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WO2025006697A1 - Treatment methods for subjects with non-small cell lung cancer having an aberration in egfr - Google Patents

Treatment methods for subjects with non-small cell lung cancer having an aberration in egfr Download PDF

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Publication number
WO2025006697A1
WO2025006697A1 PCT/US2024/035743 US2024035743W WO2025006697A1 WO 2025006697 A1 WO2025006697 A1 WO 2025006697A1 US 2024035743 W US2024035743 W US 2024035743W WO 2025006697 A1 WO2025006697 A1 WO 2025006697A1
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Prior art keywords
egfr
cancer
subject
administered
treatment
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PCT/US2024/035743
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French (fr)
Inventor
Jeffery Jones
Kohei Hayashi
Yoshimi Aoyagi
Volker Wacheck
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Taiho Pharmaceutical Co., Ltd.
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Publication of WO2025006697A1 publication Critical patent/WO2025006697A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof

Definitions

  • the present invention relates to methods of treating cancers harboring an aberration in EGFR.
  • Amivantamab a bispecific antibody targeting EGFR and mesenchymal-epithelial transition factor (MET), requires intravenous administration and causes frequent infusion reactions (IRRs). While more effective for some patients, amivantamab treatment is associated with adverse events including rash, infusion- related reactions, infected skin around the nail, muscle and joint pain, shortness of breath, nausea, fatigue, swelling of hands, ankles, feet, face, or the entire body, sores in the mouth, cough, constipation, vomiting, and changes in certain blood tests (e.g., decreased albumin levels, increased glucose levels, increased liver enzymes) and has the further disadvantage of requiring intravenous administration.
  • adverse events including rash, infusion- related reactions, infected skin around the nail, muscle and joint pain, shortness of breath, nausea, fatigue, swelling of hands, ankles, feet, face, or the entire body, sores in the mouth, cough, constipation, vomiting, and changes in certain blood tests (e.g., decreased albumin levels, increased glucose levels,
  • Zipalertinib (CLN-081/TAS6417) is a novel EGFR tyrosine kinase inhibitor (TKI) with broad activity against EGFR mutations (including ex20ins) and increased selectivity for ex20ins versus wild-type (WT) EGFR.
  • TKI EGFR tyrosine kinase inhibitor
  • WT wild-type
  • zipalertinib (TAS6417) a more promising side-effect or adverse effect profile. Higher specificity and selectivity can allow for high doses of zipalertinib to be used without widespread adverse effects or administration for longer periods of time.
  • a method of treating a subject with a cancer having at least one aberration in EGFR comprising administering to the subject an effective amount of (S)-N-(4-amino-6- methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof.
  • Compound (1) The structure of (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide is depicted below and will be referred to herein as Compound (1): (1), wherein the subject has previously been treated with a systemic treatment which is at least one selected from the group consisting of a chemotherapeutic agent and a molecularly targeted therapeutic.
  • a systemic treatment which is at least one selected from the group consisting of a chemotherapeutic agent and a molecularly targeted therapeutic.
  • the EGFR-targeting therapeutic other than Compound (1) is at least one selected from the group consisting of gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, poziotinib, mobocertinib, lazertinib, sunvozertinib, DZD9008, BDTX-189, necitumumab, pembrolizumab, brigatinib, icotinib, neratinib, olmutinib, rociletinib, vandetanib, lapatinib, duligotuzumab, panitumumab, zalutumumab, cetuximab, depatuxizumab, depatuxizumab mafodotin, imgatuzumab, matuzumab, and nimotu
  • non-EGFR-targeting therapeutic is at least one selected from the group consisting of crizotinib, ceritinib, alectinib, ensartinib, entrectinib, repotrectinib, belizatinib, alkotinib, foritinib, CEP-37440, TQ-B3139, PLB1003, zotizalkiv, lorlatinib, conteltinib, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, bevacizumab, ipilimumab, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine.
  • systemic treatment is a systemic treatment with a chemotherapeutic agent selected from the group consisting of carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.
  • a chemotherapeutic agent selected from the group consisting of carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.
  • a method of treating a subject with a cancer having at least one aberration in EGFR comprising administering to the subject an effective amount of (S)-N-(4- amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof and an effective amount of a platinum anticancer agent.
  • FIG. 1 shows a plot of tumor volume over time in preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin, with a maximum dose of Compound (1) (TAS6417) of 200 mg/kg.
  • FIG. 2 shows a plot of body weight change over time in preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin, with a maximum dose of Compound (1) (TAS6417) of 200 mg/kg.
  • FIGS. 3A and 3B show plots of clinical activity of zipalertinib (Compound (1); TAS6417) in EGFR ex20ins patients with NSCLC with postbaseline target lesion assessments
  • FIG. 3 A is a waterfall plot for response of target lesions by dose level (* indicates confirmed response, E indicates previous EGFR-targeted Q: 10 treatment)
  • FIG. 3B is a swimmers plot for time to response and treatment duration by dose level (EGFR, epidermal growth factor receptor; ex20ins, insertions in EGFR exon 20; NSCLC, non-smallcell lung cancer).
  • EGFR epidermal growth factor receptor
  • ex20ins insertions in EGFR exon 20
  • NSCLC non-smallcell lung cancer
  • FIGS. 5 A and 5B are images from MRI with gadolinium enhancement before (FIG. 5 A) and after (FIG. 5B) treatment with zipalertinib (EGFR, epidermal growth factor receptor; ex20ins, insertions in EGFR exon 20; NSCLC, non-small-cell lung cancer).
  • EGFR epidermal growth factor receptor
  • ex20ins insertions in EGFR exon 20
  • NSCLC non-small-cell lung cancer
  • FIG. 6 shows a schematic depiction of the Phase 1/2 study design.
  • a single-patient accelerated design was used for escalation of doses from 30 to 100 mg twice a day.
  • grade 2 toxicity occurred in the first patient, and the study transitioned to a rolling six design.
  • Lower-dose cohorts could be expanded with a rolling six design if the dose level achieved serum drug concentrations that were associated with response in preclinical tumor models. This occurred at the first dose level of 30 mg twice a day.
  • the SRC made decisions about expansion of cohorts at higher dose levels to six patients and chose only to expand the 65 mg twice a day cohort.
  • the 100 and 150 mg dose levels were expanded on the basis of safety considerations.
  • Expansion of a dose level to 13 patients was permitted on the basis of the observation of a single response in the first six patients at any dose level.
  • the SRC chose to expand the 65, 100, and 150 mg dose levels to 13 patients, but not the 30 or 45 mg dose levels.
  • Expansion of the 100 mg dose level from 13 to 36 patients was based on the protocol-defined achievement of four or more responses.
  • the 65 mg dose level also met this criterion, it was not expanded at the discretion of the SRC.
  • DLT doselimiting toxicity
  • SRC safety review committee.
  • the 100 mg dose has a good balance between efficacy and adverse events. As the dose is increased there is a tendency for more adverse events.
  • FIG. 7 shows Kaplan-Meier curves of PFS by dose level (PFS, progression-free survival).
  • FIG. 8 is a waterfall plot displaying best percent change from baseline in sum of target lesion diameters by location of EGFR exon20ins determined by local laboratory testing and investigator response (EGFR, Q: 14 epidermal growth factor receptor; ORR, objective response rate, * indicates response was confirmed).
  • EGFR 12 epidermal growth factor receptor
  • ORR objective response rate
  • FIG. 9 shows a plot of average unbound plasma concentration over time for the 30, 65, 100, and 150 mg dose levels.
  • the 50% growth inhibitory concentration of cell lines expressing wild-type and two exon 20 insertion mutation expressing cell lines EGFR, epidermal growth factor receptor; WT, wild-type.
  • FIG. 10 shows a plot of tumor volume over time in preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin + pemetrexed, with a maximum dose of Compound (1) (TAS6417) of 100 mg/kg.
  • FIG. 11 shows a plot of mean body weight change throughout treatment for the preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin + pemetrexed, with a maximum dose of Compound (1) (TAS6417) of 100 mg/kg.
  • FIG. 12 shows a plot of tumor volume over time in preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin + pemetrexed, with a maximum dose of Compound (1) (TAS6417) of 50 mg/kg.
