunomedics/Gilead) , US2018271992 (Tmmunomedics/Gilead), W 02018217227
(Immunomedic s/ Gilead) , US 2019248917 (Immunomedic s/Gilead), CN 111534585
(Immunomedic s/ Gilead) , US2021093730 (Immunomedic s/Gilead) , U S 2021069343
(Immunomedic s/ Gilead) , US8435539 (Immunomedics/Gilead), US8435529
(Immunomedic s/Gilead), US9492566 (Immunomedic s/Gilead), W02003074566 (Gilead),
WO2020257648 (Gilead), US2013039861 (Gilead), WO2014163684 (Gilead), US9427464 (LivTech/Chiome), US10501555 (Abruzzo Theranostic/Oncoxx), WO2018036428 (Sichuan Kelun Pharma), WO2013068946 (Pfizer), W02007095749 (Roche), and W02020094670 (SynAffix).
[0130] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises an antibody selected from sacituzumab (hRS7), datopotamab (hTINA HILI), and a Trop-2 binding fragment thereof. In some embodiments, the anti-Trop-2 ADC is sacituzumab (hRS7). In some embodiments, the anti-Trop-2 antibody is datopotamab (hTINA HILI).
[0131] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises a VH-CDR1, a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2 and a VL-CDR3 selected from one of Tables 1 to 4. In some embodiments, the anti-Trop-2 ADC comprises the following VH- CDR1 , a VH-CDR2, a VH-CDR3, a VL-CDR1 , a VL-CDR2 and a VL-CDR3 amino acid sequences (according to Kabat), respectively:
• SEQ ID NOs: 1, 2, 3, 4, 5, and 6, or
• SEQ ID NOs: 7, 8, 9, 10, 11, and 12.
[0132] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprise variable domains (VH and VL) selected from Table 5. In some embodiments, the anti-Trop-2 ADC comprises the following VH and VL amino acid sequences, respectively:
• SEQ ID NOs: 49 and 50, or
• SEQ ID NOs: 51 and 52.
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000029_0003
Figure imgf000030_0001
[0133] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises an anti-Trop-2 antibody, an anti-cancer agent payload, and an optional linker connecting antibody and pay load. In some embodiments, the linker is non-cleavable (e.g., a maleimidocaproyl or maleimidomethyl cyclohexane- 1 -carboxylate linker). In some embodiments, the linker is cleavable. In some embodiments, the linker is acid cleavable (e.g., a hydrazone linker). In some embodiments, the cleavable linker is reducible (e.g., a disulphide linker). In some embodiments, the linker is protease cleavable (e.g., a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from linkers disclosed in USPN 7,999,083 (e.g., CL2A, CL6, CL7, CLX, or CLY). In some embodiments, the linker is CL2A. Additional linker chemistries useful for anti- Trop-2 ADCs are described, for example, in WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), W022010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), W015098099 (Daiichi Sankyo; datopotamab deruxtecan), WO21147993 (Jiangsu Hengrui Medicine; SHR- A1921), and W021052402 (Sichuan Baili Pharmaceutical; BL-M02D1).
[0134] Exemplary anti-cancer agent payloads that can be used in anti-Trop-2 ADCs in the methods provided herein include, for example, microtubule inhibitors, DNA cleavage agents, and topoisomerase I inhibitors. In some embodiments, the microtubule inhibitor is an auristatin (e.g., monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF), a taxane, a vinca alkaloid, an epothilone) or maytansinoid (e.g., mertansine (DM1) or ravtansine (DM4)). In some embodiments, the DNA cleavage agent is a calicheamicin (e.g., ozogamicin). In some embodiments, the topoisomerase I inhibitor is a camptothecin (e.g., an irinotecan, topotecan, belotecan, or exatecan derivative, such as SN38 or Dxd). In some embodiments, the topoisomerase I inhibitor is SN38. In some embodiments, the topoisomerase I inhibitor is Dxd. In some embodiments, the topoisomerase I inhibitor is not a camptothecin (i.e. non-camptothecin topoisomerase 1 inhibitor). In some embodiments, the non-camptothecin topoisomerase 1 inhibitor is selected from an indenosinoquinoline (e.g., indeno[l,2-c]isoquinoline, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)), a phenanthridine (e.g., topovale (ARC-111), and a indolocarbazole (e.g., BE-13793C).
[0135] Additional illustrative anti-cancer agent payloads that can be conjugated to anti-Trop-2 ADCs include without limitation anthracyline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD), or dimer thereof, DNA cross-linking agent SC-DR002 (D6.5), duocarmycin, a duocarmycin (A, B l, B2, Cl, C2, D, SA, CC-1065), tubulysin B and analogs thereof (e.g., Tubl96), and other anti-cancer agents described herein.
[0136] Exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), W022010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), W015098099 (Daiichi Sankyo; datopotamab deruxtecan), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Baili Pharmaceutical; BL-M02D1 ).
[0137] In some embodiments of the methods provided herein, the anti-Trop-2 ADC is selected from sacituzumab govitecan (Immunomedic s/Gilead), datopotamab deruxtecan (DS- 1062, Dato- Dxd; Daiichi Snakyo/AstraZeneca), SKB-264 (KL-A264; Klus Pharma, Sichuan Kelun Pharma), ESG-401 (Shanghai Escugen Bio technology/Le vena Biopharma), JS-108 (DAC-002; Junshi Bio/Hangzhou DAC), FDA018-ADC (Shanghai Fudan Zhangjiang Bio Pharma), STI-3258 (Sorrento), OXG-64 (Oncoxx), BD1-4702 (OBI Pharma), BL-M02D1 (Systimmune), Anti-Trop- 2 Ab (Mediterrania Theranostic/Legochem), KD-065 (Nanjing KAEDI Biotech), Anti-Trop2 sdAb (Kisoli Biotech), Anti-Trop-2 ADC (Shandong Fontacea), LIV-2008 (LivTech/Yakult Honsha), TROP2-TRACTr (BiTE; Janux), TROP-2-TR700 (Chiome, photosensitizer), TROP2- XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Hangzhou DAC Biotech, Shanghai Junshi Biosciences), El-3s (Immunomedics/Gilead, IBC Pharmaceuticals), s BioTech), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody- CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital), and hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison). In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan (Immunomedics/Gilead). In some embodiments, the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02 and BAT-8003. In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan. In some embodiments, the anti-Trop-2 ADC is datopotamab deruxtecan (DS-1062, Dato-Dxd; Daiichi Snakyo/AstraZeneca). Further examples of useful anti-Trop-2 therapeutics include, but are not limited to, those described in W02016201300 (Gilead), and CN108440674 (Hangzhou Lonzymc Biological Technology).
[0138] Exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described, for example, in USPN 7,999,083 and USPN 9,028,833, which are hereby incorporated herein by reference in their entireties. In some embodiments, the anti-Trop-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-Trop-2 ADC has a structural formula of mAb-CL2A-SN-38, with a structure represented by:
Figure imgf000033_0001
(described, e.g., in USPN 7,999,083). In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is >7.0 (e.g., DAR = 7.6). In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti- Trop2 ADC is between 7.0 and 8.0 (e.g., DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises sacituzumab (hRS7; described, e.g., in W02003074566, Figures 3 and 4). In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan (IMMU-132). Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) composed of the following 3 components:
• The humanized monoclonal antibody hRS7 IgGlK, which binds to trophoblast cellsurface antigen 2 (Trop-2; TACSTD2; EGP-1; NCBI Gene ID: 4070), a transmembrane calcium signal transducer that is overexpressed in many epithelial cancers, including triple-negative breast cancer (TNBC).
• The camptothecin-derived agent SN-38, a topoisomerase I inhibitor.
A hydrolyzable linker (CL2A) that links the humanized monoclonal antibody to SN-38. [0139] Additional exemplary anti-Trop-2 ADCs that can be used in the methods provided herein arc described in WO21225892 (Shanghai Escugcn Biotechnology). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by:
Figure imgf000034_0001
attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC has a DAR of between 1 and 8. In some embodiments, the anti-Trop-2 ADC has a DAR of between 7.0 and 8.0. In some embodiments, the anti-Trop-2 ADC is ESG-401 (STI-3258).
[0140] Additional exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate (TL035) having a structure represented by:
Figure imgf000034_0002
Attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC has a DAR of between 1 and 8. In some embodiments, the anti-Trop-2 ADC has a DAR of between 7.0 and 8.0. In some embodiments, the anti-Trop-2 ADC has a DAR of about 7.0. In some embodiments, the anti-Trop-2 ADC is KL-A264.
[0141] Additional exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in US2016297890 (Daiichi Sankyo). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by:
Figure imgf000035_0001
attached to an anti-Trop-2 antibody (e.g., hTINAl-HILl). In some embodiments, the anti-Trop-2 ADC has a DAR of between 1 and 8. In some embodiments, the anti-Trop-2 ADC has a DAR of <7.0. In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is datopotamab deruxtecan.
Topi ADCs
[0142] In some embodiments, the ADCs that can be co-administered in the methods provided herein comprise a tumor antigen (TA) targeted antibody, a topoisomerase I inhibitor payload, and an optional linker connecting the TA targeted antibody and payload (Topi ADC). In some embodiments, the TA targeted antibody in the Topi ADC is an anti-Trop-2 antibody. In some embodiments, the TA targeted antibody in the Topi ADC does not comprise an anti-Trop-2 antibody.
[0143] In some embodiments, the Topi ADCs that can be co-administered in the methods provided herein comprise an antibody that binds a tumor antigen selected from carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2/neu, BrE3, CD1, CDla, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, ED-B fibronectin, EGP-1, EGP-2, EGF receptor (ErbBl), ErbB2, ErbB3, Factor H, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia inducible factor (HIF), HM1.24, insulin-like growth factor (ILGF), IFN-a, IFN-p, IL-y, IE-2R, IE-4R, IE-6R, IE-13R, IE-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL- 12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, la, HM1.24, gangliosides, HCG, HLA-DR, HLA- G, CD66a-d, MAGE, mCRP, MCP-1 , MTP-1 A, MTP-1B, macrophage migration-inhibitory factor (MIF), MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), PSA (prostatespecific antigen), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Ee(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigens, tumor necrosis antigens, tumor angiogenesis antigens, TNF-cc., TRAIL receptor (R1 and R2), VEGFR, R ANTES, T101 , cancer stem cell antigens, complement factors C3, C3a, C3b, C5a, C5, and an oncogene product.
[0144] In some embodiments, the Topi ADCs that can be co-administered in the methods provided herein comprise an antibody that binds a tumor antigen selected from CEACAM5 (NCBI Gene ID: 1048), CEACAM6 (NCBI Gene ID: 4680), CD74 (NCBI Gene ID: 972), CD19 (NCBI Gene ID: 930), CD20 (NCBI Gene ID: 931), CD22 (NCBI Gene ID: 933), CSAp (NCBI Gene ID: 126731), HLA-DR, HLA-G, MUC5ac (NCBI Gene ID: 4586), and AFP (NCBI Gene ID: 174).
[0145] In some embodiments, the Topi ADCs that can be used to perform the methods provided herein comprise an antibody selected from gemtuzumab, brentuximab, belantamab, camidanlumab. trastuzumab, inotuzumab, glembatumumab, anetumab, mirvetuximab, depatuxizumab, vadastuximab, labetuzumab, ladiratuzumab, loncastuximab, patritumab, lifastuzumab, indusatumab, polatuzumab, pinatuzumab, coltuximab, upifitamab, indatuximab, milatuzumab, rovalpituzumab, enfortumab, tisotumab, tusamitamab. disitamab, telisotuzumab, and antigen-binding fragments thereof.
[0146] In some embodiments, the Topi ADC that can be used in the methods provided herein comprise an antibody selected from hLLl (anti-CD74; USPN 7,312,318), 11LL2 (anti-CD22; USPN 7,074,403), hRFB4 (anti-CD22), hPAM4 (anti-MUC5ac; USPN 7,282,567), hMN-3 (anti- NOTCH3; USPN 7,541,440), hMN-14 (labetuzumab; anti-CEAC AM5 ; USPN 6,676,924); hMN15 (anti-CEACAM6; USPN 7,541,440); hA19 (anti-CD19; USPN 7,109,304), hA20 (anti- CD22; USPN 7,251,164), hMu-9 (anti-CSAp; USPN 7,387,773), hL243 (anti-HLA-DR; USPN 7,612,180), and hIMMU-31 (anti- AFP; USPN 7,300,655), which are also described, e.g., in USPN 7,999,083.
[0147] In some embodiments of the methods provided herein, the Topi ADC comprises a linker connecting a topoisomerase I inhibitor payload with a tumor antigen targeted antibody. In some embodiments, the linker is non-cleavable (e.g., a maleimidocaproyl or maleimidomethyl cyclohexane- 1 -carboxylate linker). In some embodiments, the linker is cleavable. Tn some embodiments, the linker is acid clcav blc (c.g., a hydrazone linker). In some embodiments, the cleavable linker is reducible (e.g., a disulphide linker). In some embodiments, the linker is protease cleavable (e.g., a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from linkers disclosed in USPN 7,999,083 (e.g., CL2A, CL6, CL7, CLX, or CLY). In some embodiments, the linker is CL2A. Additional linker chemistries useful for anti-TopI ADCs are described, for example, in WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI- 3258), W022010797 (BiOneCure Therapeutics; BIO- 106), CN112237634 (Shanghai Fudan- Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), W015098099 (Daiichi Sankyo; datopotamab deruxtecan), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and W021052402 (Sichuan Baili Pharmaceutical; BL-M02D1).
[0148] In some embodiments of the methods provided herein, the Topi ADC comprises a topoisomerase I inhibitor that is a camptothecin (e.g., an irinotecan, topotecan, belotecan, or exatecan derivative, such as Dxd or SN38). In some embodiments, the topoisomerase I inhibitor in the Topi ADC is Dxd. In some embodiments, the topoisomerase I inhibitor in the Topi ADC is SN38. In some embodiments, the topoisomerase I inhibitor in the Topi ADC is not a camptothecin. In some embodiments, the non-camptothecin topoisomerase I inhibitor is selected from an indenosinoquinoline (e.g., indeno[l,2-c]isoquinoline, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)), a phenanthridine (e.g., topovale (ARC-111), and a indolocarbazole (e.g., BE-13793C).
[0149] In some embodiments, the Topi ADC has a structural formula of mAb-CL2A-SN-38, with a structure represented by:
Figure imgf000037_0001
(described, e.g., in U.S. Patent No. 7,999,083). [0150] Tn some embodiments, the Topi ADC that can be used in a method provided herein includes an antibody targeting carcinocmbryonic antigen-related cell adhesion molecule 5 (CEACAM5; CD66e; NCBI Gene ID: 1048). In some embodiments, the CEACAM5 antibody is hMN-14 (e.g., as described in WO1996011013). In some embodiments, the anti-CEACAM5 ADC is as described in W02010093395 (anti-CEACAM5-CL2A-SN38). In some embodiments, the Topi ADC is labetuzumab govitecan (IMMU-130).
[0151] In some embodiments, the Topi ADC that can be used in a method provided herein comprises an antibody targeting MHC class II cell surface receptor encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in W02006094192). Tn some embodiments, the HLA-DR-ADC is as described in W02010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibody and/or fusion protein provided herein is administered with the HLA-DR-ADC IMMU-140.
[0152] Additional exemplary Topi ADCs that can be co-administered in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology). In some embodiments, the Topi ADC comprises a linker-payload conjugate having a structure represented by:
Figure imgf000038_0001
attached to a tumor antigen targeted antibody.
[0153] Additional exemplary Topi ADCs that can be co-administered in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical). In some embodiments, the Topi ADC comprises a linker-payload conjugate (TLO35) having a structure represented by:
Figure imgf000039_0001
attached to a tumor antigen targeting antibody.
[0154] Additional exemplary Topi ADCs that can be co-administered in the methods provided herein are described in US2016297890 (Daiichi Sankyo). In some embodiments, the Topi ADC comprises a linker-payload conjugate having a structure represented by:
Figure imgf000039_0002
attached to a tumor antigen targeting antibody (e.g., trastuzumab). In some embodiments, the Topi ADC has a DAR of about 4. In some embodiments, the Topi ADC is trastuzumab-deruxtecan (T- DXd).
Adenosine Pathway Inhibitors
[0155] The adenosine pathway is one of several pathways that can promote tumor immune evasion in the tumor microenvironment. It is believed that the conversion of pro-inflammatory extracellular ATP into immunosuppressive adenosine (eADO) can favor tumor progression and escape from antitumor immunity. The role of the adenosine pathway in immuno-oncology is described, for example, in Allard et al., (2020) Nat Rev Clin Oncol 17, 611-629. [0156] Adenosine pathway inhibitors that can be co-administered in the methods provided herein can include, for example, inhibitors of CD39 (cctonuclcosidc triphosphate diphospohydrolasc-1; ENTPD1; NCBI Gene ID: 953); inhibitors of CD73 (exto-5’ -nucleotidase; NT5E; NCBI Gene ID: 4907), or antagonists of adenosine receptors, such as adenosine A2A receptor (AD0RA2A; NCBI Gene ID: 135) or adenosine AIB receptor (AD0RA2B; NCBI Gene ID: 136). In some embodiments, the adenosine pathway inhibitors that can be co-administered in the methods provided herein include Inhibitors of CD38 (cyclic ADP ribose hydrolase; NCBI Gene ID: 952).
CD39 inhibitors
[0157] CD39 inhibitors that can be co-administered in the methods provided herein include small molecule inhibitors and large molecule inhibitors (e.g., anti-CD39 antibodies) of CD39. Exemplary CD39 inhibitors are described, for example in WO09095478, WO12085132, WO16073845, WO17157948, WO18049145, WO18065552, WO18065622, WO19027935, WO19178269, W021056610, WG21037037, WO21055329, WO21088838, and WO22111576. In some embodiments, the CD39 inhibitor is selected from TTX-030 (AbbVie/Trishula), IPH5201 (AstraZeneca/Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secama Pharmaceuticals), JS-019 (Shanghai Junshi Biosciences); anti-CD39 (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPDl (Biotheus).
CD73 inhibitors
[0158] CD73 inhibitors that can be co-administered in the methods provided herein include small molecule inhibitors and large molecule inhibitors (e.g., anti-CD73 antibodies) of CD73.
Exemplary CD73 inhibitors that can be used in the methods provided herein are described, for example, in US Patent No. 11,001,603, the compounds of which are hereby incorporated by reference herein. Additional illustrative CD73 inhibitors that can be co-administered in the methods provided herein are described, for example in WO15164573, W016055609, W016075099, WO16081746, WO16081748, W017064043, WO17098421, W017100670, WO17118613, WO17153952, WO18013611, WO18067424, WO18065627, WO18094148, WO18110555, WO18119284, WO18137598, WO18183635, W018208980, WO18208727, WO18215535, WO18237173, WO18237157, WO19053617, W019090111, WO19129059, WO19168744, WO19166701, WO19173291, WO19173692, WO19170131, WO19224025, WO19232244, WO19246403, WG20046813, W020047082, W020051686, W020097127, WO20098599, W020139803, WO20143836, WG20143710, W020151707, WO20205538, W020202038, W020210970, W020210938, WO20216697, W020221209, WO20244606, WO20253568, WO20257429, WO21011689, WG21029450, WO21032173, W021040356, WO21041319, WO21043229, W021044005, WO21087136, WO21087463, W021088901, WO21097223, WO21105916, WO21113625, WO21138467, WO21205383, WO21213466, WO21213475, WO21216898, WO21222522, WO21227306, WO21241729, WO21257643, WO2 1259199, WO22007677, WO22052886, WO22068929, WO22083049, WO22083049, W022090711, WO22095975, WO22095953, W022096020, and WO22121914. In some embodiments, the CD73 inhibitor is selected from oleclumab (AstraZeneca), BMS-986179
(BMS), uliledlimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB68O, Arcus Biosciences), mupadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCAOO186 (Incyte), IB 1325 (Innovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB- BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3sBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPDl, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene/Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is quemliclustat (AB680, GS-0680), uliledlimab, mupadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV93O, BMS-986179, or oleclumab. In some embodiments, the CD73 inhibitor is oleclumab or quemliclustat. In some embodiments, the CD73 inhibitor is quemliclustat.
Adenosine Receptor Antagonists
[0159] The adenosine receptor antagonists that can be co-administered in the methods provided herein can be selective antagonists of adenosine A2A receptor (A2AR; ADORA2A) or A2B receptor (A2BR; ADORA2B), or dual A2A/2BR antagonists. In some embodiments, the adenosine receptor antagonist is a selective A2aR antagonist. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist selected from imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarns Therapeutics), and TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a selective A2BR antagonist. In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) selective antagonist selected from PBF-1129 (Palobiofarma) and TT-702 (Toon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual A2A/2BR antagonist. In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist selected from etrumadenant (AB928, Arcus Biosciences), INCB 106385 (Incyte), M1069 (Merck KGaA), A2aR/A2bR (Domain/Merck KgaA), HM87277 (Al/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), and TT-53 (Tarns Therapeutics). In some embodiments, the adenosine receptor antagonist is etrumadenant. The adenosine receptor antagonists can be small molecule antagonists or large molecule antagonists.
[0160] Additional illustrative adenosine receptor antagonists that can be co-administered in the methods provided herein are described, for example, in WO07103776, WO07134958, W008086201, W009009178, WG09033161, WO09037463, WO09037468, WO09037467, WO09055548, W009055308, W010008775, WO11027805, WO11050160, WO11055391, WO12135084, W014101120, WO14101113, WO14106861, WO15027431, W016081290, WO16126570, W016200717, WO16209787, W017008205, WO18013951, W019086074, WO2019118313, WO20053263, W020106558, W020103930, W020103939, W020106560, W020112706, W020112700, WO20216152, W020135210, WO20135195, W020150677, W020150675, W020150674, W020150676, WO20152132, W020156505, W020159905, WO21018172, WO20227156, WO2101873, W020260196, WO20253867, WO20263058, WO20260857, W021011670, W021093701, W021041360, WO21099832, WO21105916, WO21146631, WO21156439, WO21179074, WO21185256, WO21194623, WO21191376, WO21191380, WO21191378, WO21191379, WO21224636, WO22020552, W022020550, WO22023772, W022072601 and WO22123272.
[0161] Exemplary adenosine receptor antagonists that can be used in the methods provided herein are described, for example, in US Patent No. 10,399,962, the compounds of which are hereby incorporated by reference. In some embodiments, the adenosine pathway inhibitor is a dual antagonist of adenosine A2A receptor (A2AR; ADORA2A) and A2B receptor (A2BR; ADORA2B). In some embodiments, the adenosine pathway inhibitor is etrumadenant (AB928; GS-0928), taminadenant, TT-10, TT-4, or M 1069. In some embodiments, the adenosine pathway inhibitor is etrumadenant. [0162] Etrumadenant (AB928) is a small molecule dual antagonist of both A2AR and A2BR that can inhibit the adcnosinc-drivcn impairment of tumor-infiltrating lymphocytes (mainly through A2AR on CD8+ T cells and NK cells) and myeloid cells (through A2BR on dendritic cells and macrophages) in the absence of any agonist activity. Etrumadenant can achieve high penetration of tumor tissue, robust potency in the presence of high adenosine concentrations, and shows low nonspecific protein binding.
PD(L)1 Inhibitors
[0163] In some embodiments, the combination treatment methods provided herein comprise coadministering a PD(L)1 inhibitor. PD(L)1 inhibitors that can be co-administered can include small molecule PD(L)1 inhibitors and large molecule PD(L)1 inhibitors (e.g., anti-PD(L)-l antibodies).
[0164] Exemplary small molecule PD(L)1 inhibitors that can be co-administered in the methods provided herein include, for example, CA-170, GS-4224, GS-4416 and lazertinib (GNS-1480; PD- Ll/EGFR). Additional illustrative small molecule PD(L)1 inhibitors are described, for example, in Guzik et al. (2019) Molecules 24(11), 2071.
Anti-PD(L)1 Antibodies
[0165] Exemplary anti-PD-(L)l antibodies that can be co-administered in the method provided herein include, for example, pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)! antibody is zimberelimab.
[0166] Additional illustrative anti-PD-(L)l antibodies that can be co-administered in the methods provided herein include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP- 224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP- 3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, retifanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-63723283), genolimzumab (CBT-501), LZM-009, prolgolimab (BCD-100), lodapolimab (LY-3300054), SHR-1201, camrelizumab (SHR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT- 1 06, avelumab (MSB0010718C), CX-072, CBT-502, dostarlimab (TSR-042), MSB-2311 , JTX- 4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, cnvafolimab (KN-035), sintilimab (IBI- 308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1 105-01, GS-4224, GS-4416, INCB086550, MAX10181, zimberelimab (AB 122), spartalizumab (PDR-001), and compounds disclosed in WO2018195321, W02020014643, WO2019160882, or WO2018195321, as well as multi- specific inhibitors FPT-155 (CTLA4/PD- L1/CD28), PF-06936308 (PD-1/ CTLA4), MGD-013 (PD-l/LAG-3), FS-118 (LAG-3/PD-L1), RO-7247669 (PD-l/LAG-3), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), RO-7121661 (PD-l/TIM-3), RG7769 (PD-l/TIM-3), TAK-252 (PD-1/OX40L), XmAb-20717 (PD-1/CTLA4), AK-104 (CTLA4/PD-1), FS-118 (LAG-3/PD-L1), FPT-155 (CTLA4/PD-L1/CD28), GEN-1046 (PD-L1/4-1BB), bintrafusp alpha (M7824; PD-Ll/TGFp-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1), and INBRX-105 (4-1BB/PDL1).
Anti-TIGIT Antibodies
[0167] Exemplary anti-TIGIT antibodies that can be co-administered in the methods provided herein include, for example, tiragolumab, vibostolimab, domvanalimab, AB3O8, AK127, BMS- 986207, ralzapastotug, and etigilimab. In some embodiments, the anti-TIGIT antibody is domvanalimab. In some embodiments, the anti-TIGIT antibody is AB308. In some embodiments, the anti-TIGIT antibody is ralzapastotug.
[0168] In some embodiments, the anti-TIGIT antibody is an Fc-silent antibody. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent, or eliminate binding to an Fc receptor. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyRIV. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent, or eliminate ADCC, ADCP, and/or CDC. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region to reduce, prevent, or eliminate binding to Fc receptors, wherein the one or more substitutions occur at EU index positions 228, 233, 234, 235, 235, 235, 236, 237, 265, 297, 322, 327, 328, 330, 331, and any combination thereof. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region to reduce, prevent, or eliminate binding to Fc receptors, wherein the one or more substitutions comprise S228P, E233P, E234A, L235A, E235E, E235F, G236R, G237A, D265A, N297A, K322A, A327G, E328R, A330S, P331S, and any combination thereof. Additional mutations in the Fc region that reduce, prevent, or eliminate binding to Fc receptors and alternative strategies for reducing, preventing, or eliminating binding to Fc receptors are described in, e.g., Saunders, Front Immunol. (2019) 10:1296; Tao, J Exp Med. (1993) 178:661-667; Canfield and Morrison, J Exp Med. (1991) 173(6): 1483-1491; Armour, Eur. J. Immunol. (1999) 29(8): 2613-2624; Shields, J. Biol. Chem. (2001) 276(9):6591-6604, and U.S. No. 6,624,821.
[0169] In some embodiments, the anti-TIGIT antibody is an Fc-enabled antibody. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable or enhance binding to an Fc receptor. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable or enhance binding to FcyR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enable or enhance binding to FcyRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enable or enhance binding to FcyRIV. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable or enhance ADCC, ADCP, and/or CDC. In some embodiments, the anti-PD- (E)l antibody comprises one or more substitutions in Fc region to enhance or enable binding to Fc receptors, wherein the one or more substitutions occur at EU index positions 234, 235, 236, 239, 243, 247, 267, 268, 292, 298, 300, 305, 324, 326, 330, 332, 333, 334, 339, 345, 396, 430, and any combination thereof. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region to enhance or enable binding to Fc receptors, wherein the one or more substitutions comprise F234L, L235V, G236A, S239D, F243L, P247I, S267E, H268E, R292P, S298A, Y300L, V305I, S324T, K326W, A33OE, I332E, E333A, E333S, K334A, A339Q, E345G, P396L, E430G, and any combination thereof. In some embodiments, the Fc-enabled antibody comprises a modified IgGl domain characterized by substitutions at S239D, A33OL, and I332E (Eu numbering). Alternatively, the anti-TIGIT antibody contains or has a glycoform perturbation. In some embodiments, the anti-TIGIT antibody contains or has an N-linked Fc glycosylation. Tn some embodiments, the anti-TTGTT antibody contains or has sialylation, galactosylation, bisecting sugars, fucosylation, or any combination thereof. Additional mutations in the Fc region that enhance or enable binding to Fc receptors and alternative strategies for enhancing or enabling binding to Fc receptors are described in Saunders, 2019.
Treatment Methods
[0170] In one aspect, provided herein are methods of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of a Trop-2 positive (Trop-2+) cancer comprising coadministering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor). In some embodiments, the methods provided herein include treating a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor). In some embodiments, the methods provided herein include treating the recurrence or metastasis of a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor). In some embodiments, the methods provided herein include preventing or delaying the recurrence or metastasis of a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor). In some embodiments, the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors. In some embodiments, the plurality of adenosine pathway inhibitors comprises a CD73 inhibitor and an adenosine receptor antagonist. In some embodiments, the CD73 inhibitor is quemliclustat and the adenosine receptor antagonist is etrumadenant.
[0171] In some embodiments, the methods provided herein are for treating a Trop-2 positive cancer comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
[0172] In another aspect, provided herein are methods of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of a tumor antigen positive (TA+) cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen (TA) targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (Topi ADC); and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor). In some embodiments, the methods provided herein include treating a tumor antigen positive (TA+) cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor). In some embodiments, the methods provided herein include treating the recurrence or metastasis of a tumor antigen positive cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor). In some embodiments, the methods provided herein include preventing or delaying the recurrence or metastasis of a tumor antigen positive cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
[0173] In some embodiment, the methods provided herein are for treating a tumor antigen positive cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., CD39 inhibitor, CD73 inhibitor, or A2R inhibitor).
[0174] In some embodiments, provided herein are methods of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of a tumor antigen (e.g., Trop-2) positive cancer comprising co-administering to a subject the combinations provided herein. In some embodiments, the treatment methods provided herein mitigate the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering the combinations provided herein. In some embodiments, the treatment methods provided herein reduce the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering the combinations provided herein. In some embodiments, the treatment methods provided herein prevent the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering the combinations provided herein. In some embodiments, the treatment methods provided herein delay the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering the combinations provided herein.
[0175] In some embodiments, the methods provided herein further comprise co-administering an additional therapeutic agent or therapeutic modality, or a combination thereof. In some embodiments, the methods provided herein comprise co-administering one, two, or three additional therapeutic agents or therapeutic modalities, or combinations thereof. In some embodiments, the additional therapeutic agent comprises chemotherapy (e.g., a chemotherapy treatment of physician’s choice, or an indicated standard of care for a specific therapeutic setting). In some embodiments, the additional therapeutic agent comprises an immune checkpoint inhibitor (CPI; e.g., anti-CTLA4 antibody, anti-PD(L)! antibody, anti-TTGTT antibody). Tn some embodiments, the additional therapeutic agent comprises an anti-PD(L)l antibody (e.g., an anti- PD-1 antibody or an anti-PD-Ll antibody), and optionally an anti-TIGIT antibody. In some embodiments, the additional therapeutic agent comprises an anti-PD-(L)l antibody. In some embodiments, the additional therapeutic agent comprises an anti-TIGIT antibody. In some embodiments, the additional therapeutic agent comprises an anti-PD-(Ll) antibody and an anti- TIGIT antibody. In some embodiments, the additional therapeutic agent comprises a) zimberelimab and domvanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vibostolimab, e) pembrolizumab and domvanalimab, f) pembrolizumab and AB3O8, g) MK-7684A (pembrolizumab/vibostolimab coformulation), h) durvalumab and domvanalimab, i) zimberelimab and ralzapastotug, or j) pembrolizumab and ralzapastotug. In some embodiments, the additional therapeutic agent comprises zimberelimab and domvanalimab. In some embodiments, the additional therapeutic agent comprises zimberelimab and ralzapastotug. In some embodiments, the additional therapeutic modality comprises surgery or radiation therapy.
[0176] In some embodiments of the methods provided herein, the subject is a cancer patient. In some embodiments, the subject is a human cancer patient. In some embodiments, the subject is treatment naive. In some embodiments, the subject (e.g., human cancer patient) has not received a taxane (e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel) therapy before administration of a combination therapy provided herein. In some embodiments, the subject (e.g., human cancer patient) has not received a checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)l antibody) before administration of a combination therapy provided herein. In some embodiments, the subject (e.g. human cancer patient) has not received a topoisomerase I inhibitor therapy (e.g., irinotecan) before administration of a combination therapy provided herein. Tn some embodiments, the subject has received one or more lines of previous anti-cancer therapy before administration of a combination provided herein. In some embodiments, the subject (e.g., human (m)CRPC patient) has received a new hormonal agent (NHA; first- or second-generation nonsteroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) prior to administration of a combination therapy provided herein. In some embodiments, the subject (e.g., human (m)CRPC patient) has shown disease progression after prior NHA treatment (first- or second-generation non-steroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) before administration of a combination therapy provided herein. In some embodiments, the subject has received a prior anticancer therapy selected from surgery, radiation therapy, chemotherapy (including NHA therapy), checkpoint inhibitor therapy (e.g. anti-PD(L)l antibody). In some embodiments, the subject has a cancer that is resistant or refractory to one or more anti-cancer therapies. In some embodiments, the cancer is resistant or refractory to one or more anti-cancer therapies selected from radiation therapy, chemotherapy (including NHA therapy), and checkpoint inhibitor therapy (e.g., anti- PD(L)1 antibody). In some embodiments, the subject (e.g., human (m)CRPC patient) has shown disease progression after prior NHA treatment (first- or second-generation non-steroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) and has not received a taxane (e.g., docetaxel, cabazitaxel), checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)l antibody), or a topoisomerase I inhibitor (e.g., irinotecan) before administration of a combination therapy provided herein. In some embodiments, the subject (e.g., human (m)NSCLC patient) has shown disease progression after platinum-based chemotherapy. In some embodiments, the subject (e.g., human (m)NSCLC patient) has shown disease progression after checkpoint inhibitor therapy (e.g., anti-PD-(L)l antibody or anti-CTLA4 antibody therapy). In some embodiments, the subject has progressed after platinum-based chemotherapy and checkpoint inhibitor therapy (e.g., anti-PD-(L)l antibody or anti-CTLA4 antibody therapy), received either in combination or sequentially in any order. In some embodiments, the subject (e.g., human (m)NSCLC patient) has progressed after a tyrosine kinase inhibitor therapy targeting specific genomic alterations in a cancer. Exemplary tyrosine kinase inhibitors that are useful to address specific genomic alterations in lung cancer (e.g., EGFR mutations or deletions) include gefitinib, erlotinib, afatinib, dacomitinib, neratinib, osimertinib, rociletinib, olmutinib, ASP8273 (Astellas), nazartinib, PF-06747775 (Pfizer), avitinib, and HS- 10296 (Jiangsu Hansoh). In some embodiments, the subject (e.g., human (m)CRPC or (m)NSCLC patient) has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing).