  • FIG. 13 shows a plot of tumor volume over time in preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin + pemetrexed, with a maximum dose of Compound (1) (TAS6417) of 100 mg/kg.
  • FIG. 14 shows a plot of mean body weight change throughout treatment for the preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin + pemetrexed, at various doses of carboplatin + pemetrexed and Compound (1).
  • FIG. 15 shows a plot of tumor volume over time in preclinical animal studies of various treatment regimens involving continued treatment with Amivantamab or with Compound (1) (TAS6417), with a dose of Compound (1) (TAS6417) of 200 mg/kg.
  • FIG. 16 is a summary of patient demographics module C ami overall.
  • FIG. 17 is a summary of the best overall tumor response based on investigator assessment per RECITS vl .1.
  • FIG. 18 is a waterfall plot for best change from baseline in target lesions.
  • FIG. 19 is a swim plot for study treatment duration.
  • FIG. 20 is a Kaplan Meier plot of progression free survival based on RECITS vl .1.
  • FIG. 21 is a summary of treatment-related adverse events of any grade observed in > 10% of patients.
  • FIG. 22 is a summary of grade 3 treatment-related adverse events in > 2 patients.
  • Compound (1) also known as zipalertinib and TAS6417, is a potent, and highly selective EGFR-tyrosine kinase inhibitor (TKI), as described in W02018079310, which is fully incorporated by reference herein in its entirety and Hasako, S. et al “TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations”, Mol Cancer Ther; 17 (8), 2018, pp.1648-1657). Biochemical assays have shown that Compound (1) inhibited the in vitro phosphorylation activity of EGFR and EGFR mutants that harbor an exon 20 insertion mutation.
  • TKI EGFR-tyrosine kinase inhibitor
  • Compound (1) showed intensive cellular potency in inhibiting the phosphorylation of mutant EGFRs that possess a wide spectrum of in-frame insertion mutations in exon 20 (A763_Y764insFQEA, V769_D770insASV, D770_N771insG, D770_N771insSVD, H773_V774insNPH, and H773_V774insPH).
  • Compound (1) also showed moderate inhibition against WT EGFR.
  • Consistent with the intracellular target inhibition Compound (1) demonstrated a more potent and selective inhibitory effect on the proliferation of the cells expressing EGFR with exon 20 insertion mutations than on cells expressing WT EGFR.
  • Compound (1) inhibited the growth of five cell lines out of a panel of seven NSCLC cell lines harboring mutant EGFR (V769_D770insASV for LXF 2478L cells; D770_N771insSVD for NCI-H1975 EGFR D770_N771insSVD cells; delE746_A750 for HCC827 and PC-9 cells; and L858R plus T790M for NCI-H1975) with GI50 values ranging from 1.92 ⁇ 0.21 nmol/L to 86.5 ⁇ 28.5 nmol/L.
  • KRAS mutant cell lines, NCI- 1123 cells, and NCI-H460 cells that exhibit EGFR-independent cell growth did not respond to Compound (1) (GI50 > 3000 nmol/L).
  • CLN-081 suppressed the growth of NSCLC cells with EGFR exon 20 insertions (LXF 2478 and NCI-H1975 EGFR D770_N771insSVD cells) through a mechanism associated with the inhibition of the phosphorylation of EGFR and its downstream molecules and the induction of caspase 3/7.
  • the antitumor efficacy of twice-daily Compound (1) administration to nude mice transplanted with the human NSCLC cell line NCI-H1975 EGFR D770_N771insSVD is not inferior to that of once-daily Compound (1) administration.
  • Compound (1) showed intensive cellular potency in inhibiting the phosphorylation of mutant EGFRs that possess mutations in exon 18 or exon 21 (G719A, G719S, G719C, E709K, E709A, L861Q), and the activity was higher than erlotinib and osimertinib.
  • Compound (1) also showed intensive inhibition against EGFRs harboring a combination of acquired resistance mutation T790M and either exon 18 or exon 21 mutations (G719A+T790M, L861Q+T790M) (W02019045036, incorporated herein by reference in its entirety; Udagawa, H. et al.
  • TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations” Mol Cancer Res 2019;17:2233-43).
  • Compound (1) inhibited the growth of Ba/F3 cell lines harboring EGFR with mutations in exon 18 (G719A, G719A+T790M) or exon 21 (L861Q, L861Q+T790M) with IC50 ranging from 9.0 nmol/L to 37.5 nmol/L, which were significantly lower than the IC50 for inhibiting Ba/F3 harboring wild type EGFR (597.3 nmol/L).
  • the selectivity index defined as the ratio between IC50 for WT EGFR and mutant EGFR containing cell lines, was much higher for Compound (1) compared to erlotinib and afatinib.
  • the selectivity index for Compound (1) is higher than osimertinib.
  • Compound (1) showed intensive cellular potency in inhibiting the phosphorylation of mutant EGFRs that possess mutations in exon 18 or exon 21 (G719A, G719S, G719C, E709K, E709A, L861Q), and the activity was higher than erlotinib and osimertinib.
  • Compound (1) also showed intensive inhibition against EGFRs harboring a combination of acquired resistance mutation T790M and either exon 18 or exon 21 mutations (G719A+T790M, L861Q+T790M).
  • Compound (1) showed intensive cellular potency in inhibiting the phosphorylation of mutant EGFRs that possess L718Q mutation in exon 18 in combination with exl9del+T790M or L858R+T790M (i.e., L718Q+ exl9del+T790M or L718Q+ L858R+T790M), and both the absolute activity and the selectivity over baseline mutations (exl9del+T790M or L858R+T790M) was higher than osimertinib, erlotinib and Afatinib (W02020138400, incorporated herein by reference in its entirety).
  • Compound (1) showed intensive cellular potency in inhibiting the phosphorylation of mutant EGFRs that possess mutations at L792 (L792H, L792F, L792Y) in exon 20 in combination with exl9del+T790M or L858R+T790M (i.e.
  • Compound (1) demonstrated favorable safety and tolerability and encouraging preliminary clinical activity among patients with recurrent or metastatic EGFR ex20ins mutant Non-Small-Cell Lung Cancer (NSCLC) previously treated with anti-cancer agents including other TKIs, monoclonal antibodies, ALK (anaplastic lymphoma kinase) agents . Objective responses were observed across the range of dose levels tested and across a diverse spectrum of ex20ins mutations. In a heavily previously-treated patient population, Compound (1) led to rapid and durable tumor regression. Although data from this ongoing study are maturing, it is notable that 24 of 73 (33%) of patients remain on study at the time of the data cutoff.
  • NSCLC Non-Small-Cell Lung Cancer
  • the safety profile of Compound (1) is better than with that of other EGFR ex20ins- directed therapies. Diarrhea occurred in 91% of patients treated with mobocertinib, 92% with poziotinib, and 54% with sunvozertinib, with over 20% of patients experiencing grade >3 diarrhea with mobocertinib and pozotinib.4,6,7 Although amivantamab causes less diarrhea, dermatologic toxicities including rash (84%) are more common and IRRs occur in 64% of patients.
  • Compound (1) represents a more tolerable oral treatment option for patients with EGFR exon 20 insertion mutations than other currently available agents.
  • This promising safety profile may be due to the increased selectivity for mutant EGFR (e.g., ex20ins mutant EGFR) versus wild-type EGFR.
  • Compound (1) a novel oral irreversible pyrrolo-pyrimidine inhibitor of ex20ins- mutant EGFR, demonstrated encouraging antitumor activity (as evidenced by both the ORR and PFS), with an acceptable safety profile and reduced WT EGFR-related toxicity in previously-treated patients with EGFR ex20ins-mutant NSCLC.
  • the risk-benefit profile of Compound (1) is encouraging and Compound (1) may represent an alternative treatment option for these patients.
  • x, y, and/or z means any element of the seven-element set ⁇ (x), (y), (z), (x, y), (x, z), (y, z), (x, y, z) ⁇ .
  • x, y and/or z means "one or more of x, y and z”.
  • endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).
  • values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
  • “up to” a number includes the number (for example, 50).
  • the term “in the range” or “within a range” includes the endpoints of the stated range.
  • exemplary means serving as a non-limiting example, instance, or illustration.
  • terms “e.g.,” and “for example” set off lists of one or more non-limiting aspects, examples, instances, or illustrations.
  • substantially refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. Biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena. For example, “substantially” may refer to being within at least about 20%, alternatively at least about 10%, alternatively at least about 5% of a characteristic or property of interest.
  • EGFR refers to a human epidermal growth factor receptor protein and is also referred to as ErbB-1 or HERE
  • wild-type EGFR refers to EGFR that has no somatic mutation and is specifically a protein consisting of the amino acid sequence represented by SEQ ID NO: 1 (GenBank accession number: NP — 005219.2).
  • molecularly targeted therapeutic refers to an anticancer therapeutic that functions by interfering with specific targeted molecules needed for cancer -related functions such as carcinogenesis and tumor growth. Molecularly targeted therapeutics are distinct from chemotherapeutics which interfere with all rapidly dividing cells in a non-specific manner. A molecularly targeted therapeutic may be a small molecule (compound) or an antibody. Examples of the "molecular targeted therapeutics” include, but are not limited to, kinase inhibitors, proteasome inhibitors, monoclonal antibodies, mTOR inhibitors, TNF inhibitors, and T-cell inhibitors.
  • antagonists are used interchangeably, and they refer to a compound or agent having the ability to inhibit a biological function of a target protein or polypeptide, such as by inhibiting the activity or expression of the target protein or polypeptide. Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein or polypeptide. While some antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein or polypeptide by interacting with other members of the signal transduction pathway of that target protein or polypeptide are also specifically included within this definition.
  • Non-limiting examples of biological activity inhibited by an antagonist include those associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease.
  • anticancer agent refers to any agent useful in the treatment of a neoplastic condition.
  • One class of anti-cancer agents comprises chemotherapeutic agents.
  • “Chemotherapy” means the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.
  • cell proliferation or “proliferation of the cells” refers to a phenomenon by which the cell number has changed as a result of cell division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.
  • selective inhibition or “selectively inhibit” as applied to a biologically active agent refers to the agent's ability to selectively reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.
  • a compound that selectively inhibits exon 20 mutant EGFR over wildtype EGFR has an activity of at least about 2* against the mutated EGFR relative to the compound's activity against the wild-type EGFR isoform (e.g., at least about 3*, about 5*, about 10x, about 20*, about 50*, or about 100*).
  • in vivo refers to an event that takes place in a subject's body. In vivo also includes events occurring in rodents, such as rats, mice, guinea pigs, and the like.
  • in vitro refers to an event that takes places outside of a subject's body.
  • an in vitro assay encompasses any assay conducted outside of a subject.
  • In vitro assays encompass cell-based assays in which cells, alive or dead, are employed.
  • In vitro assays also encompass a cell-free assay in which no intact cells are employed.
  • therapeutic effect encompasses a therapeutic benefit as described above.
  • a “prophylactic effect” includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • ORR Overall response rate
  • Compound (1) can be used directly (free form) or in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the pharmaceutically acceptable salt of Compound (1) is not particularly limited, and examples thereof include addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, and the like; salts with alkali metals such as potassium, sodium, and the like; salts with alkaline earth metals such as calcium,
  • the pharmaceutically acceptable salts can be synthesized by conventional chemical methods, generally by reacting Compound (1) with a stoichiometric amount or sub-stoichiometric amount (e.g., 0.5 eq) of the appropriate base or acid in water or in an organic solvent (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile), or in a mixture of the two.
  • a stoichiometric amount or sub-stoichiometric amount e.g., 0.5 eq
  • an organic solvent e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
  • Compound (1) or a pharmaceutically acceptable salt thereof may be in the form of a “solvate”, which refers to a physical association of a referenced compound with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding.
  • the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a nonordered arrangement.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
  • Solvate encompasses both solution phase and isolable solvates.
  • Exemplary solvent molecules which may form the solvate include, but are not limited to, water, methanol, ethanol, //-propanol, isopropanol, //-butanol, isobutanol, tertbutanol, ethyl acetate, glycerin, acetone, and the like.
  • the terms “treat”, “treating”, or the “treatment” of cancers in the present disclosure includes any effect, e.g., lessening, reducing, modulating, stabilizing, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • these terms may refer to: (1) a stabilization, reduction (e.g., by more than 10%, 20%, 30%, 40%, 50%, preferably by more than 60% of the population of cancer cells and/or tumor size as compared to prior to administration), or elimination of the cancer cells, (2) inhibiting cancerous cell division and/or cancerous cell proliferation, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by unregulated or aberrant cellular division, (4) an increase in disease-free, relapse-free, progression-free, and/or overall survival, duration, or rate, (5) a decrease in hospitalization rate, (6) a decrease in hospitalization length, (7) eradication, removal, or control of primary, regional and/or metastatic cancer, (8) a stabilization or reduction (e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, preferably at least 80% relative to the initial growth rate) in the growth of a tumor or neoplasm, (9) an impairment
  • the cancers which can be treated herein are EGFR-positive cancers.
  • EGFR-positive means a cancer in which an EGFR protein aberration and/or an EGFR gene aberration is detected/detectable.
  • the EGFR protein/gene may be detected/detectable as wild-type or in altered form (e.g., mutated).
  • Examples of types of cancers which can be treated include, but are not limited to, glandular tumors, carcinoid tumors, undifferentiated carcinomas, angiosarcoma, adenocarcinoma, gastrointestinal cancers (e.g., colorectal cancers (“CRC”) including colon cancer and rectal cancer, biliary cancers including gall bladder cancer and bile duct cancer (cholangiocarcinoma), anal cancer, esophageal cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor(s), gastrointestinal stromal tumor(s) (“GIST”), liver cancer, duodenal cancer and small intestine cancer), lung cancers (e.g., non-small cell lung cancer (“NSCLC”), squamous-cell lung carcinoma, large-cell lung carcinoma, small cell lung carcinoma, invasive mucinous adenocarcinoma, mesothelioma and other lung cancers such as bronchial tumors and pleuropulmonary blast
  • Cancers also suitable for treatment may include, but are not limited to, hematological and plasma cell malignancies (e.g., cancers that affect blood, bone marrow and/or lymph nodes) such as multiple myeloma, leukemias and lymphomas, myelodysplastic syndromes and myeloproliferative disorders.
  • Leukemias include, without limitation, acute lymphoblastic leukemia (“ALL”), acute myelogenous (myeloid) leukemia (“AML”), chronic lymphocytic leukemia (“CLL”), chronic myelogenous leukemia (“CML”), acute monocytic leukemia (“AMoL”), hairy cell leukemia, and/or other leukemias.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous (myeloid) leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • AoL acute monocytic leukemia
  • Lymphomas include, without limitation, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (“NHL”).
  • NHL is B-cell lymphomas and/or T-cell lymphomas.
  • NHL includes, without limitation, diffuse large B-cell lymphoma (“DLBCL”), small lymphocytic lymphoma (“SLL”), chronic lymphocytic leukemia (“CLL”), mantle cell lymphoma (“MCL”), Burkitt’s lymphoma, cutaneous T-cell lymphoma including mycosis fungoides and Sezary syndrome, AIDS-related lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia (“WM”)), primary central nervous system (CNS) lymphoma, central nervous system malignant lymphoma, and/or other lymphomas.
  • DLBCL diffuse large B-cell lymphoma
  • SLL small lymphocytic lymph
  • cancers which can be treated also include metastatic brain tumors, for example, brain metastases of any of the above cancer types, e.g., lung cancers, breast cancers, gastric (stomach) cancer, bladder cancer, or biliary cancers including gall bladder cancer and bile duct cancer, etc., which have metastasized to the brain.
  • metastatic brain tumors for example, brain metastases of any of the above cancer types, e.g., lung cancers, breast cancers, gastric (stomach) cancer, bladder cancer, or biliary cancers including gall bladder cancer and bile duct cancer, etc., which have metastasized to the brain.