[0177] In some embodiments, the subject is a human prostate cancer patient. In some embodiments, the human patient has castrate resistant prostate cancer (CRPC). In some embodiments, the human patient has metastatic CRPC (mCRPC). In some embodiments, the human patient with CRPC or mCRPC ((m)CRPC) is treatment naive. In some embodiments, the human patient with (m)CRPC has not received a taxane (e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel) therapy before administration of a combination therapy provided herein. In some embodiments, the human patient with (m)CRPC has not received a checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)l antibody) before administration of a combination therapy provided herein. In some embodiments, the human patient with (m)CRPC has not received a topoisomerase I inhibitor therapy (e.g., irinotecan) before administration of a combination therapy provided herein. In some embodiments, the human patient with (m)CRPC has received one or more lines of anti-cancer therapy before administration of a combination provided herein. In some embodiments, the human patient with (m)CRPC has shown disease progression on one or more lines of anti-cancer therapy before administration of a combination provided herein. In some embodiments, the human patient with (m)CRPC has received a new hormonal agent (NHA; first- or second-generation non-steroidal antiandrogens, abiraterone) (NHA experienced) prior to administration of a combination therapy provided herein. In some embodiments, the human patient with (m)CRPC) has shown disease progression after prior NHA treatment (first- or second-generation non-steroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) before administration of a combination therapy provided herein In some embodiments, the human patient with (m)CRPC has received a prior anti-cancer therapy selected from surgery, radiation therapy, chemotherapy (including NHA therapy), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)l antibody). Tn some embodiments, the human patient with (m)CRPC has a cancer that is resistant or refractory to one or more anti-cancer therapies. In some embodiments, the cancer is resistant or refractory to one or more anti-cancer therapies selected from radiation therapy, chemotherapy (including NHA therapy), and checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti- PD(L)1 antibody). In some embodiments, the human patient with (m)CRPC has received a prior NHA treatment (first- or second-generation non-steroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) (NHA experienced) and has not received a taxane (e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel) or checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)l antibody) (taxane and CPI naive) before administration of a combination therapy provided herein. In some embodiments, the human patient with (m)CRPC has received a prior NHA treatment (first- or second-generation nonsteroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) (NHA experienced) and has not received a taxane (e.g., paclitaxel, nab- paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)l antibody), or topoisomerase I inhibitor (e.g., irinotecan) before administration of a combination therapy provided herein. In some embodiments, the human patient with (m)CRPC has shown disease progression after prior NHA treatment (first- or second- generation non-steroidal antiandrogens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or combinations thereof) and has not received a taxane (e.g., paclitaxel, nab- paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)l antibody), or a topoisomerase I inhibitor (e.g., irinotecan) before administration of a combination therapy provided herein. In some embodiments, the human patient with (m)CRPC has histologically confirmed adenocarcinoma of the prostate and metastatic castrate resistant with tumor progression while on androgen deprivation therapy (ADT; including orchiectomy) with castrate levels of serum (total) testosterone (<1.7 nmol/L or 50 ng/dL) defined by PSA and/or radiographic criteria according to PCWG3. In some embodiments, the human patient (m)CRPC has metastatic castrate resistant adenocarcinoma of the prostate with tumor progression while on androgen deprivation therapy (e.g., including orchiectomy) with castrate levels of serum (total) testosterone (< 1.7 nmol/L or 50 ng/dL) defined by prostate specific antigen (PSA) and/or radiographic criteria according to The Prostate Cancer Working Group 3 (PCWG3) and measurable or non-measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. In some embodiments, the human patient with (m)CRPC has Eastern Cooperative Oncology Group performance status 0 or 1 with a life expectancy >3 months. In some embodiments, the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing).
[0178] In some embodiments, the subject is a human lung cancer patient. In some embodiments, the human patient has non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is squamous. In some embodiments, the NSCLC is non-squamous. In some embodiments, the lung cancer does not have an actionable genomic alteration (e.g., an EGFR or ALK mutation, insertion, deletion, or the like) for which treatment with a targeted therapy (e.g., a targeted tyrosine kinase inhibitor therapy) is indicated (actionable genomic alteration). Exemplary actionable genomic alterations and targeted tyrosine kinase inhibitor therapies are described, e.g., in Sullivan and Planchard Front. Med. (2017) 3:76. In some embodiments, the human NSCLC patient has shown disease progression after platinum-based chemotherapy. In some embodiments, the human NSCLC patient has shown disease progression after checkpoint inhibitor therapy (e.g., anti-PD- (L)l antibody or anti-CTLA4 antibody therapy). In some embodiments, the human NSCLC patient has progressed after platinum-based chemotherapy and checkpoint inhibitor therapy (e.g., anti-PD-(L)! antibody or anti-CTLA4 antibody therapy), received either in combination or sequentially in any order. In some embodiments, the human NSCLC patient has progressed after a tyrosine kinase inhibitor therapy targeting specific genomic alterations in a cancer. Exemplary tyrosine kinase inhibitors that are useful to address specific genomic alterations in lung cancer (e.g., EGFR mutations or deletions) include gefitinib, erlotinib, afatinib, dacomitinib, neratinib, osimertinib, rociletinib, olmutinib, ASP8273 (Astellas), nazartinib, PF-06747775 (Pfizer), avitinib, and HS- 10296 (Jiangsu Hansoh).
[0179] In some embodiments of the methods provided herein, the combinations provided herein are administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combinations provided herein are administered in an adjuvant setting (e.g., following a primary treatment such as surgery or radiation therapy). In some embodiments, the combinations provided herein are administered in a therapeutic setting (e.g., as the primary therapy). In some embodiments, the combinations provided herein are administered in a maintenance setting.
[0180] In some embodiments of the methods provided herein, the cancer is a hematological cancer. In some embodiments, the cancer includes a solid tumor. In some embodiments, the cancer includes a malignant tumor. Tn some embodiments, the cancer includes a metastatic cancer. In some embodiments, the cancer is resistant or refractory to one or more anticanccr therapies. In some embodiments, greater than about 50% of the cancer cells delectably express one or more cell surface immune checkpoint receptors (e.g., so-called “hot” cancer or tumor). In some embodiments, greater than about 1% and less than about 50% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so called “warm” cancer or tumor). In some embodiments, less than about 1% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so called “cold” cancer or tumor).
[0181] In some embodiments of the methods provided herein, the cancer is a hematological cancer, e.g., a leukemia (e.g., Acute Myelogenous Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), B-cell ALL, Myelodysplastic Syndrome (MDS), myeloproliferative disease (MPD), Chronic Myelogenous Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), undifferentiated leukemia), a lymphoma (e.g., small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), Waldestrom’s macroglobulinemia (WM)) and/or a myeloma (e.g., multiple myeloma (MM)).
[0182] In some embodiments of the methods provided herein, the cancer is an epithelial tumor (e.g., a carcinoma, a squamous cell carcinoma, a basal cell carcinoma, a squamous intraepithelial neoplasia), a glandular tumor (e.g., an adenocarcinoma, an adenoma, an adenomyoma), a mesenchymal or soft tissue tumor (e.g., a sarcoma, a rhabdomyosarcoma, a leiomyosarcoma, a liposarcoma, a fibrosarcoma, a dermatofibrosarcoma, a neurofibrosarcoma, a fibrous histiocytoma, an angiosarcoma, an angiomyxoma, a leiomyoma, a chondroma, a chondrosarcoma, an alveolar soft-part sarcoma, an epithelioid hemangioendothelioma, a Spitz tumor, a synovial sarcoma), or a lymphoma.
[0183] In some embodiments, the cancer includes a solid tumor in or arising from a tissue or organ, such as:
• bone (e.g., adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of the bone, giant cell tumour of bone, haemangiomas and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, Desmoid tumor, Ewing sarcoma);
• lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands e.g., pleomorphic salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumors);
• esophagus e.g., Barrett's esophagus, dysplasia and adenocarcinoma);
• gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumors (GISTs), metastatic deposits, gastric carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, anus;
• pancreas (e.g., serous neoplasms, including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)-associated serous cystic neoplasm, serous cystadenocarcinoma; mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), intraductal oncocytic papillary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, including acinar cell cystadenoma, acinar cell cystadcnocarcinoma, pancreatic adenocarcinoma, invasive pancreatic ductal adenocarcinomas, including tubular adenocarcinoma, adenosquamous carcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine neoplasms, neuroendocrine microadenoma, neuroendocrine tumors (NET), neuroendocrine carcinoma (NEC), including small cell or large cell NEC, insulinoma, gastrinoma, glucagonoma, serotonin-producing NET, somatostatinoma, VIPoma, solid-pseudopapillary neoplasms (SPN), pancreatoblastoma); gall bladder (e.g. carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic cholangiocarcinoma) ; neuro-endocrine (e.g., adrenal cortical carcinoma, carcinoid tumors, phaeochromocytoma, pituitary adenomas);
• thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumors, papillary carcinoma, adenocarcinoma);
• liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, York sac tumor, carcinosarcoma, rhabdoid tumor);
• kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wilms tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma);
• breast (e.g. , invasive ductal carcinoma, including without limitation, acinic cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich/clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including without limitation, pleomorphic carcinoma, signet ring cell carcinoma);
• peritoneum (e.g., mesothelioma; primary peritoneal cancer);
• female sex organ tissues, including ovary (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Mullerian tumors, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., carcinoma of the cervix, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial carcinoma (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasia), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumors, endometrial malignant mullerian mixed tumours, gestational trophoblastic tumors (partial hydatiform mole, complete hydatiform mole, invasive hydatiform mole, placental site tumour)), vulva, vagina;
• male sex organ tissues, including prostate, testis (e.g., germ cell tumors, spermatocytic seminoma), penis;
• bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma);
• brain, (e.g., gliomas (e.g., astrocytomas, including non-infiltrating, low-grade, anaplastic, glioblastomas; oligodendrogliomas, ependymomas)), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, Non-Hodgkin lymphomas (NHLs), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, pituitary tumors;
• eye (e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris hamartoma);
• head and neck (e.g., nasopharyngeal carcinoma, Endolymphatic Sac Tumor (ELST), epidermoid carcinoma, laryngeal cancers including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, transglottic carcinoma), carcinoma in situ, verrucous, spindle cell and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinomas, laryngeal sarcoma), head and neck paragangliomas (e.g., carotid body, jugulotympanic, vagal); thymus (e.g., thymoma);
• heart (e.g., cardiac myxoma);
• lung (e.g., small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant cell carcinomas, spindle cell carcinomas, pleuropulmonary blastoma);
• lymph e.g., lymphomas, including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (NHL), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, Epstein-Barr virus (EBV)-associatcd lymphoproliferative diseases, including B cell lymphomas and T cell lymphomas e.g., Burkitt lymphoma; large B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low grade B cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK/T cell lymphoma, nasal type; peripheral T cell lymphoma, cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma; follicular T cell lymphoma; systemic T cell lymphoma), lymphangioleiomyomatosis);
• central nervous system (CNS) (e.g., gliomas including astrocytic tumors (e.g., pilocytic astrocytoma, pilomyxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme) and gliomatosis cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g., subependymom, myxopapillary ependymoma, ependymomas (e.g., cellular, papillary, clear cell, tanycytic), anaplastic ependymoma), optic nerve glioma, and nongliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors, medulloblastoma, meningeal tumors, primary CNS lymphomas, germ cell tumors, Pituitary adenomas, cranial and paraspinal nerve tumors, stellar region tumors); neurofibroma, meningioma, peripheral nerve sheath tumors, peripheral neuroblastic tumours (including without limitation neuroblastoma, ganglioneuroblastoma, ganglioneuroma), trisomy 19 ependymoma); • neuroendocrine tissues (e.g., paraganglionic system including adrenal medulla (pheochromocytomas) and extra-adrenal paraganglia ((extra-adrenal) paragangliomas);
• skin (e.g., clear cell hidradenoma, cutaneous benign fibrous histiocytomas, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumors); and
• soft tissues (e.g. , aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid-type fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, Ewing's tumors/primitive neurectodermal tumors (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastoma, lipoma, chondroid lipoma, liposarcoma I malignant lipomatous tumors, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant melanoma of soft parts, myoepithelial carcinoma, myoepithelioma, myxoinriainmatory fibroblastic sarcoma, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, nonrhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well-differentiated liposarcoma.
[0184] In some embodiments, the cancer is positive for a tumor antigen selected from carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2/neu, BrE3, CD1, CDla, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20 (e.g., C2B8, hA20, 1F5 MAbs), CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, fibronectin splice variant, ED-B fibronectin (e.g., L19), EGP-1, EGP-2 (e.g., 17- 1A), EGF receptor (ErbB l), ErbB2, ErbB3, Factor H, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia inducible factor (HIF), HM1.24, insulin-like growth factor (ILGF), IFN-a, IFN-p, IFN-y, IE-2R, IL-4R, IL-6R, IL-13R, IE-15R, IL-17R, IE-18R, IE-2, IE-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, la, HM1.24, gangliosides, HCG, the HLA-DR, CD66 (e.g., CD66a-d), MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (PTGF), PSA (pro state- specific antigen), PSMA, PAM4, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Lc(y), mcsothclin, S100, tcnascin, TAC, Tn antigen, Thomas-Friedenreich antigens, tumor necrosis antigens, tumor angiogenesis antigens, TNF-oc, TRAIL receptor (R1 and R2), VEGFR, RANTES, T101, complement factors C3, C3a, C3b, C5a, and C5, and an oncogene product.
[0185] In some embodiments, the cancer is positive for a tumor antigen selected from CD74, CD22, Trop-2, CEA, CSAp Mu-9, AFP, CC49, and PSMA.
[0186] In some embodiments, the cancer is Trop-2 positive. In some embodiments, the Trop-2 positive cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC); HR positive/Her-2 negative (HR+/Her-2 ) breast cancer; HR positive/Her-2 low breast cancer), colorectal cancer, lung cancer, stomach cancer, urinary tract cancer, urothelial cancer, bladder cancer, renal cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer, and prostatic cancer. In some embodiments, the prostatic cancer is castrate-resistant prostate cancer (CRPC). In some embodiments, the lung cancer is non-small lung cancer (NSCLC). In some embodiments, the Trop- 2 positive cancer is (i) unresectable, locally advanced or (ii) metastatic cancer (e.g., mCRPC or mNSCLC). In some embodiments, the Trop-2 positive cancer is resistant or refractive to one or more anti-cancer therapy.
[0187] In some embodiments of the methods provided herein, the Trop-2 positive cancer is prostate cancer. In some embodiments, the Trop-2 positive cancer is metatstatic prostate cancer. In some embodiments, the Trop-2 positive cancer is castrate resistant prostate cancer (CRPC). In some embodiments, the Trop-2 positive cancer is metatstatic castrate resistant prostate cancer (mCRPC). In some embodiments, the Trop-2 positive cancer is metastatic castrate resistant adenocarcinoma of the prostate showing tumor progression on androgen deprivation therapy (e.g., including orchiectomy) with castrate levels of serum (total) testosterone (< 1.7 nmol/L or 50 ng/dL) defined by prostate specific antigen (PSA) and/or radiographic criteria according to The Prostate Cancer Working Group 3 (PCWG3); measurable or non-measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l.
[0188] In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop2 antibody drug conjugate; and b) an adenosine pathway inhibitor. In some embodiments, the anti-Trop-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase inhibitor is a camptothecin analog. In some embodiments, the camptothecin analog is an irinotecan derivative, a topotecan derivative, or an exatecan derivative. In some embodiments, the camptothecin analog is SN38 or Dxd. In some embodiments, the camptothecin analog is SN38. In some embodiments, the camptothecin analog is connected to an anti-Trop-2 antibody via a hydrolyzable linker. In some embodiments, the hydrolyzable linker is CL2A (e.g., as described in US 7,999,083). In some embodiments, the camptothecin analog is connected to an anti-Trop-2 antibody via a protease cleavable linker. In some embodiments, the anti-Trop-2 ADC has a structure mAb-CL2A-SN-38, represented by:
Figure imgf000060_0001
(described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0. In some embodiments, the DAR of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop-2 ADC is about 7.6. In some embodiments, the anti-Trop-2 ADC comprises the anti-Trop-2 antibody sacituzumab (hRS7, described, e.g., in W02003074566, Figures 3 and 4). In some embodiments, the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS- 1062), ESG-401, SKB-264, DAC-02 and BAT-8003. In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan. In some embodiments, the anti-Trop-2 ADC is datopotamab deruxtecan (DS- 1062). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist. In some embodiments, the CD39 inhibitor is selected from TTX-030 (AbbVie/Trishula), IPH5201 (AstraZeneca/Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secarna Pharmaceuticals), JS-019 (Shanghai Junshi Biosciences); AB598 (anti-CD39) (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPDl (Biotheus). In some embodiments, the CD73 inhibitor is selected from oleclumab (AstraZeneca), BMS-986179 (BMS), uliledlimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB680, Arcus Biosciences), mupadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Hcnlius Biotech), INCA00186 (Incytc), IBI325 (Innovcnt Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPDl, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene/Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is oleclumab or quemliclustat. In some embodiments, the CD73 inhibitor is quemliclustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), or TT- 228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenant (AB928, Arcus Biosciences), INCB 106385 (Incyte), M1069 (Merck KgaA), A2aR/A2bR (Domain/Merck KgaA), HM87277 (Al/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is etrumadenant. In some embodiments, the adenosine pathway inhibitor is quemliclustat or etrumadenant. In some embodiments, the adenosine pathway inhibitor is etrumadenant. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from a CD39 inhibitor, a CD73 inhibitor, and an adenosine receptor antagonist. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from a CD73 inhibitor and an adenosine receptor antagonist. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, ulilcdlimab, imaradenant, NIR178, and ctrumadcnant. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC having a structure mAb-CL2A-SN-38, represented by:
Figure imgf000062_0001
and b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uliledlimab, imaradenant, NIR178, and etrumadenant. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan or datopotamab deruxtecan (DS-1062); and b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uliledlimab, imaradenant, NIR178, and etrumadenant. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan; and b) etrumadenant. In some embodiments, the methods provided herein further comprise co-administering an additional therapeutic agent or therapeutic modality, or a combination thereof. In some embodiments, the additional therapeutic agent comprises an immune checkpoint inhibitor (CPI). In some embodiments, the CPI comprises an anti-PD(L)l antibody (e.g., an anti-PD-1 antibody or an anti- PD-L1 antibody), and optionally an anti-TIGIT antibody. In some embodiments, the anti-PD(L)l antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD(L)l antibody is zimberelimab. In some embodiments, the anti-TIGIT antibody is selected from tiragolumab, vibostolimab, domvanalimab, AB308, AK127, BMS- 986207, ralzapastotug, and etigilimab. In some embodiments, the anti-TIGIT antibody is domvanalimab. In some embodiments, the additional therapeutic agent comprises an anti-PD(L)! antibody and an anti-TIGIT antibody. In some embodiments, the additional therapeutic agent comprises a) zimberelimab and domvanalimab, b) zimberelimab and AB3O8, c) atezolizumab and tiragolumab, d) pembrolizumab and vibostolimab, e) MK-7684A (pembrolizumab/vibostolimab coformulation), f) durvalumab and domvanalimab, g) zimberelimab and ralzapastotug, or h) pembrolizumab and ralzapastotug. In some embodiments, the anti-PD(L)l antibody is zimberelimab and the anti-TIGIT antibody is domvanalimab. In some embodiments, the additional therapeutic modality comprises surgery or radiation therapy. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); b) an adenosine pathway inhibitor selected from oleclumab, BMS- 986179, uliledlimab, imaradenant, NIR178, and etrumadenant, and c) an anti-PD(L)l antibody. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) an anti-Trop-2 ADC having a structure mAb-CL2A-SN-38, represented by:
Figure imgf000063_0001
b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uliledlimab, imaradenant, NIR178, and etrumadenant, and c) an anti-PD(L)l antibody. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g. , a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan or datopotamab deruxtecan (DS- 1062); b) an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uliledlimab, imaradenant, NIR178, and etrumadenant; and c) and anti-PD(L)l antibody. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan; b) etrumadenant; and c) an anti-PD(L)l antibody. In some embodiments, the anti-PD(L)l antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cctrclimab, gcnolimzumab, prolgolimab, lodapolimab, camrclizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD(L)l antibody is zimberelimab. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan; b) etrumadenant; and c) zimberelimab. In some embodiments, the Trop-2 positive cancer is castrate resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC). In some embodiments, the Trop-2 positive cancer is CRPC. In some embodiments, the Trop-2 positive cancer is metastatic (e.g., mCRPC, mNSCLC). In some embodiments, the Trop-2 positive cancer is resistant or refractive of one or more anti-cancer therapy (e.g., NHA resistant or refractive mCRPC).