  • the treatment methods of the present disclosure are particularly useful in the treatment of solid cancers (e.g., cancers having solid tumors) such as lung cancer (e.g., nonsmall cell lung cancer (“NSCLC”), invasive mucinous adenocarcinoma, etc.), breast cancer (e.g., extrahepatic ductal carcinoma in situ (“DCIS”), lobular carcinoma in situ (“LCIS”), etc.), gastric cancer, bladder cancer, biliary cancer, brain cancer (e.g., glioblastoma), colorectal cancer, pancreatic cancer, and ovarian cancer, as well as any of the above which have metastasized to the brain.
  • lung cancer e.g., nonsmall cell lung cancer (“NSCLC”), invasive mucinous adenocarcinoma, etc.
  • breast cancer e.g., extrahepatic ductal carcinoma in situ (“DCIS”), lobular carcinoma in situ (“LCIS”), etc.
  • gastric cancer e.g.
  • NSCLC is the most common form of lung cancer and is histologically divided into adenocarcinoma, squamous cell carcinoma (SCC) and large cell carcinoma.
  • SCC squamous cell carcinoma
  • NSCLC nonsquamos NSCLC.
  • the methods disclosed herein may also be used as a tumor-agnostic treatment for malignancies having an aberration in EGFR, for example, where EGFR aberrations are found in the form of constitutive ErbB-mediated pathway activation due to aberrant ligand binding, for example NRG1 fusion-driven tumors.
  • EGFR aberrations are key oncogenic drivers for certain types of cancers.
  • EGFR aberrations can cause activation of a variety of signaling pathways, including Ras and phosphoinositide 3 -kinase (PI3K), which in turn contributes to various tumorigenic processes.
  • Ras phosphoinositide 3 -kinase
  • an “aberration” in EGFR refers to gain-of-function changes such as protein overexpression, gene amplification (e.g., copy-number alterations), activating gene mutation/activating protein mutation (e.g., insertion, point, or deletion mutations), activating protein overexpression, activating chromosomal translocation/insertion/inversion, activating gene rearrangement or gene fusion (a subset of gene rearrangements), misregulation/dysregulation, and the like, including combinations thereof, that result in or contributes to cancer formation and/or development.
  • gene amplification e.g., copy-number alterations
  • activating gene mutation/activating protein mutation e.g., insertion, point, or deletion mutations
  • activating protein overexpression e.g., chromosomal translocation/insertion/inversion
  • activating gene rearrangement or gene fusion a subset of gene rearrangements
  • misregulation/dysregulation e.g., misregulation/dysregulation, and the like
  • cancers harboring EGFR aberrations may express (i) amplified or overexpressed EGFR, including those of the wildtype variety; (ii) constitutively activated EGFR (including those of the wild-type variety) due to aberrant ligand binding, such as through an aberrancy in NRG1, e.g., NRG1 fusion-driven binding; (iii) altered EGFR, for example, via activating gene and/or protein mutation(s); or (iv) a combination of aberrations, for example where EGFR is amplified/overexpressed and altered e.g., via mutation(s) in the EGFR gene and/or protein.
  • any reference to EGFR amino acid sequence information is based on human wild-type EGFR isoform a, which is accessible from the National Center for Biotechnology Information (NCBI) Protein Database as Accession No. NP_ 005219.2, P00533.2, etc.
  • Isoforms of EGFR are also known by those of ordinary skill in the art, and the present disclosure also encompasses those isoforms.
  • alterations e.g., mutations
  • the alteration in the isoform may be located in a different position from the position identified for EGFR due to deletion or insertion of an amino acid(s) in the isoform, but that the alteration in the isoform nevertheless corresponds to the position identified for EGFR.
  • Aberrations in EGFR may be in the form of gene amplification and/or protein overexpression.
  • Aberrations in EGFR may be in the form of one or more mutations in the EGFR protein.
  • EGFR mutations may be located in the tyrosine kinase domain of EGFR, including, but are not limited to, one or more of: exon 18 (in the region of 688-728); exon 19 (in the region of 729-761); exon 20 (in the region of 762-823); and exon 21 (in the region of 824- 875).
  • EGFR exon 18 mutations may include, but are not limited to, point mutations such as E709X or G719X (where X is an arbitrary amino acid), exemplified by E709K, E709A, E709G, G719A, G719S, and G719C, deletion mutations, and deletion insertion mutations, for example deletion of glutamic acid at position 709 and threonine at position 710 and insertion of aspartic acid (DelE709_T710insD), and the like.
  • point mutations such as E709X or G719X (where X is an arbitrary amino acid), exemplified by E709K, E709A, E709G, G719A, G719S, and G719C
  • deletion mutations for example deletion of glutamic acid at position 709 and threonine at position 710 and insertion of aspartic acid (DelE709_T710insD), and the like.
  • EGFR exon 19 mutations may include, but are not limited to, “classical” Exon 19 deletion mutations of at least three amino acid residues, as well as deletion insertion mutations, for example DelE746_A750 (deletion of glutamic acid at position 746 to alanine at position 750), DelL747_P753insS (deletion of leucine at position 747 to proline at position 753 and insertion of serine), DelE746_T751insA, DelE746_S752insD, DelL747 T751, DelL747_A750insP, and the like.
  • EGFR exon 20 mutations may include, but are not limited to, point mutations such as T790M, S768I, V769M, and H773R, deletion mutations, and insertion mutations.
  • compound (1) or its pharmaceutically acceptable salts have been found to be surprisingly active in cancers harboring one or more EGFR exon 20 insertion mutations.
  • EGFR exon 20 insertion mutations are found with relatively high prevalence in non-small lung cancer (NSCLC) as well as sinonasal squamous cell carcinoma (SNSCC), are associated with de novo resistance to current clinically available EGFR inhibitors and are therefore preferred targets for treatment herein.
  • NSCLC non-small lung cancer
  • SNSCC sinonasal squamous cell carcinoma
  • EGFR exon 20 insertion mutations may be heterogeneous in-frame insertions of between 1-7 amino acids (indicated as “insX”) across a span of about 15 amino acids (D761- C775) in exon 20, for example D761_E762insX (insertion of between 1-7 amino acid residues “X” in between aspartic acid at position 761 and glutamic acid at position 762), A763_Y764insX, Y764_V765insX, V765_M766insX, A767_S768insX, S768_V769insX, V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, H773_V774insX, and V774_C775insX.
  • insX 1-7 amino acids
  • D761_E762insX insertion of between 1-7 amino acid
  • deletion insertion mutations such as DelD770insX (deletion of aspartic acid at position 770 and insertion of 1-7 amino acids “X”) and DelN771insX (Simon Vyse and Paul H. Huang, Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther. 2019 Mar 8;4:5).
  • EGFR exon 20 insertion mutations include, but are not limited to, A763_Y764insFQEA, A763_Y764insTLA, Y764_V765insHH, A767_S768insASV, A767_S768insTLA, S768dupSVD, S768_V769insVAS, S768_V769insAWT, V769_D770insGV, V769_D770insCV, V769_D770insDNV, V769_D770insGSV, V769_D770insGVV, V769_D770insMASVD, V769_D770insASV, V769_D770insGE, V769_D770delInsDGEL, V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771ins
  • a preferred embodiment of the present disclosure involves treating a subject with a cancer, specific mention being made to non-small lung cancer (NSCLC), harboring an EGFR exon 20 insertion mutation, particularly in cases where such cancers are locally advanced or where such cancers have metastasized to the brain.
  • EGFR exon 21 mutations may include, but are not limited to, point mutations such as L858X and L861X (where X is an arbitrary amino acid), such as the “classical” exon 20 activating mutation L858R, as well as L833V, H835L, L838V, A839T, K846R, and L861Q.
  • Exemplary EGFR proteins which contain multiple mutations, and can be treated herein may include, but are not limited to, DelE746_A750/T790M and T790M/L858R.
  • Mutations in the EGFR protein may be those set forth in Japanese Patent Application No. 2020-121525, the contents of which are incorporated herein by reference in their entirety.
  • Aberrations in EGFR may also be in the form of gene amplification and/or one or more genetic alterations in EGFR, such as EGFR gene rearrangements, and resultant mutations in EGFR in which particular exons or exon parts are deleted.