[0189] In some embodiments, the methods provided herein comprise co-administering to a subject e.g., a human cancer patient) having a tumor antigen positive (TA+) cancer an effective amount of a) a Topi ADC; and b) an adenosine pathway inhibitor. In some embodiments, the Topi ADC comprises a camptothecin analog. In some embodiments, the camptothecin analog is an irinotecan derivative, a topotecan derivative, or an exatecan derivative. In some embodiments, the camptothecin analog is SN38 or Dxd. In some embodiments, the camptothecin analog is SN38. In some embodiments, the camptothecin analog is connected to a tumor antigen targeted antibody via a hydrolyzable linker. In some embodiments, the hydrolyzable linker is CL2A (e.g., as described in US 7,999,083). In some embodiments, the camptothecin analog is connected to a tumor antigen targeted antibody via a protease cleavable linker. In some embodiments, the Topi ADC has a structure mAb-CL2A-SN-38, represented by:
Figure imgf000064_0001
(described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the tumor antigen targeted antibody in the Topi ADC is selected from gemtuzumab, brentuximab, belantamab, camidanlumah, trastuzumab, inotuzumab, glembatumumab, anetumab, mirvetuximab, dcpatuxizumab, vadastuximab, labctuzumab, ladiratuzumab, loncastuximab, patritumab, lifastuzumab, indusatumab, polatuzumab, pinatuzumab, coltuximab, upifitamab, indatuximab, milatuzumab, rovalpituzumab, enfortumab, tisotumab, tusamitamab, disitamab, telisotuzumab, and antigen-binding fragments thereof. In some embodiments, the tumor antigen targeted antibody in the Topi ADC is selected from hLLl, hLL2, RFB4, hA19, hA20, hRS7, hPAM4, hMN-3, hMN-14, hMu-9, hRl, CC49, hL243, D2/B, hlmmu-31, and antigen binding fragments thereof. In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is >7.5 (e.g., DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises the anti-Trop-2 antibody sacituzumab (hRS7, described, e.g., in W02003074566, Figures 3 and 4). In some embodiments, the Topi ADC is trastuzumab deruxtecan. In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist. In some embodiments, the CD39 inhibitor is selected from TTX-030 (AbbVie/Trishula), IPH5201 (AstraZeneca/Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secama Pharmaceuticals), JS-O19 (Shanghai Junshi Biosciences); anti-CD39 (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPDl (Biotheus). In some embodiments, the CD73 inhibitor is selected from oleclumab (AstraZeneca), BMS-986179 (BMS), uliledlimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB68O, Arcus Biosciences), mupadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), TNCAOO186 (Tncyte), IBT325 (Tnnovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB- BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPDl, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene/Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is oleclumab or quemliclustat. In some embodiments, the CD73 inhibitor is quemliclustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; AD0RA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarns Therapeutics), or TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; AD0RA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenant (AB928, Arcus Biosciences), INCB 106385 (Incyte), M1069 (Merck KGaA), A2aR/A2bR (Domain/Merck KGaA), HM87277 (Al/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), TT-53 (Tarns Therapeutics). In some embodiments, the methods provided herein further comprise co-administering an additional therapeutic agent or therapeutic modality, or a combination thereof. In some embodiments, the additional therapeutic agent comprises an immune checkpoint inhibitor. In some embodiments, the CPI comprises an anti-PD(L)l antibody (e.g., an anti-PD-1 antibody or an anti-PD-Ll antibody), and optionally an anti-TIGIT antibody. In some embodiments, the anti-PD(L)l antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD(L)l antibody is zimberelimab. In some embodiments, the anti-TIGIT antibody is selected from tiragolumab, vibostolimab, domvanalimab, AB3O8, AK127, BMS-986207, ralzapastotug, and etigilimab. In some embodiments, the anti-TIGIT antibody is domvanalimab. In some embodiments, the additional therapeutic agent comprises an anti-PD(L)l antibody and an anti- TIGIT antibody. In some embodiments, the additional therapeutic agent comprises a) zimberelimab and domvanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vibostolimab, e) MK-7684A (pembrolizumab/vibostolimab coformulation), f) durvalumab and domvanalimab, g) zimberelimab and ralzapastotug, or h) pembrolizumab and ralzapastotug. In some embodiments, the anti-PD(L)l antibody is zimberelimab and the anti-TIGIT antibody is domvanalimab. In some embodiments, the additional therapeutic modality comprises surgery or radiation therapy. In some embodiments, the tumor antigen positive cancer is positive for a tumor antigen selected from carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2/neu, BrE3, CD1, CDla, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, ED-B fibronectin, EGP-1, EGP-2, EGF receptor (ErbB1 ), ErbB2, ErbB3, Factor H, FHL-1 , Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia inducible factor (HIF), HM1.24, HER-2/ncu, insulin-like growth factor (ILGF), IFN-α , IFN-p, IL-γ. IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, la, HM1.24, gangliosides, HCG, HLA- DR, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration-inhibitory factor (MTF), MUC1 , MUC2, MUC3, MUC4, MUC5, placental growth factor (Pl GF), PSA (prostate-specific antigen), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas -Friedenreich antigens, tumor necrosis antigens, tumor angiogenesis antigens, TNF-α , TRAIL receptor (R1 and R2), VEGFR, RANTES, T101, cancer stem cell antigens, complement factors C3, C3a, C3b, C5a, C5, and an oncogene product.
[0190] General dosing and administration regimens and pharmaceutical compositions for antibody-drug conjugates, adenosine pathway inhibitors, and additional therapeutic agents that can be used in the methods provide herein are known to a skilled artisan. For example, general dosing and administration regimens and pharmaceutical compositions are described in W02014/092804A1 for exemplary ADCs, including sacituzumab govitecan, in WO2017120508 for exemplary CD73 inhibitors, including quemliclustat, in W02018136700A1 for exemplary adenosine receptor antagonists, including etrumadenant, and in W02017025051A1 for exemplary anti-PD(L)l antibodies, including zimberelimab.
[0191] In the methods provided herein, the ADC (e.g., sacituzumab govitecan), adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat), and, optionally, the anti-PD(L)l antibody (e.g., zimberelimab) can be co-administered simultaneously, continuously, or sequentially. In some embodiments, the ADC (e.g., sacituzumab govitecan), adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat), and, optionally, the anti-PD(Ll) antibody (e.g., zimberelimab) are co-administered on the same day (e.g., on day 1 of a 21-day treatment cycle). In some embodiments, the ADC (e.g., sacituzumab govitecan), adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat), and, optionally, the anti-PD(Ll) antibody (e.g., zimberelimab) are co-administered sequentially or continuously. In some embodiments, the ADC (e.g., sacituzumab govitecan), adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat), and, optionally, the anti-PD(Ll) antibody (e.g., zimberelimab) are co-administered sequentially. In some embodiments, sacituzumab govitecan and etrumadenant are co-administered sequentially on day 1 of a 21 -day treatment cycle, wherein etrumadenant is co-administcrcd orally at least 30 minutes prior to the start of an intravenous infusion of sacituzumab govitecan. In some embodiments, sacituzumab govitecan, etrumadenant, and zimberelimab are co-administered sequentially on day 1 of a 21 -day treatment cycle, wherein etrumadenant is co-administered orally at least 30 minutes prior to the start of an intravenous infusion of zimberelimab, and sacituzumab govitecan is coadministered intravenously after completion of the zimberelimab infusion.
[0192] In some embodiments of the methods provided herein, sacituzumab govitecan is coadministered on day 1 and day 8 of a 21 -day treatment cycle. In some embodiments, sacituzumab govitecan is co-administered intravenously (IV). Tn some embodiments, sacituzumab govitecan is co-administered at a dose of 8 mg/kg to 10 mg/kg. In some embodiments, sacituzumab govitecan is co-administered at a dose of 8 mg/kg or 10 mg/kg. In some embodiments, sacituzumab govitecan is co-administered at a dose of 10 mg/kg. In some embodiments, sacituzumab govitecan is coadministered intravenously (IV) at a dose of 8 mg/kg or 10 mg/kg on day 1 and day 8 of a 21-day treatment cycle.
[0193] In some embodiments of the methods provided herein, etrumadenant is co-administered once daily (QD). In some embodiments, etrumadenant is co-administered orally (PO). In some embodiments, etrumadenant is co-administered at a dose of 75 mg or 150 mg. In some embodiments, etrumadenant is co-administered at a dose of 150 mg. Tn some embodiments, etrumadenant is co-administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg. In some embodiments, etrumadenant is co-administered orally (PO) once daily (QD) at a dose of 150 mg.
[0194] In some embodiments of the methods provided herein, an anti-PD(L)l antibody (e.g., zimberelimab) is co-administered once every three weeks (Q3W). In some embodiments, an anti- PD(L)1 antibody is co-administered intravenously (IV). In some embodiments, an anti-PD(L)l antibody is co-administered at a dose of 360 mg.
[0195] In some embodiments of the methods provided herein, sacituzumab govitecan is coadministered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 8 mg/kg or 10 mg/kg; etrumadenant is co-administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21 -day treatment cycle, and, optionally, zimberelimab is coadministered on day 1 of the 21-day treatment cycle (Q3W) at a dose of 360 mg.
[0196] In some embodiments of the methods provided herein, sacituzumab govitecan is coadministered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 10 mg/kg; etrumadenant is co-administered orally (PO) once daily (QD) at a dose of 150 mg on each day of the 21-day treatment cycle, and, optionally, zimberelimab is co-administered on day 1 of the 21-day treatment cycle (Q3W) at a dose of 360 mg.
[0197] In some embodiments, the methods provided herein have anti-cancer effects as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, tumor response or progression is determined according to RECIST version 1.1. In some embodiments, the ORR is defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response determined by the investigator according to the Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, the PSA response is defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on 2 consecutive assessments measured at least 3 to 4 weeks apart. Tn some embodiments, the radiographic response defined as the proportion of participants with a best overall response of CR or PR according to RECIST v 1.1. In some embodiments, DCR is defined as the proportion of participants with a best overall RECIST response of CR, PR, or stable disease (SD). In some embodiments, the DCR is at least 6 months. In some embodiments, PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiographic progression, bone scan progression, or other) or death, whichever occurs first. Depending on data availability, time to progression due to specific reasons (e.g., PSA progression or radiographic progression) may also be presented individually. In some embodiments, OS is defined as the time from treatment assignment until death due to any cause.
[0198] In some embodiments, the methods provided herein further comprise determining tumor antigen (e.g., Trop-2) expression levels in a sample from the subject. The determination of tumor antigen (e.g., Trop-2) expression levels can occur with any clinical analytics method known to a skilled artisan. Samples can include liquid biopsy samples (e.g., blood samples) and solid tumor biopsy samples. Tumor antigen (e.g., Trop-2) expression levels can be determined at the DNA, RNA, or protein level. Illustrative methods for the determination of tumor antigen (e.g., Trop-2) expression levels include western blot, immunohistochemistry, QPCR, exome sequencing, FACS, and the like.
[0199] In some embodiments of the methods provided herein, an anti-CD47 antibody is not coadministered to the subject or human patient (CD47; integrin associated protein; IAP; NCBI Gene ID: 961). In some embodiments, the subject or human patient is not co-administered an anti-CD47 antibody selected from magrolimab, lemzoparlimab, letaplimab, ligufalimab, AO- 176, IBI-322, ZL-1201, IMC-002, SRF-231, CC-90002 (a.k.a., INBRX-103), NI-1701 (a.k.a., TG-1801) and STI-6643. In some embodiments, the subject or human patient is not co-administered magrolimab.
[0200] In some embodiments of the methods provided herein, an MCL1 inhibitor is not coadministered to the subject or human patient (MCL1; myeloid leukemia cell differentiation protein; NCBI Gene ID: 4170). In some embodiments, the subject or human patient is not coadministered an MCL1 inhibitor selected from GS-9716, AMG-397, AMG-176, PRT-1419, and S6431. In some embodiments, the subject or human patient is not co-administered GS-9716.
[0201] In some embodiments of the methods provided herein, a FLT3 agonist is not coadministered to the subject or human patient (FLT3; fms like tyrosine kinase; CD135; NCBI Gene ID: 2322). In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK- 605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.
Kits
[0202] Provided herein are kits for use as a medicament, wherein the kit comprises a) TROP-2- targeted antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an adenosine pathway inhibitor; and c) optionally an anti-PD-(L)l antibody.
[0203] Also provided herein are kits for use as a medicament, wherein the kit comprises a) a tumor antigen (TA) targeted ADC comprising a topoisomerase I inhibitor (Topi ADC); b) an adenosine pathway inhibitor; and c) optionally an anti-PD-(L)! antibody. [0204] Also described herein are kits comprising one or more unitary doses of the active agents, e.g., a) an anti-Trop-2 ADC (c.g., sacituzumab govitccan) or Topi ADC; b) an adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) an anti-PD(L)l antibody (e.g., zimberelimab), and formulations thereof, as described herein, and instructions for use. In various embodiments the a) anti-Trop-2 ADC (e.g., sacituzumab govitecan) or Topi ADC; b) adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab) can be in the same or different containers. The kit can further contain a least one additional reagent, e.g. an anti-TIGIT antibody. Kits typically include a label indicating the intended use of the contents of the kit. The term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
[0205] In some embodiments, one or more of the a) anti-Trop-2 ADC (e.g., sacituzumab govitecan) or Topi ADC; b) adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab), are provided in a dosage form (e.g., a therapeutically effective dosage form). In some embodiments, one or more of the a) anti-Trop-2 ADC (e.g., sacituzumab govitecan) or Topi ADC; b) adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab) are provided in two or more different dosage forms (e.g., two or more different therapeutically effective dosage forms). In the context of a kit, one or more of the a) anti-Trop-2 ADC (e.g., sacituzumab govitecan) or Topi ADC; b) adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab) can be provided in liquid or solid form in any convenient packaging (e.g., stick pack, dose pack, etc.).
[0206] The a) anti-Trop-2 ADC (e.g., sacituzumab govitecan) or Topi ADC; b) adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab) can be provided in the same or separate containers, as appropriate. In various embodiments, the a) anti-Trop-2 ADC (e.g., sacituzumab govitecan) or Topi ADC; b) adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab) are provided in separate containers. Compositions comprising one or more of the a) anti-Trop-2 ADC (e.g., sacituzumab govitecan) or Topi ADC; b) adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat); and optionally c) anti-PD(L)l antibody (e.g., zimberelimab) are provided in one or more containers, the containers having a label. Suitable containers include, for example, bottles, vials, ampoules, syringes (including pre-loaded syringes), and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The active agent in one composition is a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or Topi ADC. The active agent in a second composition is an adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat). The active agent in an optional third composition is optionally c) anti-PD(L)l antibody (e.g., zimberelimab). The label on, or associated with, the container indicates that the composition is used for treating the condition of choice. The article of manufacture may further comprise one or more containers comprising a pharmaceutically- acceptable buffer, e.g., for use as diluent. Illustrative buffers include without limitation phosphate -buffered saline, Ringer’s solution and/or dextrose solution. The kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
[0207] In addition to the above components, the subject kits may further include (in certain embodiments) instructions for practicing the subject methods. These instructions may be present in the subject kits in a variety of forms, one or more of which may be present in the kit. One form in which these instructions may be present is as printed information on a suitable medium or substrate, e.g., a piece or pieces of paper on which the information is printed, in the packaging of the kit, in a package insert, and the like. Yet another form of these instructions is a computer readable medium, e.g., diskette, compact disk (CD), flash drive, and the like, on which the information has been recorded. Yet another form of these instructions that may be present is a website address which may be used via the internet to access the information at a removed site.
Exemplary Embodiments
[0208] In some embodiments, provided herein is a method of treating metastatic castrateresistant prostate cancer (mCRPC) comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; and b) etrumadenant. In some embodiments, the method further comprises co-administering zimberelimab to the human patient. In some embodiments, the human mCRPC patient has previously progressed on androgen deprivation therapy (ADT). In some embodiments, the human mCRPC patient has previously progressed on one or more next generation hormonal agents (NHAs, e.g., abiraterone, enzalutamide, darolutamide, apalutamide). In some embodiments, the human mCRPC patient is checkpoint inhibitor (CPI) and taxanc naive. In some embodiments, the human mCRPC patient has RECIST 1.1 measurable or non-measurable disease.