  • EGFR variant I EGFRvI; deletion of N-terminal part
  • EGFR variant II EGFRvII; deletion of exons 14 and 15
  • EGFR variant III EGFRvIII; deletion of exons 2-7)
  • EGFR variant IV EGFRvIV; deletion of exons 25-27
  • EGFR variant V EGFRvV; deletion of exons 25-28.
  • EGFRvIII results from the inframe deletion of 801 base pairs spanning exons 2-7, with this deletion removing 267 amino acids from the extracellular domain, thereby creating a junction site between exons 1 and 8 and a new glycine residue.
  • alterations confer enhanced tumorgenicity, such as increased rates of proliferation, reduced apoptosis, increased angiogenesis, and increased invasiveness compared to unaltered EGFR, mediated by several downstream signaling pathways, including PI3K/Akt, Ras/Raf/MAPK, signal transducer and activator of transcriptase 3 (Stat3), and nuclear factor kappa-B (NF-KB).
  • PI3K/Akt PI3K/Akt
  • Ras/Raf/MAPK Ras/Raf/MAPK
  • Stat3 signal transducer and activator of transcriptase 3
  • NF-KB nuclear factor kappa-B
  • a preferred embodiment of the present disclosure involves treating a subject with GBM harboring an EGFR amplification and/or an EGFRvIII mutation.
  • Aberrations in EGFR may also be in the form of constitutively activated EGFR (including those of the wild-type variety) due to aberrant ligand binding.
  • One example of which is cancers having an aberration in NRG1.
  • An “aberration” in NRG1 refers to gain-of- function changes such as protein overexpression, gene amplification (e.g., copy-number alterations), activating gene mutation/activating protein mutation (e.g., insertion, point, or deletion mutations), activating chromosomal translocation/insertion/inversion, activating gene rearrangement or gene fusion (a subset of gene rearrangements), misregulation/dysregulation, and the like, including combinations thereof, that result in or contributes to cancer formation and/or development.
  • NRG1 Aberrations in NRG1 may be in the form of NRG1 overexpression.
  • NRG1 overexpression has been found to be associated with aggressive tumor features and poor prognosis in gastric cancer patients (Yun, S. et al. Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients; Gastric Cancer (2018) 21 :225-236).
  • NRG1 gene fusions result in irregular expression of the epidermal growth factor (EGF)-like domain of NRG1 on the cell surface, which serves as a ligand for ErbB3 (HER3) and induces the formation of heterodimers, most frequently ErbB2-ErbB3, but also with EGF receptor (EGFR; ErbBl) and ErbB4.
  • EGF epidermal growth factor
  • HER3 epidermal growth factor
  • EGFR EGF receptor
  • ErbBl EGF receptor
  • PI3K-Akt phosphoinositide 3- kinase-protein kinase B
  • MAPK mitogen-activated protein kinase
  • NRG1 fusion-positive cancers cause aberrant activation of EGFR and/or HER2, and thus in a preferred embodiment, the present disclosure involves treating a subject with an NRG1 fusion-driven tumor.
  • Cancers driven by one or more aberrations in NRG1 may include, but are not limited to, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, biliary cancer, ovarian cancer, and gastric cancer.
  • NRG1 fusions may include, but are not limited to, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, biliary cancer, and ovarian cancer.
  • NRG1 fusions may be formed from various fusion partners (listed below as X in X- NRG1), the selection of fusion partner is not particularly limiting.
  • NRG1 fusions include, but are not limited to, DOC4-NRG1, CD74-NRG1, SLC3A2-NRG1, SDC4- NRG1, RBPMS-NRG1, WRN-NRG1, VAMP2-NRG1, ATP1B1-NRG1, ROCK1-NRG1, RALGAPA1-NRG1, TNC-NRG1, MDK-NRG1, DIP2B-NRG1, MRPL13-NRG1, DPYSL2- NRG1, PARP8-NRG1, ITGB1-NRG1, P0MK-NRG1, APP-NRG1, CDH6-NRG1, ATP1B1- NRG1, and CLU-NRG1 (J. Laskin et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol. 2020 Dec;31(12): 1693-1703).
  • ErbB-mediated constitutive pathway activation include, but are not limited to, EGF, TGF-a, HB- EGF, amphiregulin, betacellulin, epigen, and epiregulin.
  • EGF EGF
  • TGF-a TGF-a
  • HB- EGF HB- EGF
  • amphiregulin betacellulin
  • epigen epigen
  • epiregulin epigen-derived growth factor
  • cancers at various stages and resectabilities may respond to the disclosed treatment
  • the methods herein may be particularly useful in the treatment of unresectable or advanced (stage III, “locally advanced”) and metastatic (stage IV) disease, “recurrent,” “resistant”, and “refractory” cancers — cancer that heretofore has failed to respond to medical treatment.
  • “Recurrent” cancers are cancers that have recurred (come back), usually after a period of time during which the cancer could not be detected. The cancer may come back to the same place as the original (primary ) tumor or to another place in the body.
  • “Refractory” cancers may present as resistance/intractability from the start.
  • “Resistant” cancers may present following the acquisition of resistance/intractability by the cancer cells during the course of prior therapy, and thus can include relapsed cancer that responds initially to treatment, but returns, often in a more aggressive/resistant form. Resistant cancers may also be described as having “secondary resistance”, “acquired resistance”, or similar term.
  • the cancer may be a recurrent, resistant, or refractory EGFR-positive cancer, preferably a recurrent, resistant, or refractory cancer in which EGFR is genetically amplified and/or overexpressed.
  • Example cancer types may include, but are not limited to, recurrent, resistant, or refractory EGFR-positive NSCLC. Particularly relevant to the present disclosure at cancers which are locally advanced and/or which have metastasized to the brain of the subject.
  • Subjects with a recurrent, resistant, or refractory cancer who have previously undergone at least one treatment regimen with one or more anticancer agents may be treated with Compound (1) or its pharmaceutically acceptable salt and the platinum anticancer agent.
  • the recurrent, resistant, or refractory cancer may have acquired resistance to, or intractability from, the prior treatment regimen(s).
  • a subject with an EGFR- positive cancer treated previously with one or more anticancer agents, and that failed to respond to or relapsed from the prior treatment(s) with the anticancer agent(s) may develop resistance/intractability as a result of exposure of the cancer to the anticancer agent(s).
  • Resistance/intractability may manifest in the cancer in the form of EGFR aberrations e.g., overexpression and/or mutations, or any other cancer driver alterations that result in loss-of- function of tumor suppressor genes/proteins or gain-of-function alterations in oncogenes/oncogene-encoded proteins.
  • EGFR aberrations e.g., overexpression and/or mutations, or any other cancer driver alterations that result in loss-of- function of tumor suppressor genes/proteins or gain-of-function alterations in oncogenes/oncogene-encoded proteins.
  • Prior treatment regimen(s) may have been performed with a variety of anticancer agents, examples of such anticancer agents will be discussed hereinafter.
  • An embodiment of the present disclosure involves administering Compound (1) or its pharmaceutically acceptable salt to a subject with EGFR-positive cancer that has not previously undergone at least one systemic treatment with a molecularly targeted therapeutic.
  • An embodiment of the present disclosure involves administering Compound (1) or its pharmaceutically acceptable salt to a subject with EGFR-positive cancer that has previously undergone at least one systemic treatment with a molecularly targeted therapeutic.
  • administration of Compound (1) or its pharmaceutically acceptable salt to a subject with EGFR-positive cancer that has previously undergone at least one systemic treatment is initiated following the systemic treatment decreasing in efficacy or effectiveness, following a disease relapse, following a disease progression, following a failure of the subject to respond to treatment, or a combination of these.
  • Examples of systemic treatments with a molecularly targeted therapeutic include, but are not limited to, treatment with one or more EGFR inhibitor(s) (i.e., EGFR inhibitors other than Compound (1), such as gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, poziotinib, mobocertinib, lazertinib, sunvozertinib, furmonertinib amivantamab, DZD9008, BDTX-189, necitumumab, pembrolizumab, brigatinib, icotinib, neratinib, olmutinib, rociletinib, vandetanib, lapatinib, duligotuzumab, panitumumab, zalutumumab, cetuximab, depatuxizumab, depatuxizum
  • the methods may involve a pre-screening step to determine whether the subject has an aberration in EGFR and is a good candidate for treatment.
  • the aberration(s) may be determined from family history of cancers involving the aberration(s), by genotyping the subject or analyzing any biological sample from the subject including blood or tumor samples taken from the subject using assays such as those described hereinafter, or from historical records or previous testing performed on the subject. If the subject is determined to be EGFR-positive, and to harbor one or more aberrations therein such as those described in the present disclosure, treatment with Compound (1) or its pharmaceutically acceptable salt is appropriate.
  • a step of detecting that the EGFR expressed by the malignant tumor patient has an exon 20 insertion mutation can be performed prior to the administration of Compound (1).
  • Predictive biomarkers which may be used to identify individuals who are likely to be responsive to treatment herein, include, but are not limited to, EGFR overexpression/amplification or other gene alterations at DNA, RNA or protein level, for example, in breast cancer; EGFR exon 20 insertions and other activating mutations, for example, in lung cancer (e.g., NSCLC); EGFRvIII mutation, EGFR amplification and/or O 6 - methylguanine-DNA methyltransferase (MGMT) promoter methylation, for example, in brain cancer (e.g., GBM).
  • a companion diagnostic (CDx) test may be developed to analyze biological samples.
  • EGFR aberrations including aberrations that cause protein activation via aberrant ligand binding, e.g., NRG1 fusion-driven EGFR as described above
  • IVD in vitro diagnostic
  • NGS next generation sequencing
  • PCR polymerase chain reaction
  • ISH in situ hybridization
  • IHC immunohistochemistry
  • flow cytometry or other assays that can determine EGFR aberrations on tumor tissues or circulating tumor DNA (ctDNA), RNA, protein, etc.
  • NGS next generation sequencing
  • PCR polymerase chain reaction
  • ISH in situ hybridization
  • IHC immunohistochemistry
  • flow cytometry or other assays that can determine EGFR aberrations on tumor tissues or circulating tumor DNA (ctDNA), RNA, protein, etc.
  • a sample used for detection of the EGFR aberration is not particularly limited as long as it is a biological sample derived from a malignant tumor patient, such as a sample collected from a malignant tumor patient and containing malignant tumor cells.
  • biological samples include body fluids (blood, urine, etc.), tissues, extracts thereof, and cultures of collected tissues.
  • the collection method of a biological sample can be suitably selected according to the kind of biological sample.
  • the biological sample is prepared by appropriate processing depending on the detection method.
  • the reagent for example, reagent containing a primer or a probe
  • the reagent used for detection can be adjusted by a commonly used method according to the detection method.
  • the term "effective amount” is a therapeutically effective or pharmaceutically effective amount.
  • the effective amount of the compound according to an embodiment of the present invention refers to an amount of the compound which is sufficient to achieve a biological response or therapeutic response of a subject, such as causing reduction or prevention of an activity of enzyme or protein; or improving a symptom, alleviating a medical state, delaying or retarding progression of disorder, or preventing a disease.
  • pharmaceutically acceptable salt refers to a salt prepared from pharmaceutically acceptable non-toxic bases or acids.
  • administer refers to the methods that may be used to enable delivery of the active ingredient to the desired site of biological action.
  • Routes or modes of administration are as set forth herein. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical/transdermal, and rectal/vaginal administration.
  • oral administration is preferred.
  • intravenous injection is preferred.
  • intravenous injection is preferred.
  • intravenous injection is preferred.
  • intravenous injection is preferred.
  • intravenous injection is preferred.
  • intravenous injection is preferred.
  • intravenous injection is preferred.
  • co-admini strati on encompasses administration of two or more agents to a subject such that both agents and/or their metabolites are present in the subject at the same time.
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a single fixed dose composition in which both agents are present.
  • the term “administration schedule” is a plan in which the type, amount, period, procedure, etc. of the drug in the drug treatment are shown in time series, and the dosage, administration method, administration order, administration date, and the like of each drug are indicated.
  • the date specified to be administered is determined before the start of the drug administration.
  • the administration is continued by repeating the course with the set of administration schedules as “courses”.
  • “continuous” means administration every day without interruption during the treatment course. If the administration schedule follows an “intermittent” administration schedule, then one or more days of administration may be followed by one or more “rest days” or days of nonadministration of drug within the course.
  • a “drug holiday” indicates that the drug is not administered in a predetermined administration schedule. For example, after undergoing several courses of treatment, a subject may be prescribed a regulated drug holiday as part of the administration schedule, e.g., prior to re-recommencing active treatment.
  • the dosage amount and treatment duration are dependent on factors, such as bioavailability of a drug, administration mode, toxicity of a drug, gender, age, lifestyle, body weight, the use of other drugs and dietary supplements, the disease stage, tolerance and resistance of the body to the administered drug, etc., and then determined and adjusted accordingly.
  • An appropriate dosage amount may differ from one individual to another.
  • An appropriate dosage amount in any individual case may be determined using techniques, such as dose escalation.
  • An appropriate dosage can include an amount of Compound (1).
  • An appropriate dosage can also include an amount of an additional therapeutic agent (e.g., a platinum anticancer agent), as described below. These amounts can be varied independently or can be jointly varied (e.g., a single dosage can be varied to maintain a specific ratio of the amount of Compound (1) to the amount of the additional therapeutic agent).
  • the subject having a cancer with at least one aberration in EGFR can be treated with Compound (1) or its pharmaceutically acceptable salt at dose levels of from about 10 mg/day, from about 15 mg/day, from about 20 mg/day, from about 30 mg/day, from about 40 mg/day, from about 50 mg/day, from about 60 mg/day, from about 80 mg/day, from about 100 mg/day, from about 125 mg/day, from about 140 mg/day and up to about 500 mg/day, up to about 480 mg/day, up to about 450 mg/day, up to about 400 mg/day, up to about 350 mg/day, up to about 300 mg/day, up to about 250 mg/day, up to about 240 mg/day, up to about 200 mg/day, up to about 150 mg/day.
  • Compound (1) or its pharmaceutically acceptable salt at dose levels of from about 10 mg/day, from about 15 mg/day, from about 20 mg/day, from about 30 mg/day, from about 40 mg/day, from about 50 mg/day, from about 60
  • the dosing level may be varied within the ranges such as from about 10 mg/day to about 500 mg/day, from about 20 mg/day to about 300 mg/day, and from about 30 mg to about 150 mg/day. In one embodiment, the dosing level is about 100 mg/day.
  • the administration dose level can be changed during an administration schedule, for example, the administration can begin with low dose for some time and then increased, or, the administration can begin with high dose for some time and then decreased.
  • the administration dosage can be reduced, but is not limited.
  • the dosage may, for example, be decreased from 300 mg/day to 150 mg/day, from 300 mg/day to 100 mg/day, and from 100 mg/day to 50 mg/day.
  • the dosing can be continuous (daily; 7 days of administration in a week) or intermittent (alternating one or more dosing days with one or more non-dosing days, such as 4 days-on/3 days-off), for example, depending the pharmacokinetics and a particular patient’s clearance/accumulation of the drug.
  • the dosing schedule should be selected using sound medical judgement. Dosage can be adjusted depending on the occurrence of side effects and symptoms. For example, reduction from twice per day(BID) to once per day(QD). Daily administration is preferred.
  • the dosing can be performed every other day (QOD), once per day (QD), twice per day (BID) or more than twice per day (TID, etc.), with doses of about 60 to 300 mg/day being preferred, with dosed of about 200mg/day being most preferred.
  • the daily dose may be administered as a single dose or multiple individual divided doses.
  • one (1) tablet, containing 50 mg of Compound (1) or its pharmaceutically acceptable salt may be administered to the patient once per day (QD) for a total dose of 50 mg/day.
  • two (2) tablets, each containing 50 mg of Compound (1) or its pharmaceutically acceptable salt may be administered to the patient once per day (QD) for a total dose of 100 mg/day.