[0209] In some embodiments, provided herein is a method of treating castrate resistant prostate cancer (CRPC) comprising co-administering to a human patient an effective amount of a) an anti- Trop-2 ADC; b) a CD73 inhibitor or adenosine receptor antagonist; and, optionally, c) an anti- PD(L)1 antibody. In some embodiments, the CRPC is metastatic CRPC (mCRPC). In some embodiments, the anti-Trop-2 ADC has a structural formula of mAb-CL2A-SN-38, with a structure represented by:
Figure imgf000073_0001
(described, e.g., in USPN 7,999,083). In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0 (e.g., DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by:
Figure imgf000073_0002
attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate (TL035) having a structure represented by:
Figure imgf000074_0001
attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by:
Figure imgf000074_0002
attached to an anti-Trop-2 antibody (e.g., hTINAl-HILl). In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02 and BAT-8003. In some embodiments, the anti-Trop-2 antibody is sacituzumab govitecan or datopotamab deruxtecan. In some embodiments, the anti-Trop-2 antibody is sacituzumab govitecan. In some embodiments, the CD73 inhibitor is selected from oleclumab (AstraZeneca), BMS-986179 (BMS), uliledlimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB680, Arcus Biosciences), mupadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3Sbio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPDl, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene/Calithera), GB7002 (Genbase Bio), ATG-037 (Antcngcnc), and CD73i (Biothcus). In some embodiments, the CD73 inhibitor is selected from oleclumab and quemliclustat. In some embodiments, the CD73 inhibitor is quemliclustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; AD0RA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), or TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; AD0RA2B) antagonist, such as PBF- 1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenant (AB928, Arcus Biosciences), INCB 106385 (Incyte), M1069 (Merck KgaA), A2aR/A2bR (Domain/Merck KgaA), HM87277 (Al/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), and TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is etrumadenant. In some embodiments, the anti-PD(L)1 antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD(L)l antibody is zimberelimab. In some embodiments, the human patient is not co-administered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
[0210] In some embodiments, provided herein is a method of treating castrate resistant prostate cancer (CRPC) comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; and b) etrumadenant. In some embodiments, the CRPC is metastatic CRPC (mCRPC). In some embodiments, the CRPC or mCRPC ((m)CRPC) is resistant or refractive to at least one anti-cancer therapy. In some embodiments, the human patient has shown disease progression after prior treatment with a new hormonal agent (NHA; first- or second- generation non-steroidal antiandrogens, abiraterone, enzalutamide, darolutamide, apalutamide). In some embodiments, the human patient has not received a prior taxane therapy (e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), checkpoint inhibitor therapy (e.g., anti- CTLA4 antibody, anti-PD(L)l antibody), topoisomerase I inhibitor therapy (e.g., irinotecan). In some embodiments, the human patient with (m)CRPC has histologically confirmed adenocarcinoma of the prostate and metastatic castrate resistant with tumor progression while on androgen deprivation therapy (ADT ; including orchiectomy) with castrate levels of scrum (total) testosterone (<1.7 nmol/L or 50 ng/dL) defined by PSA and/or radiographic criteria according to PCWG3. In some embodiments, the human patient (m)CRPC has metastatic castrate resistant adenocarcinoma of the prostate with tumor progression while on androgen deprivation therapy (e.g., including orchiectomy) with castrate levels of serum (total) testosterone (< 1.7 nmol/L or 50 ng/dL) defined by prostate specific antigen (PSA) and/or radiographic criteria according to The Prostate Cancer Working Group 3 (PCWG3) and measurable or non-measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l. In some embodiments, the human patient with (m)CRPC has Eastern Cooperative Oncology Group performance status 0 or 1 with a life expectancy >3 months. In some embodiments, the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing). In some embodiments, sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 8 mg/kg or 10 mg/kg and etrumadenant is administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21-day treatment cycle. In some embodiments, sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 10 mg/kg and etrumadenant is administered orally (PO) once daily (QD) at a dose of 150 mg on each day of the 21-day treatment cycle. In some embodiments, the methods provided herein have anti-cancer effects as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, the ORR is defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response determined by the investigator according to the Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, the PSA response is defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on 2 consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, the radiographic response defined as the proportion of participants with a best overall response of CR or PR according to RECIST vl.l. In some embodiments, DCR is defined as the proportion of participants with a best overall RECTST response of CR, PR, or stable disease (SD). Tn some embodiments, the DCR is at least 6 months. In some embodiments, PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiographic progression, bone scan progression, or other) or death, whichever occurs first. Depending on data availability, time to progression due to specific reasons (e.g., PSA progression or radiographic progression) may also be presented individually. In some embodiments, OS is defined as the time from treatment assignment until death due to any cause. In some embodiments, the human patient is not coadministered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
[0211] Tn some embodiments, provided herein is a method of treating castrate resistant prostate cancer (CRPC) comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; b) etrumadenant and c) zimberelimab. In some embodiments, the CRPC is metastatic CRPC (mCRPC). In some embodiments, the CRPC or mCRPC ((m)CRPC) is resistant or refractive to at least one anti-cancer therapy. In some embodiments, the human patient has shown disease progression after prior treatment with a new hormonal agent (NHA; first- or second-generation non-steroidal antiandrogens, e.g, abiraterone, enzalutamide, darolutamide, apalutamide). In some embodiments, the human patient has not received a prior taxane therapy (e.g., paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)l antibody), topoisomerase I inhibitor therapy (e.g., irinotecan). In some embodiments, the human patient with (m)CRPC has histologically confirmed adenocarcinoma of the prostate and metastatic castrate resistant with tumor progression while on androgen deprivation therapy (ADT ; including orchiectomy) with castrate levels of serum (total) testosterone (<1.7 nmol/L or 50 ng/dL) defined by PSA and/or radiographic criteria according to PCWG3. In some embodiments, the human patient (m)CRPC has metastatic castrate resistant adenocarcinoma of the prostate with tumor progression while on androgen deprivation therapy (e.g., including orchiectomy) with castrate levels of serum (total) testosterone (< 1.7 nmol/L or 50 ng/dL) defined by prostate specific antigen (PSA) and/or radiographic criteria according to The Prostate Cancer Working Group 3 (PCWG3) and measurable or non-measurable disease per the Response Evaluation Criteria in Solid Tumors (RECTST) vl .l . Tn some embodiments, the human patient with (m)CRPC has Eastern Cooperative Oncology Group performance status 0 or 1 with a life expectancy >3 months. In some embodiments, the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or nextgeneration DNA sequencing). In some embodiments, sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 8 mg/kg or 10 mg/kg, etrumadenant is administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21-day treatment cycle, and zimberelimab is administered on day 1 of the 21- day treatment cycle (Q3W) at a dose of 360 mg. In some embodiments, sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 10 mg/kg, etrumadenant is administered orally (PO) once daily (QD) at a dose of 150 mg on each day of the 21-day treatment cycle, and zimberelimab is administered on day 1 of the 21-day treatment cycle (Q3W) at a dose of 360 mg. In some embodiments, the methods provided herein have anticancer effects as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, hr some embodiments, the ORR is defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response determined by the investigator according to the Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, the PSA response is defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on 2 consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, the radiographic response defined as the proportion of participants with a best overall response of CR or PR according to RECIST vl.l. In some embodiments, DCR is defined as the proportion of participants with a best overall RECIST response of CR, PR, or stable disease (SD). In some embodiments, the DCR is at least 6 months. In some embodiments, PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiographic progression, bone scan progression, or other) or death, whichever occurs first. Depending on data availability, time to progression due to specific reasons (e.g., PSA progression or radiographic progression) may also be presented individually. In some embodiments, OS is defined as the time from treatment assignment until death due to any cause. In some embodiments, the human patient is not co-administered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist. [0212] Tn some embodiments, provided herein is a method of treating metastatic non-small cell lung cancer (mNSCLC) comprising co-administcring to a human mNSCLC patient an effective amount of a) sacituzumab govitecan; b) etrumadenant; and c) an anti-PD-(L)l antibody. In some embodiments, the anti-PD-(L)l antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)l antibody is zimberelimab. In some embodiments, the human mNSCLC patient has progressed after platinumbased chemotherapy. In some embodiments, the human mNSCLC patient has progressed after checkpoint inhibitor therapy (e.g., anti-PD-(L)l antibody or anti-CTLA4 antibody therapy). In some embodiments, the human mNSCLC patient has progressed after platinum-based chemotherapy and anti-PD-(L)l antibody therapy, received either in combination or sequentially (in any order). In some embodiments, the human mNSCLC patient is treatment naive.
[0213] In some embodiments, provided herein is a method of treating non-small cell lung cancer (NSCLC) comprising co-administering to a human patient an effective amount of a) an anti-Trop- 2 ADC; b) a CD73 inhibitor or adenosine receptor antagonist; and, optionally, c) an anti-PD(L)l antibody. In some embodiments, the NSCLC is metastatic NSCLC (mNSCLC). In some embodiments, the anti-Trop-2 ADC has a structural formula of mAb-CL2A-SN-38, with a structure represented by:
Figure imgf000079_0001
(described, e.g., in USPN 7,999,083). In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0 (e.g., DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by:
Figure imgf000080_0001
attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate (TL035) having a structure represented by:
Figure imgf000080_0002
Attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by:
Figure imgf000080_0003
attached to an anti-Trop-2 antibody (e.g., hTINAl-HILl). In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02 and BAT-8003. In some embodiments, the anti-Trop-2 antibody is sacituzumab govitecan or datopotamab deruxtecan. In some embodiments, the anti-Trop-2 antibody is sacituzumab govitecan. Tn some embodiments, the CD73 inhibitor is selected from oleclumab (AstraZeneca), B MS-986179 (BMS), ulilcdlimab (I-MAB Biopharma), AK119 (Akcso Biopharma), quemliclustat (AB680, Arcus Biosciences), mupadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPDl, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene/Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is selected from oleclumab and quemliclustat. In some embodiments, the CD73 inhibitor is quemliclustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), or TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF- 1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenant (AB928, Arcus Biosciences), INCB 106385 (Incyte), M1069 (Merck KGaA), A2aR/A2bR (Domain/Merck KGaA), HM87277 (Al/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), and TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is etrumadenant. In some embodiments, the anti-PD-(L)l antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)l antibody is zimberelimab. In some embodiments, the human patient is not co-administered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
[0214] Tn some embodiments, provided herein is a method of treating non-small cell lung cancer (NSCLC) comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; b) etrumadenant; and c) an anti-PD-(L)l antibody. In some embodiments, the anti-PD- (L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atczolizumab, avclumab, durvalumab, cosibclimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)l antibody is zimberelimab. In some embodiments, the NSCLC is metastatic NSCLC (mNSCLC). In some embodiments, the NSCLC or mNSCLC ((m)NSCLC) is resistant or refractive to at least one anti-cancer therapy. In some embodiments, the human mNSCLC patient has progressed after platinum-based chemotherapy. In some embodiments, the human mNSCLC patient has progressed after checkpoint inhibitor therapy (e.g., anti-PD-(L)l antibody or anti-CTLA4 antibody therapy). In some embodiments, the human mNSCLC patient has progressed after platinum-based chemotherapy and anti-PD-(L)l antibody therapy, received either in combination or sequentially (in any order). In some embodiments, the human mNSCLC patient is treatment naive. In some embodiments, the human patient with (m)NSCLC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy, followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing). In some embodiments, sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21 -day treatment cycle at a dose of 8 mg/kg or 10 mg/kg and etrumadenant is administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21-day treatment cycle. In some embodiments, sacituzumab govitecan is administered intravenously (IV) on day 1 and day 8 of a 21-day treatment cycle at a dose of 10 mg/kg and etrumadenant is administered orally (PO) once daily (QD) at a dose of 150 mg on each day of the 21-day treatment cycle. In some embodiments, the methods provided herein have anti-cancer effects as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, tumor response or progression is determined according to RECIST version 1.1. In some embodiments, the human patient is not co-administered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
[0215] Disclosed herein are methods of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of breast cancer comprising co-administering to a human patient an effective amount of: (a) sacituzumab govitecan; and (b) a CD73 inhibitor. Tn some embodiments, the CD73 inhibitor is olcclumab, BMS-986179, ulilcdlimab, AK119, qucmliclustat, mupadolimab, HLX23, INCA00186, IB 1325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037. In some embodiments, the CD73 inhibitor is quemliclustat (AB680, GS- 0680), uliledlimab, mupadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS- 986179, or oleclumab. In some embodiments, the CD73 inhibitor is quemliclustat (AB680, GS- 0680). In some embodiments, the method further comprises co-administering an anti-PD-(L)l antibody to the human patient. In some embodiments, the anti-PD-(L)l antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the method further comprises co-administering zimberelimab to the human patient. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is resistant or refractory to one or more anti-cancer therapies. In some embodiments, the breast has progressed following prior anti-cancer therapy (first- or second-generation anti-cancer therapy, e.g., hormone therapy). In some embodiments, the human patient has not received a prior therapy selected from taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy. In some embodiments, the human patient has not received a prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy. In some embodiments, the taxane therapy comprises paclitaxel, nab-paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel. In some embodiments, the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti- PD(L)1 antibody. In some embodiments, the topoisomerase I inhibitor therapy comprises a topotecan, irinotecan, belotecan, or exatecan. In some embodiments, the methods provided herein have anti-cancer effects as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), radiographic response rate, and change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, tumor response or progression is determined according to RECTST version 1.1. In some embodiments, the human patient is not co-administcrcd an additional therapeutic agent selected from an MCL- 1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.
EXAMPLES
[0216] The following examples are offered to illustrate, but not to limit the claimed invention.
EXAMPLE 1
A Phase 1/2 Study of Trop-2 ADC, Adenosine Receptor Antagonist, and PD(L)1 Antagonist Combination Therapy for Metastatic Castrate Resistant Prostate Cancer
[0217] A clinical study is conducted administering human patients with metastatic castrate resistant prostate cancer (mCRPC) with a combination of an anti-Trop-2 antibody and an adenosine receptor antagonist. Optionally, a subgroup of patients is treated with a combination of an anti-Trop-2 antibody, an adenosine receptor antagonist, and an anti-PD-(L)l antibody.
[0218] In one arm of the study, human mCRPC patients are treated with a combination of sacituzumab govitecan and etrumadenant. In an optional additional arm of the study human mCRPC patients are treated with a combination of sacituzumab govitecan (SG), etrumadenant, and zimberelimab.
[0219] The patient population in this study can include previously treated mCRPC patients who have progressed on androgen deprivation therapy (ADT) and/or next generation hormonal agents (NHAs). mCRPC patients who are CPI and taxane naive can also be included. Additional patients can have RECIST 1.1 measurable or non-measurable disease.
[0220] Primary endpoints in the study can include composite overall response rate (ORR; PSA/RECIST Response) and safety.
[0221] Secondary endpoints can include ORR per RECIST 1.1, PSA response rate per PCWG3, disease control rate (DCR), or pharmacokinetics (PK).
[0222] Exploratory endpoints can include progression free survival, overall survival, or certain biomarkers. Investigational Products
Sacituzumab govitecan
[0223] Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) composed of the following 3 components: o The humanized monoclonal antibody hRS7 IgGlK, which binds to trophoblast cellsurface antigen 2 (Trop-2), a transmembrane calcium signal transducer that is overexpressed in many epithelial cancers, including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). o The camptothecin-derived agent SN-38, a topoisomerase I inhibitor. o A hydrolyzable linker CL2A that links the humanized monoclonal antibody to SN-38.
[0224] Binding of Trop-2 by the parental RS7 antibody has been shown to result in internalization and processing of the antibody by the targeted cells (Shih LB, et al. Journal of Nuclear Medicine. (1994) 35(5):899-908; Stein R, et al. Cancer Research. (1995) 55(14):3132- 9.). Because of its hydrolyzable linker, SG will release its SN 38 payload both intra- and extracellularly in the tumor microenvironment (Goldenberg DM, et al. Oncotarget (2015) 6(26):22496Govindan SV, et al. Molecular Cancer Therapeutics (2013) 12(6):968-78). SG delivers significantly greater amounts of SN 38 to a Trop 2-cxprcssing tumor than conventional irinotecan chemotherapy (Sharkey RM, et al. Clinical Cancer Research (2015) 21(22):5131-8). The extracellular release of SN 38 from SG also allows for bystander killing of Trop 2 negative tumor cells (Lopez S, et al. Oncotarget (2020) l l(5):560;Perrone E, et al. Frontiers in Oncology (2020): 118; Zeybek B, et al. Scientific Reports (2020) 10(l):973)Thus, SG can deliver cytotoxic chemotherapy to tumors, including adjacent cancer cells, in concentrations that are higher than those with standard chemotherapy and may reduce toxic effects in normal tissues that do not express the target.
[0225] In the clinical studies described herein, sacituzumab govitecan is generally administered at 10 mg/kg as an IV infusion on Days 1 and 8 of a 21-day cycle. Etrumadenant
[0226] Etrumadenant (also known as AB928, GS-0928) is a low-molecular-weight, orally bioavailable, selective dual antagonist of adenosine receptors adenosine 2a receptor (A2aR) and adenosine 2b receptor (A2b ). The therapeutic rationale for the clinical development of etrumadenant stems from the realization that most tumors contain high extracellular levels of adenosine, which activates A2aR and A2bR on T cells and myeloid cells, respectively, resulting in the impairment of T-cell activation and proliferation. Utilizing a variety of biochemical, cell-based, and in vivo models, etrumadenant has been shown to selectively reverse the immunosuppressive effects caused by high concentrations of adenosine, without causing any immune activation effects on its own. Tn prostate cancer, A2bR is upregulated and the activity of prostatic acid phosphatase (PAP) produces additional adenosine, suggesting this tumor type may be more susceptible than others to adenosine-mediated immunosuppression. Etrumadenant can achieve high penetration of tumor tissue, robust potency in the presence of high adenosine concentrations, and only small shift in potency from nonspecific protein binding. As a result, etrumadenant is expected to effectively block adenosine’s immunosuppressive and cancer cell -intrinsic effects. Etrumadenant exhibits PK/pharmacodynamics consistent with once-daily dosing and has been well tolerated in dose escalation studies as a single agent and in Phase lb/2 studies administered in combination with chemo/immunotherapy across multiple advanced solid tumor indications.
[0227] Tn the clinical studies described herein, etrumadenant is generally administered orally at a dose of 75 mg or 150 mg QD.
Zimberelimab
[0228] Zimberelimab is a fully human IgG4 monoclonal antibody targeting human PD- 1. PD- 1 is a type I transmembrane protein that is part of the immunoglobulin gene superfamily and the CD28 family of cell surface receptors. The structure of PD-1 consists of 1 immunoglobulin variable-like extracellular domain and 1 cytoplasmic domain containing an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif. PD-1 has 2 known ligands, PD-L1 (B7 Hl and CD274) and programmed cell death ligand 2 (PD-L2; B7 DC and CD73), which are members of the B7 family and are expressed on the plasma membrane of cancer cells and tumor-infiltrating leukocytes. Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1, but they do not bind to other CD28 family members. [0229] PD-1 is an inhibitory immune checkpoint protein that is expressed on activated B cells, T cells, and myeloid cells, and it plays a key role in limiting the activity of effector T cells. It also provides a major resistance mechanism by which tumor cells can escape immune surveillance. When activated by its ligands, PD-1 induces a state of anergy or unresponsiveness in T cells, and the cells are unable to produce optimal levels of effector cytokines or carry out other effector T- cell functions. PD-1 may also induce apoptosis in T cells via its ability to inhibit survival signals. Under normal circumstances, PD-1 is important for limiting the extent of T cell-mediated immune responses. PD- 1 -deficient animals develop various autoimmune phenotypes, including autoimmune cardiomyopathy and a lupus-like syndrome with arthritis and nephritis.
[0230] The interaction of PD-1 expressed on activated T cells and PD-L1 expressed on tumor cells negatively regulates immune response and dampens anticancer immunity. PD-L1 is abundantly expressed on a variety of human tumors, and its expression correlates with reduced patient survival in esophageal, pancreatic, and other types of cancers. Therefore, the PD-1/PD-L1 pathway is an important target for tumor immunotherapy. Activation of the PD-1/PD-L1 signaling pathway results in a decrease in tumor-infiltrating lymphocytes, a decrease in T cell proliferation, and an increase in immune evasion by cancerous cells. Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is also blocked.
[0231] In the clinical studies described herein the selected dose of zimberelimab is generally 360 mg administered IV Q3W.
Investigational Plan
[0232] This is a Phase lb/2, open-label, multicenter platform trial to evaluate the antitumor activity and safety of SG plus etrumadenant-based combination therapy (Table 6) in participants with mCRPC.
[0233] The treatment arms will be conducted in 2 stages: Stage 1 and Stage 2. Depending on the treatment arm and stage, enrollment may or may not involve randomization. The decision to begin randomized enrollment in a specific treatment arm will be made by the sponsor for each combination therapy. Stage 1
[0234] During Stage 1, approximately 15 participants will be enrolled and will receive investigational products at the single agent recommended dose for expansion; standard of care therapies will be administered according to label instructions. The decision to begin enrollment in a specific treatment arm in Stage 1 will be made by the sponsor. The study includes the following anus:
SG + Etrumadenant: Sacituzumab govitecan 10 mg/kg on Days 1 and 8 of a 21-day cycle + Etrumadenant 150 mg QD.
SG+ Etrumadenant + Zimberelimab: Sacituzumab govitecan 10 mg/kg on Days 1 and 8 of a 21-day cycle + Etrumadenant 150 mg QD + Zimberelimab 360 mg Q3W.
[0235] Initial enrollment of 6 participants followed by a pause may occur in treatment arms of novel combination to allow for safety evaluation. If clinical activity (e.g., 1 or more responses in 15 participants) is observed in a treatment arm during Stage 1, approximately 25 additional participants may be enrolled in that am during Stage 2. Treatment arms with insufficient clinical activity or unacceptable toxicity will not proceed to Stage 2.
Stage 2
[0236] During Stage 2, up to 25 additional participants will receive an SG + etrumadenant-based combination therapy explored in Stage 1 or, for applicable arms, a standard of care control appropriate for the participant population under study (Table 6). The decision to begin randomized enrollment to a control arm will be made by the sponsor based on emerging data. The sponsor may also decide to delay or suspend enrollment within a given treatment arm. Additional participants may be enrolled to ensure balance among treatment arms with respect to demographic and baseline characteristics to enable further subgroup analyses.
Table 6: Treatment Arms
Figure imgf000089_0001
CPI = checkpoint inhibitor; NHA = new hormonal agent; SG = sacituzumab govitecan a) Enrollment at Stage 1 may be paused after approximately 6 participants to allow for safety evaluation. b) If clinical activity is observed during Stage 1 , up to 25 additional participants may be enrolled in Stage 2 either onto an experimental arm or a standard of care control arm to better characterize potential treatment differences between experimental arms and standard of care among concurrently enrolled participants.
[0237] Regardless of therapy administered, all participants will complete 3 study periods: (1) Screening (up to 28 days); (2) Treatment; and (3) Follow-up. Participants will be evaluated for response every 12 weeks via the PCWG3 criteria (Scher HI, et al. J Clin Oncol. (2008) 26(7): 1148- 1159.) according to the investigator’s assessment until disease progression (regardless of whether the participant is still receiving treatment), the start of new anticancer therapy, withdrawal of study consent, death, or the end of the study. In Stage 2, participants who progress on standard of care control therapy (i.e. , enzalutamide or docetaxel) may be permitted to crossover to an experimental treatment arm.
[0238] All participants will be closely monitored for AEs throughout study participation. Safety assessments will consist of monitoring and recording AEs, including SAEs and AEs of special interest (AESI), performing protocol- specified safety laboratory assessments, measuring protocol- specified vital signs, and conducting other protocol- specified tests that are deemed critical to the safety evaluation of the study. All AEs and laboratory abnormalities will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Objectives and Endpoints
[0239] Primary, secondary, and exploratory objectives along with corresponding endpoints for the SG + etrumadenant with or without zimberelimab treatment arms are as follows:
Stage 1
• Primary Objective o Efficacy: To evaluate the antitumor activity of SG+etrumadenant-based treatment combinations in Stage 1. o Safety: To evaluate the safety of SG+etrumadenant-based treatment combinations in Stage 1.
• Corresponding Endpoints: o Objective response rate (ORR), defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response determined by the investigator according to the Prostate Cancer Working Group 3 (PCWG3) criteria. o Incidence and severity of adverse events (AEs) and serious adverse events (SAEs).
• Secondary Objective o To evaluate PSA response rate in Stage 1. o To evaluate radiographic response rate in Stage 1. o To evaluate clinical efficacy in Stage 1. o To determine the PK profile for components of etrumadenant-based treatment combinations in Stage 1. o To assess immunogenicity of the biologic component(s) of combination therapy where appropriate in Stage 1.
• Corresponding Endpoints o Proportion of participants with a PSA complete response (CR) and partial response (PR) as defined by PCWG3. o Proportion of participants with radiographic CR and PR as defined by PCWG3 o Disease control rate (DCR) of at least 6 months. o Serum/plasma concentration and PK parameters for components of etrumadenant- based combination therapy. o Number and percentage of participants who develop antidrug antibodies (ADAs) to the biologic component(s) of combination therapy.
• Exploratory Objectives: o To characterize the relationship between tumor tissue/blood-based biomarkers and clinical response or resistance to etrumadenant-based combination therapy. o To use tumor tissue/blood-based biomarkers in the development of diagnostic tests related to etrumadenant-based combination therapy for treatment of the disease under study.
Stage 2
• Primary Objective o To evaluate the antitumor activity of SG+etrumadenant based treatment combinations in Stage 2
• Corresponding Endpoints: o ORR, defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response determined by PCWG3 criteria.
• Secondary Objective o To evaluate the safety of SG+etrumadenant-based treatment combinations in Stage 2. o To evaluate PSA response rate in Stage 2. o To evaluate radiographic response rate in Stage 2. o To evaluate clinical efficacy in Stage 2. o To determine the PK profile for components of SG+etrumadenant-based treatment combinations therapy in Stage 2. o To assess immunogenicity of the biologic component(s) of combination therapy where appropriate in Stage 2.
• Corresponding Endpoints o Incidence and severity of AEs and SAEs. o Proportion of participants with a PSA CR and PR as defined by PCWG3. o Proportion of participants with radiographic CR and PR as defined by PCWG3. o DCR of at least 6 months. o Serum/plasma concentration and PK parameters for components of etrumadenant- based combination therapy. o Number and percentage of participants who develop ADAs to the biologic component(s) of combination therapy.
• Exploratory Objectives: o Progression-free survival. o Overall survival. o To evaluate the change from baseline in blood and tumor tissue microenvironment pharmacodynamic biomarkers in response to SG+etrumadenant-based combination therapy. o To characterize the relationship between tumor tissue/blood-based biomarkers and clinical response or resistance to SG+etrumadenant-based combination therapy. o To use tumor tissue/blood-based biomarkers in the development of diagnostic tests related to SG+etrumadenant-based combination therapy for treatment of the disease under study. o To assess and compare efficacy by tumor expression of Trop-2 and evaluate the role of Trop-2 expression as a biomarker for response to SG combination therapy. Eligibility
Inclusion Criteria
[0240] Participants are eligible to be included in the study only if all the following criteria apply:
1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Male participants > 18 years of age inclusive, at the time of signing the informed consent.
3. Ability to comply with the study protocol in the investigator’s judgment.
4. Histologically confirmed adenocarcinoma of the prostate and metastatic castrate resistant with tumor progression while on androgen deprivation therapy (ADT; including orchiectomy) with castrate levels of serum (total) testosterone (<1.7 nmol/L or 50 ng/dL) defined by PSA and/or radiographic criteria according to PCWG3. Castrate levels of testosterone must be maintained by surgical or medical means throughout study conduct.
5. Measurable (at least 1 target lesion) or nonmeasurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l (Eisenhauer EA, et al. Eur J Cancer. (2009) 45(2):228-247.). Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.
6. Participants for biopsy should have at least 2 measurable lesions at baseline: 1 for tissue sampling and 1 for radiographic response assessment.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Life expectancy > 3 months as determined by the investigator.
9. Adequate hematologic and end-organ function defined by the following laboratory test results at screening: a. Absolute neutrophil count > 1.5 x 109/L (1500/pL) without granulocyte colony stimulating factor support b. White blood cell counts > 2.5 x 109/L (2500/pL) c. Lymphocyte count > 0.5 x 109/L (500/pL) d. Platelet count > 100 x 109/L (100,000/pL) without transfusion e. Hemoglobin > 90 g/L (9.0 g/dL). Participants must not have been transfused within 2 weeks prior to screening to meet minimum platelet and hemoglobin parameters. f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2.5 x upper limit of normal (ULN), with the following exception: i. Participants with documented liver metastases: AST and ALT > 5 x ULN ii. Participants with documented liver or bone metastases: ALP > 5 x ULN g. ALP > 5 x ULN i. If ALP > 5 x ULN, then gamma-glutamyl transpeptidase must be within normal limits h. Bilirubin > 1.5 x ULN, with the following exception: i. Participants with known Gilbert syndrome: serum bilirubin level > 3 x ULN i. Albumin > 25 g/L (2.5 g/dL) j. Serum creatinine > 1.5 x ULN or creatinine clearance > 30 mL/min as determined by Cockcroft-Gault equation (Cockcroft DW and Gault MH Nephron (1976) 16( 1):31-41)
10. Negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), and total hepatitis B core antibody (HBcAb), and hepatitis C virus (HCV) antibody tests at screening. Due to safety concerns related to viral activation, development of a secondary malignancy, as well as the potential for increased treatment-related toxicity, eligible participants must not have evidence of chronic viral infection at screening.
11. Disease progression after prior NHA treatment (first- or second-generation nonsteroidal antiandrogens, abiraterone).
12. No growth factor support within 2 weeks of study drug initiation.
13. Participants with 2 or more measurable lesions will be requested to consent to provide baseline tumor tissue sample (either archival or fresh tumor biopsy). If archived specimen (within 24 months of screening) is unavailable for these patients, a fresh tumor biopsy in a lesion not previously irradiated is required (tumors progressing in a prior site of radiation may be considered after sponsor consultation). The biopsy must not put participants at undue risk and the procedure must not be more invasive than a core biopsy as documented in the medical record by the investigator. Participants with non-measurable disease at baseline will be asked to provide archival tissue (<24 months old) where it is available. Participants with non-measurable disease at baseline without available archival tissue will not be requested to provide fresh biopsy.
Exclusion Criteria
[0241] Participants are excluded from the study if any of the following criteria apply:
1. Prior treatment with immune checkpoint blockade therapies including anticytotoxic T- lymphocyte-associated protein-4, anti-PD-1, and anti-PD-Ll therapeutic antibodies
2. Prior anticancer treatment for the disease under study, including approved agents, systemic radiotherapy, or investigational therapy, within 4 weeks (or 5 half-lives) prior to initiation of study treatment. Prior focal radiotherapy must be completed at least 2 weeks prior to the initiation of study treatment
3. QTc >480 msec using Fredericia’s QT correction formula (based on an average of triplicate recordings)
4. Prior allogeneic stem cell or solid organ transplantation
5. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2) within 4 weeks (or 5 half-lives), whichever is shorter, prior to initiation of study treatment
6. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor-a agents) administered at > 10 mg/day prednisone or equivalent within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressant medication during study treatment, with the following exceptions: a. Patients who received low dose (< 10 mg/day prednisone or equivalent), systemic immunosuppressant medications or a 1-time pulse dose of systemic immunosuppressant medication (eg, 48 hours of corticosteroids for a contrast allergy) are eligible for the study after medical monitor approval has been obtained. b. Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or intranasal corticosteroids for chronic obstructive pulmonary disease or asthma, or low dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study after medical monitor approval has been obtained.
7. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the last dose of study treatment.
8. Current treatment with antiviral therapy for HBV.
9. Structurally unstable bone lesions suggesting impending fracture.
10. Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases a. Patients with a history of treated CNS metastases arc eligible, if all of the following criteria are met: i. The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. ii. Metastases are limited to the cerebellum or the supratentorial region (ie, no metastases to the midbrain, pons, medulla, or spinal cord). iii. There is no evidence of interim progression between completion of CNS directed therapy and the screening brain scan. iv. The patient has not received stereotactic radiotherapy within 7 days prior to initiation of study treatment or whole brain radiotherapy within 14 days prior to initiation of study treatment. v. The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. Anti-convulsant therapy at a stable dose is permitted. b. Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan.
11. Historjr of leptomeningeal disease.
12. History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted b. Participants with ground-glass opacities of unknown significance may be eligible following a discussion with the medical monitor. Participants must be asymptomatic and without evidence of hypoxia on ambulation.
13. History of malignancy other than prostate cancer within 2 years prior to screening, except for malignancies with a negligible risk of metastasis or death (eg, 5-year OS rate > 90%), such as nonmelanoma skin carcinoma or ductal carcinoma in situ
14. Active tuberculosis
15. Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study treatment a. Patients receiving prophylactic antibiotics (eg, to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
16. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
17. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable angina or new onset angina within 3 months prior to initiation of study treatment, myocardial infarction within 6 months prior to initiation of study treatment, or unstable arrhythmia
18. Grade > 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment
19. Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study a. Placement of central venous access catheter (eg, port or similar) is not considered a major surgical procedure and is therefore permitted.
20. Adverse events from prior anticancer therapy that have not improved to Grade < 1 or better, except for alopecia of any grade and Grade < 2 peripheral neuropathy
21. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of study treatment, may affect the interpretation of the results, or may render the patient at high risk from treatment complications 22. Known allergy or hypersensitivity to any of the study drugs or their excipients
23. Inability to swallow medications
24. Malabsorption condition that would alter the absorption of orally administered medications
25. Evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (ie, in the absence of therapeutic anticoagulation)
26. Prior treatment with an agent targeting the adenosine pathway.
27. Prior treatment with docetaxel, cabazitaxel, topoisomerase 1 inhibitors, or other taxane chemotherapy administered as a single agent or as part of a combination regimen.
28. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain Barre syndrome, or multiple sclerosis with the following exceptions: a. Patients with a history of autoimmune related hypothyroidism who are on thyroid replacement hormone are eligible for the study. b. Patients with controlled Type 1 diabetes mellitus who, in the judgment of the investigator, arc on a stable insulin regimen arc eligible for the study. c. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all following conditions are met: i. Rash must cover < 10% of body surface area. ii. Disease is well controlled at baseline and requires only low potency topical corticosteroids. d. There is no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency corticosteroids within the previous 12 months.
29. History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins. 30. Due to the potential risk for drug-drug interactions with etrumadenant, participants must not have had: a. Treatment with known BCRP substrates with a narrow therapeutic window, administered orally (eg, prazosin, rosuvastatin) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to initiation of study treatment. b. Treatment with known P-gp substrates with a narrow therapeutic window, administered orally (eg, digoxin) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to initiation of study treatment. c. Treatment with known strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) and strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to initiation of study treatment.
31. No history of gastrointestinal perforation within 6 months of enrollment.
Study Treatment
Dosage and Administration: Sacituzumab govitecan, Etrumadenant, and Zimberelimab
[0242] Participants will receive sacituzumab govitecan + etrumadenant with or without zimbelimab, as follows:
• Sacituzumab govitecan: 10 mg/kg, IV, on Days 1 and 8 of a 21-day cycle
• Etrumadenant: 150 mg, oral, once daily continuous dosing (21-day cycle)
• Zimberelimab: 360 mg, IV, every 3 weeks (Day 1 of each 21-day cycle)
[0243] Table 7 provides study intervention details: Table 7: Etrumadenant + sacituzumab govitecan with or without zimberelimab
Figure imgf000100_0001
IV = intravenous; Q3W = every 3 weeks; QD = once daily a Product names are listed in order of administration. b A participant may receive etrumadenant as a capsule or tablet but cannot receive both formulations.
[0244] The dose of SG will be calculated based on actual weight at randomization (using weight obtained either at screening or on Cycle 1 Day 1) and remains constant throughout the study, unless there is a > 10% change in body weight from baseline. Modifications to the study drug doses administered should be made for a > 10% change in body weight from baseline and according to local and regional prescribing standards. Dose modifications for changes in body weight < 10% may be made according to local institutional guidelines. Sacituzumab govitecan is administered via IV infusion. Sacituzumab govitecan will be administered in 21-day cycles on Days 1 and 8; the next cycle should start a minimum 14 days after the Day 8 dose (i.e., the Day 8 infusion will be counted as the first day of that 14-day period).
SG + Etrumadenant Administration
[0245] Etrumadenant should be taken at least 30 minutes prior to the start of IV infusion of SG. Sacituzumab govitecan is administered via IV infusion. The first infusion is administered over 3 hours. Subsequent infusions may be administered over 1 to 2 hours if previous infusions were well tolerated.
SG + Etrumadenant + Zimberelimab
[0246] Etrumadenant should be taken at least 30 minutes prior to the start of IV infusion of zimberelimab. Administer zimberelimab over a 60-minute (±5 min) IV infusion followed by a 30- minute observation (+15 min) interval. Following the zimberelimab observation period, sacituzumab govitecan should be administered as described above.
Study Treatment Administration
[0247] Table 8 provides the study treatment administration schedule.
Table 8: Study Treatment Administration
Figure imgf000101_0001
In the absence of dose delays, 1 experimental treatment cycle is 21 days in duration (Cl, C2, C3, C4).
Concomitant Medications
Permitted Therapy for Sacituzumab govitecan + Etrumadenant with or without Zimberelimab
[0248] Concomitant medications or treatments may be prescribed if considered necessary for adequate prophylactic or supportive care except for those medications identified as prohibited further below.
• For applicable participants, continued ADT will be allowed for the duration of the study. • Growth factor support for the management of treatment-emergent hematological toxicity as recommended according to the National Comprehensive Cancer Network/European Organization for Research and Treatment of Cancer guidelines.
• Anticoagulant therapy, including low-molecular-weight heparins, are allowed as clinically indicated. Applicable participants should undergo routine monitoring of coagulation parameters, including INR, according to institutional guidelines.
Premedication and Prophylaxis for Toxicides Associated with Sacituzumab Govitecan
[0249] Premedication is permitted for treatment with SG. Guidance for premedication for prevention of toxicities associated with SG is presented in Table 9.