  • one (1) tablet, containing 50 mg of Compound (1) or its pharmaceutically acceptable salt may be administered to the patient twice per day (BID) for a total dose of 100 mg/day.
  • two (2) tablets, each containing 50 mg of Compound (1) or its pharmaceutically acceptable salt may be administered to the patient twice per day (BID) for a total dose of 200 mg/day.
  • three (3) tablets, each tablet containing 10 mg of Compound (1) or its pharmaceutically acceptable salt may be administered to the subject once per day (QD) for a total dose of 30 mg/day.
  • three (3) tablets, each tablet containing 20 mg of Compound (1) or its pharmaceutically acceptable salt may be administered to the subject twice per day (BID) for a total dose of 120 mg/day.
  • the multiple individual divided doses can be equal in terms of the amount of Compound (1) or its pharmaceutically acceptable salt or can contain different amounts of Compound (1) or its pharmaceutically acceptable salt.
  • one (1) tablet, containing 50 mg of Compound (1) or its pharmaceutically acceptable salt may be administered to the patient as a first dose in a day and two (2) tablets, each containing 50 mg of Compound (1) or its pharmaceutically acceptable salt, may be administered to the patient as a second dose in a day, for a total dose of 150 mg/day.
  • the dosing whether continuous or intermittent is continued for a particular treatment cycle typically at least a 21 -day cycle, which can be repeated with or without a drug holiday. Longer or shorter cycles can also be used such as 7 days, 14 days, 18 days, 24 days, 28 days, 35 days, 42 days, or any range therebetween.
  • the treatment cycle may be repeated without a drug holiday or with a drug holiday depending upon the subject.
  • a treatment cycle of alternating and consecutive days can be used. For instance, a dosing schedule of sequential 7- day periods may be used where each period comprises alternating 4 days-on and 3 days-off Here, this schedule would involve dosing on days 1, 3, 5, 7, 8, 10, 12, 14, 15, 17, 19, 21, and so on.
  • An “adverse event” refers to any unfavorable or unintended illness or symptom thereof occurring in a patient to whom a drug has been administered. It does not matter whether there is a causal relationship with the drug or not.
  • Compound (1) may be dosed using an up-titration regimen, whereby a subject is started with a low dose for a certain period of time (e.g., 2 weeks) and then the dose is escalated.
  • the dose may be up-titrated until either a target or maximum dose is reached or the subject experiences adverse events at which point the escalation is stopped and the drug dosing is reduced to a previous dose where the adverse event was not experienced or was not serious enough to require stoppage of the treatment.
  • a subject that experiences an adverse event may also be managed with dosing interruptions (e.g., a drug holiday), if deemed appropriate.
  • Typical dosing for the continuous regimen may be 30, 45, 50, 60, 75, 100, 150, 200, 250, 300, 350, or 400 mg/day but higher or lower doses may be used depending on the subject’s response to the treatment and presence or absence of adverse events. If a dose is well-tolerated, the dose can be increased.
  • the continuous administration may be continued for one treatment cycle, e.g., 21 days, the treatment cycle may then be repeated, as desired. In some embodiments, only one treatment cycle is performed. In some embodiments, up to 10 treatment cycles are performed. In general, any number of treatment cycles can be performed, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 treatment cycles can be performed.
  • a drug holiday can be included in between any treatment cycles.
  • a treatment regimen can include treatment cycles between which a drug holiday is included and treatment cycles between which a drug holiday is not included.
  • Such continuous or intermittent administration is applicable also to combination therapies where Compound (1) or its pharmaceutical acceptable salt is administered in combination with one or more additional therapeutic agents (e.g., other anticancer agents) as described below.
  • additional therapeutic agents e.g., other anticancer agents
  • the treatment methods of the present disclosure may involve administration of Compound (1) or pharmaceutically acceptable salt thereof.
  • the treatment may also involve administration as a post-operative auxiliary chemotherapy that is performed to prevent recurrence of tumors after surgically removing tumors, as well as pre-operative auxiliary chemotherapy prior to surgery to surgically remove tumors.
  • surgery may include a lumpectomy, a mastectomy, a breast reconstruction, and the like.
  • surgery may include pneumonectomy, lobectomy, wedge resection, sleeve resection, thoracoscopy, and the like.
  • surgery may include craniotomy, ventriculoperitoneal shunt, endoscopic third ventriculostomy, surgery to put in a ventricular access catheter, and the like.
  • the treatment may also include administration of Compound (1) or pharmaceutically acceptable salt thereof during or after radiation therapy or as an adjuvant therapy to prevent recurrence of the tumor in a patient where other treatments such as surgery have rendered the patient cancer-free.
  • Subjects may be treated whom have previously undergone a treatment regimen with one or more with a molecularly targeted therapeutic, i.e., Compound (1) or its pharmaceutically acceptable salt is administered as second-, third-, fourth-, etc. line therapy.
  • Subjects may be treated whom have been previously treated with an EGFR-targeted therapeutic such as an EGFR inhibitor.
  • EGFR inhibitors may be categorized as an EGFR tyrosine kinase inhibitor or an anti-EGFR antibody, such as those set forth herein, examples of which include, but are not limited to, afatinib, gefitinib, erlotinib, osimertinib, poziotinib, lazertinib, sunvozertinib, furmonertinib, mobocertinib, lapatinib, neratinib, cetuximab, dacomitinib, panitumumab, vandetanib, DZD9008, BDTX-189, amivantamab, pembrolizumab, brigatinib, icotinib, olmutinib, rociletinib, duligotuzumab, zalutumumab, depatuxizumab, depatuxizumab mafodo
  • Compound (1) or its pharmaceutically acceptable salt may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets or capsules, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained release formulation; (3) topical application/transdermal administration, for example, as a cream, ointment, or a controlled release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets or capsules, e.
  • Formulations can be prepared using a pharmaceutically acceptable carrier or the like by using known formulation methods.
  • Pharmaceutically acceptable carriers are those materials, compositions, or vehicles, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminium hydrox
  • Pharmaceutically acceptable carriers may be categorized as various general-purpose agents such as excipients, binders, disintegrating agents, lubricants, diluents, dissolution aids, suspending agents, swelling agents, isotonic agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, corrigents, and the like.
  • excipients include, but are not limited to, lactose, sucrose, D-mannitol, glucose, starch (corn starch), calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid anhydride.
  • binders include, but are not limited to, water, ethanol, 1 -propanol, 2- propanol, simple syrup, liquid glucose, liquid a-starch, liquid gelatin, D-mannitol, carboxymethyl cellulose, hydroxypropyl cellulose (e.g., low viscosity hydroxypropyl cellulose), hydroxypropyl methylcellulose (hypromellose), hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone.
  • disintegrants include, but are not limited to, low-substituted hydroxypropyl cellulose, dry starch, partially pregelatinized starch, crystalline cellulose, carmellose sodium, carmellose calcium, D-mannitol, crospovidone, croscarmellose sodium, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • lubricants include, but are not limited to, hydrogenated oil, sucrose fatty acid ester, sodium lauryl sulfate, stearic acid, purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol.
  • Examples of colorants include, but are not limited to, edible yellow No. 5 dye, edible blue No. 2 dye, edible lake dye, iron sesquioxide, yellow sesquioxide, and titanium dioxide.
  • sweetening/flavoring agents include, but are not limited to, aspartame, saccharin (as sodium, potassium or calcium saccharin), cyclamate (as a sodium, potassium or calcium salt), sucralose, acesulfame-K, thaumatin, neohisperidin, dihydrochalcone, ammoniated glycyrrhizin, dextrose, maltodextrin, fructose, levulose, sucrose, glucose, wild orange peel, citric acid, tartaric acid, oil of wintergreen, oil of peppermint, oil of spearmint, oil of sassafras, oil of clove, cinnamon, anethole, menthol, thymol, eugenol,
  • an enteric coating or a coating to increase the persistence of effects can be provided by methods desirable for oral preparations.
  • coating agents include hydroxypropyl methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, and Tween 80 (registered trademark).
  • Compound (1) or its pharmaceutically acceptable salt are preferably formulated in solid dosage form for oral administration, such as in the form of capsules, tablets, pills, dragees, powders, granules, troches, and the like, with preference given to film-coated tablets.