Table 9
Figure imgf000102_0001
Figure imgf000103_0001
ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology; ESMO = European Society for Medical Oncology, IV = intravenous; PO = orally; SG = Sacituzumab govitecan
Prohibited Therapy for Sacituzumab govitecan + Etrumadenant with or without Zimberelimab
[0250] Use of the following concomitant therapies while receiving SG in combination with etrumadenant with or without zimberelimab is prohibited.
[0251] Concurrent experimental or investigational therapy.
• Concurrent therapy intended for the treatment of cancer (including but not limited to chemotherapy, immunotherapy, and radiotherapy for reasons other than palliative care); however, supportive care agents, including denosumab, bisphosphonates, and hormonal agents are allowed.
• Systemic immuno stimulatory agents (including but not limited to interferons and interleukin-2).
• Systemic immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprinc, methotrexate, thalidomide, and antitumor necrosis factor-a agents) administered at > 10 mg/day prednisone or equivalent on a long-term basis; acute, low dose (≤ 10 mg/day prednisone or equivalent) systemic immunosuppressant medications for management of AEs are allowed after medical monitor approval has been obtained.
• Co-administration of: o BCRP substrates with a narrow therapeutic window, administered orally (eg, prazosin, rosuvastatin) o P-gp substrates with a narrow therapeutic window, administered orally (eg, digoxin) o Strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) and strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, osaconazole, telithromycin, and voriconazole)
[0252] Use the following concomitant therapies with caution while receiving etrumadenant:
• Strong inhibitors of UDP-glucuronosyltransfcrascs (UGTs) of UGT1A1, 1A4, 1A9 and 2B4
• Sensitive substrates of BSEP, MATE1 and OCT2
[0253] Inhibitors or inducers of UGT1A1 should be avoided while receiving SG:
• SN-38 (the active metabolite of sacituzumab govitecan) is metabolized via human UGT1A1. Because of the potential to either increase (inhibitors) or decrease (inducers) the exposure to SN-38, concomitant administration of inhibitors or inducers of UGT1A1, with sacituzumab govitecan, should be avoided unless relevant in-vitro or in-vivo data suggest a lack of clinically significant impact on free SN-38 exposure or there are no therapeutic alternatives.
• Examples of UGT1A1 inducers that should be avoided while receiving SG include: Carbamazepine, efavirenz, ethinylestradiol, lamotrigine, phenobarbital, phenytoin, primidone, rifampicin, ritonavir, and tipranavir.
• Examples of UGT1 Al inhibitors that should be avoided while receiving SG include:
Amitriptyline, atazanavir, dacomitinib, dasabuvir, deferasirox, eltrombopag, enasidenib, erlotinib, flunitrazepam, flurbiprofen, fostamatinib, gemfibrozil, glecaprevir, indinavir, indomethacin, ketoconazole, nilotinib, ombitasvir, paritaprevir, pazopanib, pexidartinib, pibrentasvir, probenecid, propofol, regorafenib, rucaparib, silibinin, sorafenib, and valproic acid. Statistical Considerations
Sample Size Considerations
[0254] This study is not designed with explicit Type I error and power considerations in mind. Rather, this is a Phase lb/2 study intended to obtain preliminary safety, efficacy, and PK data on investigational combinations when administered to patients with mCRPC.
[0255] During Stage 1, participants will be enrolled into various treatment arms based on their prior cancer history. Enrollment may be paused after the accrual of approximately 6 participants in a treatment arm to allow for safety evaluation. A rate of toxicity of < 33% will be targeted, with toxicity being defined as the occurrence of either a treatment-related Grade 4 AE or a treatment- related Grade 3 AE that is not responsive to supportive care during Cycle 1. If 2 or more such events are observed, enrollment in that arm may not continue.
[0256] At the end of Stage 1, a futility analysis will be conducted in each treatment arm in order to guide continuation of enrollment into Stage 2. Futility gates will be arm-specific and anchored to existing standaid of care historical control information for use in a beta-binomial Bayesian decision-making framework.
[0257] Gating will be based on either radiographic or PSA response. Radiographic response is defined as either a CR or PR by RECIST vl.l, and PSA response is defined as percent change from baseline PSA of > 50%. At least 1 radiographic CR or PR or 2 PSA responses out of 15 evaluable participants must be observed in order to consider opening Stage 2. In this case, across a range of prior beta distributions, observing 1 or fewer PSA responses would provide greater than 80% posterior probability confidence that the PSA response rate is less than 20%. Participants must have at least 1 postbaseline radiographic disease evaluation or consecutive postbaseline PSA assessments measured at least 3 to 4 weeks apart to be considered evaluable for Stage 1 decision gating.
[0258] During Stage 2, up to 25 additional participants may be enrolled either onto an experimental arm or a standard of care control arm. The goal of this stage is to better characterize potential treatment differences between experimental arms and standard of care among concurrently enrolled participants. Representative estimates of 90% confidence intervals for potential differences in response between treatment arms are provided. Safety Endpoints
[0259] Safety analyses will be conducted in the safety-evaluable population, defined as all participants who are enrolled and receive any amount of study treatment. Safety will be assessed through summaries of AEs, as well as relevant changes in laboratory test results, vital signs, and electrocardiograms. Verbatim AE terms will be mapped and coded using the Medical Dictionary for Regulatory Activities. All AEs will be assessed for severity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
[0260] Treatment-emergent adverse events (TEAEs), defined as AEs with onset date on or after initiation of study treatment or as AEs present at baseline but which worsened after initiation of study treatment, will be summarized. Adverse events will be summarized on the participant-level using the maximum severity or grade reported. All TEAEs, SAEs, AEs leading to study treatment discontinuation, Grade 3 or higher AEs, and deaths will be listed and summarized by treatment arm with the mapped preferred terms, thesaurus level and NCI CTCAE grade, as appropriate.
[0261] In the case of crossover, participants will contribute safety information up until the time of crossover. AEs reported after crossover will be summarized separately.
Efficacy Endpoints
[0262] Efficacy analyses will be primarily conducted in the efficacy-evaluable population, defined as all participants who are enrolled and receive at least 1 dose of each drug of their assigned treatment regimen. The following prioritized efficacy endpoints will be analyzed according to PCWG3 and based on the investigator’s assessment:
[0263] ORR defined as the composite proportion of participants with a PSA response or a radiographic CR or PR (defined below).
[0264] PSA response defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on 2 consecutive assessments measured at least 3 to 4 weeks apart.
[0265] Radiographic response defined as the proportion of participants with a best overall response of CR or PR according to RECIST vl.l.
[0266] DCR is defined as the proportion of participants with a best overall RECIST response of CR, PR, or stable disease (SD). [0267] PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiographic progression, bone scan progression, or other) or death, whichever occurs first. Depending on data availability, time to progression due to specific reasons (e.g., PSA progression or radiographic progression) may also be presented individually.
[0268] OS is defined as the time from treatment assignment until death due to any cause.
[0269] Unless otherwise specified, binary endpoints will be displayed with their exact Clopper- Pearson binomial 90% confidence intervals. Time-to-event endpoint parameters will be estimated using Kaplan-Meier techniques.
Disease and Response Assessment
[0270] The primary efficacy endpoint is the ORR, defined as the composite proportion of participants with a PSA response or a radiographic complete or partial response determined by the investigator according to the PCWG3 criteria. PSA response and radiographic complete or partial response may be reported individually. For clarity, PSA response is defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on 2 consecutive assessments measured 3 to 4 weeks apart. Radiographic response is defined as the percentage of participants with measurable disease at baseline who achieve a best overall response of CR or PR according to RECIST vl.l.
[0271] Participants will undergo tumor assessments every 12 weeks (± 7 days) from start of study treatment until disease progression (regardless of whether the participant is still receiving treatment), the start of new anticancer therapy, withdrawal of consent, death, or the end of the study. At the investigator’s discretion, tumor assessments may be repeated at any time if disease progression is suspected. All participants who discontinue study treatment for reasons other than disease progression (e.g., AEs) will continue tumor assessments until death, disease progression, initiation of another systemic anticancer therapy, lost to follow-up, withdrawal of consent, or study termination, whichever occurs first.
[0272] Measurable and evaluable lesions should be assessed and documented at screening. Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to enrollment do not have to be repeated at screening.
[0273] Baseline disease assessments for all participants will include: CT scan with contrast of the chest and abdomen/pelvis, Full-body bone scan (technetium-99m [TC-99m]), and MRI scan of the brain.
[0274] Postbaseline disease assessments for all participants will include:
• CT scan with contrast of the chest and abdomen/pelvis,
• Full-body bone scan (TC-99m) for participants with bone disease documented at baseline and for participants with clinical signs or symptoms of new osseous disease, and
• MRI scan of the brain only for participants with CNS disease documented at baseline and for participants with clinical signs or symptoms of new CNS disease.
[0275] All scans should be performed in accordance with RECIST vl.l and with contrast. If contrast is medically contraindicated, a chest CT without contrast and an abdomen/pelvis MRI without contrast may be performed. If a brain MRI is contraindicated, a brain CT with contrast should be performed. If a CT scan for tumor assessment is performed in a positron emission tomography (PET)/CT scanner, the CT acquisition must be consistent with standard for a full contrast diagnostic CT scan.
[0276] All measurable and evaluable lesions identified at baseline should be reassessed at each subsequent postbaseline tumor evaluation. The same radiographic procedures used to assess disease sites at screening should be used for subsequent tumor assessments (e.g., same contrast protocol for CT scans). Response will be assessed by the investigator using PCWG3. Assessments should be performed by the same evaluator, if possible, to ensure internal consistency across disease evaluations. Results must be reviewed by the investigator before dosing at the next planned study treatment cycle.
Adverse Event Definitions
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product regardless of causal attribution. An AE can therefore be any of the following: Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product
• Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or severity of a known condition)
• Recurrence of an intermittent medical condition (eg, headache) not present at baseline
• Any deterioration in a laboratory value or other clinical test (eg, ECG, X-ray) that is associated with symptoms or leads to a change in study treatment or concomitant treatment or discontinuation from study treatment
• Events that are related to a protocol-mandated intervention, including those that occur prior to assignment of study treatment (eg, invasive screening procedures such as biopsies).
Serious Adverse Events
[0278] A serious adverse event (SAE) is any AE that meets any of the following criteria:
• Is fatal (i.e., the AE actually causes or leads to death)
• Is life threatening (i.e., the AE, in the view of the investigator, places the participant at immediate risk of death)
• Requires or prolongs inpatient hospitalization
• Results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the participant’s ability to conduct normal life functions)
• Is a congenital anomaly/birth defect
• Is a significant medical event in the investigator’s judgment (e.g., may jeopardize the participant or may require medical/surgical intervention to prevent one of the outcomes listed above)
[0279] The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE (e.g., rated as mild, moderate, or severe, or according to the National Cancer Institute [NCI] CTCAE); the event itself may be of relatively minor medical significance (such as severe headache without any further findings). Assessment of Severity
[0280] An assessment of severity grade will be made by the investigator according to the NCI CTCAE (Version 5.0). Table 10 will be used for assessing severity for AEs that are not specifically listed in the NCI CTCAE.
Table 10: Adverse Event Severity Grading Scale for Events not Specifically Listed in NCI
CTCAE
Figure imgf000110_0001
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the toilet, and taking medications, as performed by patients who are not bedridden. c If an event is assessed as a “significant medical event”, it must be reported as an SAE d Grade 4 and 5 events must be reported as SAEs should the event meet the SAE definition. EXAMPLE 2
A Phase 2 Study Evaluating the Safety and Efficacy of Trop-2 ADC, Adenosine Receptor Antagonist, and PD(L)1 Antagonist Combination Therapy in Patients with Disease Progression after Receiving Systemic Treatment for Non-Small Cell Lung Cancer
[0281] This study will evaluate the efficacy and safety of combination treatment regimens for patients with advanced or metastatic NSCLC with progression on or recurrence after platinumbased chemotherapy and PD-1/PD-L1 immunotherapy, received either in combination or sequentially. Participants must have a diagnosis of advanced or metastatic squamous or non-squamous NSCLC. Participants with EGFR, ALK, or any other known actionable genomic alterations must have also received treatment with at least 1 approved tyrosine kinase inhibitor appropriate to the genomic alteration. During a preliminary stage, participants will be randomly assigned to an experimental arm. Randomization will be stratified by histology (squamous versus non-squamous) and prior therapy for an actionable genomic alteration (yes versus no). During the expansion stage, participants will be randomly assigned to the comparator arm or an experimental arm. Participants in the comparator arm will receive either sacituzumab govitecan or docetaxel, with the comparator arm choice based on the treatment landscape at the time of initiation of the expansion stage.
Objectives and Endpoints
[0282] Primary, secondary, and exploratory objectives along with corresponding endpoints for the SG + etrumadenant + zimberelimab treatment arm are as follows:
• Primary Objective o To evaluate the objective response rate (ORR) assessed per RECIST version 1.1.
• Corresponding Endpoint: o Objective response rate (ORR), defined as the proportion of participants achieving a complete response (CR) or partial response (PR).
• Secondary Objective o To evaluate the efficacy of treatment combinations (SG+etrumadenant+zimberelimab) . o To evaluate the safety and tolerability of treatment combinations.
• Corresponding Endpoints o Progression-free survival (PFS), defined as the time from the date of randomization until disease progression (PD), as assessed by the investigator according to RECIST version 1.1 or death, whichever comes first. o Duration of response (DOR), defined as the time from the first response (CR or PR) until the first documented PD, as assessed by the investigator according to RECIST version 1.1 or death, whichever comes first. o Overall survival (OS), defined as the time from the date of randomization until death from any cause. o The incidence of treatment-emergent adverse events (TEAEs), treatment-related adverse events and laboratory abnormalities.
• Exploratory Objectives: o To evaluate biomarkers in blood and tumor biopsy samples, as applicable to treatment. o To explore biomarkers that may predict response/resistance to therapy. o To characterize the pharmacokinetics and immunogenicity, as applicable.
• Corresponding Endpoints o Change in biomarkers in response to treatment o Correlation of clinical response with biomarkers at baseline and/or on treatment/progres sion o Peak and trough concentrations over time and antidrug antibodies over time.
[0283] Efficacy endpoints of ORR, PFS, DOR, and OS will be evaluated. Computed tomography or MRI scans with contrast of chest, abdomen, pelvis, and any other involved disease sites are to be obtained in all participants until the occurrence of radiologic progression of disease requiring discontinuation of further treatment. Participants with a history of brain metastasis must have a brain MRT at screening. Tumor response and progression will be determined using RECTST version 1.1.
Eligibility
Inclusion Criteria
[0284] Participants are eligible to be included in the study only if all the following criteria apply:
1) Histologically or cytologically documented NSCLC with documented evidence of stage IV NSCLC disease at time of start of study treatment (based on the American Joint Committee on Cancer, Eighth Edition).
2) Participants willing to provide adequate tumor tissue. Tumor biopsy must have been performed on or after progression on prior line of therapy and before enrollment with no anticancer treatment between collection of tissue and enrollment.
3) Testing for EGFR and ALK is required. Testing for other actionable genomic alterations is recommended and to be performed as per local standard of care and availability of targeted treatment.
4) Participants must have progressed or experienced disease recurrence after receiving platinumbased chemotherapy in combination with anti-PD-1 or anti-PD-Ll antibody OR sequential treatment with platinum-based chemotherapy and anti-PD-1 or anti-PD-Ll antibody (in any order).
5) Documented radiographic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
Exclusion Criteria
[0285] Participants are excluded from the study if any of the following criteria apply:
1) Previously received lung cancer treatment with any of the following: a) Topoisomerase 1 inhibitors. Any agent including an ADC containing a chemotherapeutic agent targeting topoisomerase 1. b) Trop-2-targeted therapy. c) Docetaxel as monotherapy or in combination with other agents. 2) Have an active autoimmune disease that required systemic treatment in the past 2 years defined as treatment with disease-modifying agents, corticosteroids, or immunosuppressive drugs.
3) Has had an allogenic tissue/solid organ transplant.
Investigational Products
[0286] Sacituzumab govitecan, etrumadenant, and zimberelimab are as described in Example 1.
Dosages and Administration
Table 11. Administration of Experimental Treatments
Figure imgf000114_0001
[0287] Etrumadenant is administered orally, followed by zimberelimab IV, followed by sacituzumab govitecan IV.
[0288] The comparator arm during the expansion phase of the study will be either docetaxel or sacituzumab govitecan monotherapy (Table 12).
Table 12. Comparator: Administration of Docetaxel or Sacituzumab Govitecan
Figure imgf000115_0001
[0289] Concomitant treatments are as described in Example 1.
Biomarker Testing
[0290] Local tumor tissue or liquid biopsy testing will be conducted if EGFR or ALK status is unknown. EGFR testing will be performed using the Cobas® EGFR Mutation Test (Roche). For ALK, the Vysis ALK Break Apart FISH probe test (Abbott) will be used.
[0291] Additional biomarkers (in blood and tissue) may include, but are not limited to, protein expression, analyses of specific immune and tumor signatures (RNA), as well as tumor mutational burden and tumor mutations (DNA). Tumor and blood samples will be collected to measure biomarkers of response and resistance and to better understand molecular attributes predictive of treatment in lung cancer. Examples may include, but will not be limited to, PD-L1 and Trop-2 - expression, other proteins as well as mutations/gene expression (WES/RNAseq) related to any of the study treatments or related to lung cancer, tumor mutational burden, oncogenic mutations, composition of immune subsets in tumor microenvironment, and pathological features of the tumor.
EXAMPLE 3
Development of Murinized Sacituzumab Govitecan (SG) ADC, Surrogate SG ADC, and Control ADC
[0292] The purpose of this study was to develop murinized sacituzumab govitecan (SG) ADC, surrogate SG ADC, and control ADC. [0293] To engineer an anti-human Trop-2 ADC tolerated in an immunocompetent mouse model, the parental mouse antibody RS7 variable regions was fused to a mouse IgG2a backbone. The resulting murinized RS7 was coupled to CL2A linker/SN-38 payload at a high DAR (~8-9).
[0294] To engineer an anti-mouse Trop-2 ADC binding to mouse Trop-2 with proprieties similar to SG, a commercially available anti-mouse Trop-2 rabbit antibody (Sino Biological, #50922- R064) was murinized to obtain an anti-mouse Trop-2 IgG2a (Rab64/mG2a/mKap). Rab64 mAb was then coupled to CL2A linker/SN-38 payload at a high DAR (—8-9). The binding of hRS7 mAb, SG, Rab64 Ab and surrogate SG to Trop-2 was characterized by surface plasmon resonance (SPR, Table 13) and demonstrated that surrogate SG bound to both mouse and human Trop-2 in the low nanomolar range (1 .37 nM to mTrop-2 and 1.1 nM to hTrop-2).
Figure imgf000116_0001
[0295] A mouse isotype antibody control (mMAB1129/mG2a/mKap) was used as control ADC and coupled to CL2A linker/SN-38 payload in the same condition that Rab64 mAb. Table 14 summarizes the ADC constructs.
Figure imgf000117_0002
EXAMPLE 4
In vivo efficacy of murinized SG combined to anti-mouse PD1 and/or Quemliclustat (CD73i) in an immunocompetent mouse model of orthotopic breast cancer expressing human Trop-2
[0296] The purpose of this study is to determine the in vivo efficacy of murinized SG combined to anti-mouse PD1 and/or quemliclustat in an immunocompetent mouse model of orthotopic breast cancer expressing human Trop-2.
[0297] mice were acquired from Biocytogen. Female (5-7 weeks old) are injected into the left fourth mammary
Figure imgf000117_0001
fat pad with huTrop-2 transduced EO771 tumor cells. When the tumor volume reaches a mean volume of 100 mm3, mice are randomized into 12 groups (10 mice per group) and treated for four weeks with
1. PBS Biweekly (BIW) x 4 intraperitoneally (IP)
2. 200 μg/mouse of anti-mouse PD1 antibody (RMP1.14 mlgGl D265A/mKap) BIW x 2 IP
3. 200 μg/mouse of murinized SG BIW x 4 IP
4. 200 μg/mouse of murinized SG BIW x 4 IP + 200 μg/mouse of anti-mouse PD1 antibody BIW x 2 IP
5. 200 μg/mouse of Quemliclustat each day (QD) subcutaneously (SQ) x 28
6. 200 μg/mouse murinized SG BIW x 4 IP + 200 μg/mouse of Quemliclustat QD x 28 SQ 7. 200 μg/mouse of anti-mouse PD1 antibody B1W x 2 IP + 200 μg/mouse of Quemliclustat each day (QD) subcutaneously (SQ) x 28
8. 200 μg/mouse of murinized SG BIW x 4 IP + 200 μg/mouse of anti-mouse PD1 antibody BIW x 2 IP + 200 μg/mouse of Quemliclustat each day (QD) subcutaneously (SQ) x 28
[0298] Murinized SG ADC was produced as described in Example 3. The anti-mouse PD1 antibody RMP1.14 mlgGl D265A is a commercially available antibody that can be purchased, for example, from Invivogen (cat. code mpdl-mabl5-l).
[0299] Palpable tumors are measured with calipers. Mice are sacrificed when tumor sizes reached -2000 mm3. It is contemplated that the group treated with triple combinations (group 8) will survive the longest due to the combination of the anti-tumor effect of murinized SG to the activation of the tumor infiltrate via IO drugs.
[0300] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the ait and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

CLAIMS What is claimed is:
1. A method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of, a Trop-2 positive cancer comprising co-administcring to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor.
2. The method of claim 1, wherein the anti-Trop-2 ADC comprises a topoisomerase I inhibitor.
3. The method of claim 2, wherein the topoisomerase I inhibitor is a camptothecin (CPT).
4. The method of claim 2, wherein the topoisomerase I inhibitor is a topotecan, irinotecan, bclotccan, or cxatccan.
5. The method of claim 2, wherein the topoisomerase I inhibitor is SN38 or deruxtecan (Dxd).
6. The method of claim 2, wherein the topoisomerase 1 inhibitor is selected from a group consisting of irinotecan, topetecan, and SN-38.
7. The method of any one of claims 2 and 5 to 6, wherein the topoisomerase I inhibitor is SN38.
8. The method of any one of claims 1 and 5-7, wherein the anti-Trop-2 ADC has a structural formula of mAb-CL2A-SN-38, with a structure represented by:
Figure imgf000119_0001
9. The method of any one of claims 1 to 8, wherein the anti-Trop-2 ADC comprises sacituzumab (hRS7). The method of any one of claims 1 to 8, wherein the anti-Trop-2 ADC is selected from a group consisting of sacituzumab govitccan, datopotamab dcruxtccan (DS- 1062), ESG- 401, SKB-264, DAC-02 and BAT-8003. The method of any one of claims 1 to 10, wherein the anti-Trop-2 ADC is sacituzumab govitecan. The method of any one of claims 1 to 11, wherein the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist. The method of any one of claims 1 to 11, wherein the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors. The method of claim 13, wherein the plurality of adenosine pathway inhibitors comprises a CD73 inhibitor and an adenosine receptor antagonist. The method of claim 14, wherein the CD73 inhibitor is quemliclustat and the adenosine receptor antagonist is etrumadenant. The method of any one of claims 1 to 14, wherein the adenosine pathway inhibitor is an adenosine receptor antagonist. The method of any one of claims 1 to 14 and 16, wherein the adenosine pathway inhibitor is imaradenant, NIR178, ID11902, IN-A003, NTI-55, TT-10, TT-228, PBF-1129 (Palobiofarma), TT-702, etrumadenant, INCB 106385, M1069, HM87277, RVU-330, or TT-53. The method of any one of claims 1 to 14, 16 and 17, wherein the adenosine pathway inhibitor is a dual antagonist of adenosine A2A receptor (A2AR; AD0RA2A) and A2B receptor (A2BR; AD0RA2B). The method of any one of claims 1 to 14 and 16 to 18, wherein the adenosine pathway inhibitor is etrumadenant (AB928; GS-0928), taminadenant, TT-10, TT-4, or M1069. The method of any one of claims 1 to 19, wherein the adenosine pathway inhibitor is etrumadenant. The method of any one of claims 1 to 13, wherein the adenosine pathway inhibitor is a CD73 inhibitor. The method of claim 21 , wherein the CD73 inhibitor is oleclumab,
BMS-986179, ulilcdlimab, AK119, qucmliclustat, mupadolimab, HLX23, INCA00186, IB 1325, NZV930, ORIC-533, Sym024, IPH53O1, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG- 037. The method of claim 21 or 22, wherein the CD73 inhibitor is quemliclustat (AB68O, GS- 0680), uliledlimab, mupadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV93O, BMS-986179, or oleclumab. The method of any one of claims 21 to 23, wherein the CD73 inhibitor is quemliclustat. The method of any one of claims 1 to 24, wherein the method further comprises coadministering an additional therapeutic agent or therapeutic modality. The method of claim 25, wherein the additional therapeutic agent or therapeutic modality comprises one, two, three, or four additional therapeutic agents and/or therapeutic modalities. The method of claims 25 or 26, wherein the additional therapeutic agent comprises an anti-PD-(L)l antibody. The method of claim 27, wherein the anti-PD-(L)! antibody is pembrolizumab, nivolumab, ccmiplimab, pidilizumab, spartalizumab, atezolizumab, avclumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, or zimberelimab. The method of claim 28, wherein the anti-PD-(L)l antibody is zimberelimab. The method of any one of claims 25 to 29, wherein the additional therapeutic agent comprises an anti-TIGIT antibody. The method of claim 30, wherein the anti-TIGIT antibody is tiragolumab, vibostolimab, domvanalimab, AB3O8, AK127, BMS-986207, ralzapastotug, or ctigilimab. The method of claim 31, wherein the anti-TIGIT antibody is domvanalimab. The method of any one of claims 25 to 32, wherein the additional therapeutic agent comprises an anti-PD-(Ll) antibody and an anti-TIGIT antibody. The method of claim 33, wherein the additional therapeutic agent comprises a) zimberelimab and domvanalimab, b) zimberelimab and AB3O8, c) atezolizumab and tiragolumab, d) pembrolizumab and vibostolimab, e) MK-7684A (pembrolizumab/vibostolimab coformulation), f) durvalumab and domvanalimab, g) zimberelimab and ralzapastotug, or h) pembrolizumab and ralzapastotug. The method of claim 34, wherein the additional therapeutic agent comprises zimberelimab and domvanalimab. The method of any one of claims 1 to 35, wherein the Trop-2 positive cancer is a solid epithelial cancer. The method of claim 36, wherein the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC), HR+/Her2’ breast cancer, HR+/Her2low breast cancer), colorectal cancer, lung cancer, stomach cancer, urinary tract cancer, urothelial cancer, bladder cancer, renal cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer, and prostatic cancer. The method of claim 37, wherein the prostatic cancer is castrate-resistant prostate cancer (CRPC). The method of claim 37, wherein the lung cancer is non-small lung cancer (NSCLC). The method of claim 37 or 39, wherein the lung cancer is (i) squamous NSCLC or (ii) non-squamous NSCLC. The method of any one of claims 37 or 39 to 40, wherein the lung cancer is without EGFR, ALK, or other actionable genomic alterations. The method of claim 37, wherein the breast cancer is triple negative breast cancer (TNBC), HR+/Her2’ breast cancer, or HR+/Her2low breast cancer. The method of any one of claims 1 to 42, wherein the Trop-2 positive cancer is (i) unresectable, locally advanced or (ii) metastatic. The method of any one of claims 1 to 43, wherein the cancer has progressed following at least one prior anti-cancer therapy. The method of claim 44, wherein the cancer has progressed after prior new hormonal agent treatment (NHA; first- or second-generation non-steroidal anti- androgens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide). The method of claim 44, wherein the cancer has progressed or recurred after platinumbased chemotherapy. The method of claim 44 or 46, wherein the cancer has progressed or recurred after checkpoint inhibitor therapy (CPI) therapy. The method of any one of claims 44 or 46 to 47, wherein the cancer has progressed or recurred after platinum-based chemotherapy and anti-PD-(L)l antibody therapy, received either in combination or sequentially in any order. The method of any one of claims 44 or 46 to 48, wherein the cancer has progressed or recurred after a tyrosine kinase inhibitor therapy. The method of any one of claims 1 to 49, wherein the cancer is resistant or refractory to one or more anti-cancer therapies. The method of any one of claims 1 to 43, wherein the subject is treatment naive. The method of any one of claims 1 to 51, wherein the subject has not received a prior therapy selected from the group consisting of a taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy. The method of any one of claims 1 to 52, wherein the subject has not received a prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy. The method of claim 52 or 53, wherein the taxane therapy comprises paclitaxel, nab- paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel. The method of any one of claims 52 to 54, wherein the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)l antibody. The method of any one of claims 52 to 55, wherein the topoisomerase T inhibitor therapy comprises a topotccan, irinotecan, bclotccan, or cxatccan. The method of any one of claims 1 to 56, wherein the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered concurrently. The method of any one of claims 1 to 57, wherein the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered sequentially. The method of any one of claims 1 to 58, wherein the subject is human. The method of any one of claims 1 to 59, wherein the anti-Trop-2 ADC is administered at one or more doses in the range of 8 mg/kg to 10 mg/kg. The method of claim 60, wherein the anti-Trop2 ADC is administered at one or more doses of 10 mg/kg. The method of any one of claims 1 to 61, wherein the anti-Trop-2 ADC is administered intravenously. The method of any one of claims 1 to 62, wherein the anti-Trop-2 ADC is administered on days 1 and 8 of a 21 -day cycle. The method of any one of claims 1 to 63, wherein the adenosine pathway inhibitor is administered at one or more doses of 75 mg or 150 mg. The method of any one of claims 1 to 64, wherein the adenosine pathway inhibitor is administered at one or more doses of 150 mg. The method of any one of claims 1 to 65, wherein the adenosine pathway inhibitor is administered orally (PO). The method of any one of claims 1 to 64, wherein the adenosine pathway inhibitor is administered once daily (QD). The method of any one of claims 55 to 67, wherein the anti-PD(L)l antibody is administered at one or more doses of 360 mg. The method of any one of claims 55 to 68, wherein the anti-PD(L)l antibody is administered intravenously (IV). The method of any one of claims 55 to 69, wherein the anti-PD(L)! antibody is administered once every three weeks (Q3W). The method of any one of claims 10 to 70, wherein sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on day 1 and day 8 of a 21 -day treatment cycle, etrumadenant is administered orally (PO) once a day (QD) at a dose of 150 mg on each day of the 21-day treatment cycle, and, optionally, zimberelimab is administered intravenously (IV) on day 1 of the 21-day treatment cycle (Q3W). The method of any one of claims 1 to 71, wherein an anti-cancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof. The method of claim 72, wherein tumor response or progression is determined according to RECIST version 1.1. A method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of castrate-resistant prostate cancer (CRPC) comprising co-administering to a human patient an effective amount of: a) sacituzumab govitecan; and b) etrumadenant. The method of claim 74, further comprising co-administering an anti-PD-(L)l antibody to the human patient. The method of claim 75, wherein the anti-PD-(L)l antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. The method of claim 74, further comprising co-admini tering zimberelimab to the human patient. The method of any one of claims 74 to 77, wherein the CRPC is metastatic CRPC (mCRPC). The method of any one of claims 74 to 78, wherein the CRPC is resistant or refractory to one or more anti-cancer therapies. The method of claim 79, wherein the CRPC has progressed following prior NHA therapy (first- or second-generation non-steroidal antiandrogens, abiraterone). The method of any one of claims 74 to 80, wherein the human patient has not received a prior therapy selected from taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy. The method of claim 81, wherein the human patient has not received a prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy. The method of claim 81 or 82, wherein the taxane therapy comprises paclitaxel, nab- paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel. The method of any one of claims 81 to 83, wherein the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)l antibody. The method of any one of claims 81 to 84, wherein the topoisomerase I inhibitor therapy comprises a topotecan, irinotecan, belotecan, or exatecan. A method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of non-small cell lung cancer (NSCLC) comprising co-administering to a human patient an effective amount of: a) sacituzumab govitecan; b) etrumadenant; and c) an anti-PD-(L)l antibody. The method of claim 86, wherein the anti-PD-(L)l antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, rctifanlimab, balstilimab, toripalimab, cctrclimab, gcnolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. The method of claim 86 or 87, wherein the anti-PD-(L)l antibody is zimberelimab. The method of any one of claims 86 to 88, wherein the NSCLC has progressed or recurred after platinum-based chemotherapy. The method of any one of claims 86 to 89, wherein the NSCLC has progressed or recurred after checkpoint inhibitor therapy (CPI) therapy. The method of claim 90, wherein the NSCLC has progressed or recurred after platinum based chemotherapy and anti-PD-(L)l antibody therapy, received either in combination or sequentially in any order. The method of any one of claims 86 to 91, wherein the NSCLC has progressed or recurred after a tyrosine kinase inhibitor therapy. The method of any one of claims 86 to 92, wherein the NSCLC is (i) unresectable, locally advanced or (ii) metastatic. The method of any one of claims 86 to 93, wherein sacituzumab govitecan is administered intravenously (IV) at a dose of 8 mg/kg or 10 mg/kg on day 1 and day 8 of a 21 -day treatment cycle and etrumadenant is administered orally (PO) once a day (QD) at a dose of 75 mg or 150 mg on each day of the 21-day treatment cycle. The method of claim 94, wherein sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on day 1 and day 8 of a 21-day treatment cycle and etrumadenant is administered orally (PO) once a day (QD) at a dose of 150 mg on each day of the 21-day treatment cycle. The method of any one of claims 86 to 95, wherein zimberelimab is administered intravenously (IV) on day 1 of the 21-day treatment cycle (Q3W). The method of any one of claims 86 to 96, wherein an anti-cancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or combinations thereof. The method of claim 97, wherein tumor response or progression is determined according to RECIST version 1.1. The method of any one of claims 1 to 98, wherein an anti-CD47 antibody (e.g., magrolimab) is not administered to the subject or human patient. . The method of any one of claims 1 to 99, wherein an MCL1 inhibitor (e.g., GS-9716) is not administered to the subject or human patient. . The method of any one of claims 1 to 100, wherein a FLT3 agonist (e.g., GS-3583, CDX- 301) is not administered to the subject or human patient. . A method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of, a tumor antigen positive (TA+) cancer comprising co-administering to a subject an effective amount of: a) a tumor antigen (TA) targeted ADC comprising a topoisomerase I inhibitor (Topi ADC); b) an adenosine pathway inhibitor; and c) optionally an anti-PD(L)l antibody. . An anti-Trop-2 ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)l antibody in a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of Trop-2 positive cancers, wherein the method comprises administering the anti-Trop-2 ADC, adenosine pathway inhibitor, and optionally the additional anti-PD(L)l antibody to a subject. . A Topi ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)l antibody in a method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of tumor antigen positive (TA+) cancers, wherein the method comprises administering the Topi ADC, adenosine pathway inhibitor, and optionally the anti-PD(L)l antibody to a subject. . A kit for use as a medicament, wherein the kit comprises a) a TROP-2-targeted antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an adenosine pathway inhibitor; and c) optionally an anti-PD-(L)l antibody. . A kit for use as a medicament, wherein the kit comprises a) a tumor antigen (TA) targeted ADC comprising a topoisomerase I inhibitor (Topi ADC); b) an adenosine pathway inhibitor; and c) optionally an anti-PD-(L)l antibody. . A method of treating, mitigating, reducing, preventing or delaying the recurrence or metastasis of breast cancer comprising co-administering to a human patient an effective amount of: a) sacituzumab govitecan; and b) a CD73 inhibitor. . The method of claim 107, wherein the CD73 inhibitor is oleclumab, BMS-986179, uliledlimab, AK119, quemliclustat, mupadolimab, HLX23, INCA00186, IB 1325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037. . The method of claim 107, wherein the CD73 inhibitor is quemliclustat (AB680, GS- 0680), uliledlimab, mupadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or oleclumab. . The method of claim 107, wherein the CD73 inhibitor is quemliclustat (AB680, GS- 0680). . The method of any one of claims 107 to 110, further comprising co-administering an anti-PD-(L)l antibody to the human patient. . The method of claim 111, wherein the anti-PD-(L) 1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimbcrclimab. The method of claim 112, further comprising co-administering zimberelimab to the human patient. The method of any one of claims 107 to 113, wherein the breast cancer is metastatic breast cancer. The method of any one of claims 107 to 114, wherein the breast cancer is resistant or refractory to one or more anti-cancer therapies. The method of claim 115, wherein the breast has progressed following prior anti-cancer therapy (first- or second-generation anti-cancer therapy, e.g., hormone therapy). The method of any one of claims 107 to 116, wherein the human patient has not received a prior therapy selected from taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy. The method of claim 117, wherein the human patient has not received a prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy. The method of claim 117 or 118, wherein the taxane therapy comprises paclitaxel, nab- paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel. The method of any one of claims 117 to 119, wherein the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)l antibody. The method of any one of claims 117 to 120, wherein the topoisomerase I inhibitor therapy comprises a topotecan, irinotecan, belotecan, or exatecan.
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