  • Compound (1) or its pharmaceutically acceptable salt may be mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol
  • the formulations may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • One example coating formulation may include hypromellose, polyethylene glycol, titanium dioxide, and optionally a coloring agent. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • formulations may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Compound (1) or its pharmaceutically acceptable salt may be formulated for parenteral administration, for intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion administration, by combining Compound (1) or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, pH regulators, stabilizers, local anesthetics, etc.
  • compositions may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Compound (1) or its pharmaceutically acceptable salt can be combined with one or more additional therapeutic agents.
  • additional therapeutic agents include chemotherapeutic agents (e.g., cytotoxic agents), immunotherapeutic agents, hormonal and anti-hormonal agents, targeted therapy agents, and anti-angiogenesis agents.
  • the additional therapeutic agent can be an anti-cancer agent.
  • Many anti-cancer agents can be classified within one or more of these groups. While certain anticancer agents have been categorized within a specific group(s) or subgroup(s) herein, many of these agents can also be listed within one or more other group(s) or subgroup(s), as would be presently understood in the art. It should be understood that, as used here, “combined with” may refer to simultaneous treatment (e.g., co-administration with the same or different regimens), overlapping treatment, sequential treatment, or a combination of these.
  • Sequential treatment may include treatment first with Compound (1) or its pharmaceutically acceptable salt followed by treatment with one or more anticancer agents or treatment first with one or more anticancer agents followed by Compound (1) or its pharmaceutically acceptable salt.
  • a treatment gap i.e., a period of time following a conclusion or cessation of a first treatment prior to initiation of a second treatment.
  • the anticancer agent is not particularly limited, and examples thereof include, but are not limited to, a chemotherapeutic agent, a mitotic inhibitor, a plant alkaloid, an alkylating agent, an anti-metabolite, a platinum anticancer agent, an enzyme, a topoisomerase inhibitor, a retinoid, an aziridine, an antibiotic, a hormonal agent, an anti-hormonal agent, an antiestrogen, an anti-androgen, an anti-adrenal, an androgen, a targeted therapy agent, an immunotherapeutic agent, a biological response modifier, a cytokine inhibitor, a tumor vaccine, a monoclonal antibody, an immune checkpoint inhibitor, an anti-PD-1 agent, an anti- PD-L1 agent, a colony-stimulating factor, an immunomodulator, an immunomodulatory imide (IMiD), an anti-CTLA4 agent, an anti-LAGl agent, an anti-OX40 agent, a GITR agonist,
  • Non-limiting examples of chemotherapeutic agents include mitotic inhibitors and plant alkaloids, alkylating agents, anti-metabolites, platinum anticancer agents, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.
  • Non-limiting examples of mitotic inhibitors and plant alkaloids include taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel; demecolcine; epothilone; eribulin; etoposide (VP- 16); etoposide phosphate; navelbine; noscapine; teniposide; thaliblastine; vinblastine; vincristine; vindesine; vinflunine; and vinorelbine.
  • taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel
  • demecolcine epothilone
  • eribulin etoposide (VP- 16); etoposide phosphate
  • navelbine noscapine; teniposide; thaliblastine; vinblastine; vincristine; vindesine
  • alkylating agents include nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, cytophosphane, estramustine, ifosfamide, mannomustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, tris(2-chloroethyl)amine, trofosfamide, and uracil mustard; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, streptozotocin, and TA-07; ethylenimines and methylamelamines such as altretamine, thiotepa, triethylenemelamine, triethylenethiophospha
  • Non-limiting examples of anti-metabolites include folic acid analogues such as aminopterin, denopterin, edatrexate, methotrexate, pteropterin, raltitrexed, trimetrexate, and pemetrexed, of these, pemetrexed is preferable; purine analogs such as 6-mercaptopurine, 6- thioguanine, fludarabine, forodesine, thiamiprine, and thioguanine; pyrimidine analogs such as 5 -fluorouracil (5-FU), tegafur/gimeracil/oteracil potassium, tegafur/uracil, trifluridine, trifluridine/tipiracil hydrochloride, 6-azauridine, ancitabine, azacytidine, capecitabine, carmofur, cytarabine, decitabine, dideoxyuridine, doxifiuridine, doxifluridine, enocita
  • platinum anticancer agent such as oxaliplatin, cisplatin, carboplatin, and nedaplatin. Of these, carboplatin is preferable.
  • Non-limiting examples of enzymes include asparaginase and pegaspargase.
  • Non-limiting examples of topoisomerase inhibitors include acridine carboxamide, amonafide, amsacrine, belotecan, elliptinium acetate, exatecan, indolocarbazole, irinotecan, lurtotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.
  • Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin.
  • Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa.
  • Non-limiting examples of antibiotics include intercalating antibiotics; anthracenediones; anthracycline antibiotics such as aclarubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, nogalamycin, pirarubicin, and valrubicin; 6-diazo-5-oxo-L-norleucine; aclacinomysins; actinomycin; authramycin; azaserine; bleomycins; cactinomycin; calicheamicin; carabicin; carminomycin; carzinophilin; chromomycins; dactinomycin; detorubicin; esorubicin; esperamicins; geldanamycin; marcellomycin; mitomycins; mitomycin C; mycophenolic acid; olivomycins; novantrone; peb
  • Non-limiting examples of hormonal and anti-hormonal agents include anti-androgens such as abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, goserelin, leuprolide, and nilutamide; anti-estrogens such as 4-hydroxy tamoxifen, aromatase inhibiting 4(5)-imidazoles, EM-800, fosfestrol, fulvestrant, keoxifene, LY 117018, onapristone, raloxifene, tamoxifen, toremifene, and trioxifene; anti-adrenals such as aminoglutethimide, dexaminoglutethimide, mitotane, and trilostane; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone;
  • Non-limiting examples of immunotherapeutic agents include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony-stimulating factors, and immunomodulators.
  • Non-limiting examples of biological response modifiers include interferon alfa/interferon alpha such as interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon alfacon-1, peginterferon alfa-2a, peginterferon alfa-2b, and leukocyte alpha interferon; interferon beta such as interferon beta-la, and interferon beta-lb; interferon gamma such as natural interferon gamma- la, and interferon gamma- lb; aldesleukin; interleukin- 1 beta; interleukin-2; oprelvekin; sonermin; tasonermin; and virulizin.
  • interferon alfa/interferon alpha such as interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon
  • Non-limiting examples of tumor vaccines include APC 8015, AVICINE, bladder cancer vaccine, cancer vaccine (Biomira), gastrin 17 immunogen, Maruyama vaccine, melanoma lysate vaccine, melanoma oncolysate vaccine (New York Medical College), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), TICE® BCG (Bacillus Calmette-Guerin), and viral melanoma cell lysates vaccine (Royal Newcastle Hospital).
  • Non-limiting examples of monoclonal antibodies include abagovomab, adecatumumab, aflibercept, alemtuzumab, blinatumomab, brentuximab vedotin, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), daclizumab, daratumumab, denosumab, edrecolomab, gemtuzumab zogamicin, HER-2 and Fc MAb (Medarex), ibritumomab tiuxetan, idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), ipilimumab, lintuzumab, LYM-1 -iodine 131 MAb (Techni clone), mitumomab, moxetumomab, ofatumumab, polymorphic epithelial a
  • Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 agents or antibodies such as cemiplimab, nivolumab, and pembrolizumab; anti-PD-Ll agents or antibodies such as atezolizumab, avelumab, and durvalumab; anti-CTLA-4 agents or antibodies such as ipilumumab and tremelimumab; anti-LAGl agents; and anti-OX40 agents.
  • Non-limiting examples of colony-stimulating factors include darbepoetin alfa, epoetin alfa, epoetin beta, filgrastim, granulocyte macrophage colony stimulating factor, lenograstim, leridistim, mirimostim, molgramostim, nartograstim, pegfilgrastim, and sargramostim.
  • Non-limiting examples of additional immunotherapeutic agents include BiTEs, CAR- T cells, GITR agonists, imiquimod, immunomodulatory imides (IMiDs), mismatched double stranded RNA (Ampligen), resiquimod, SRL 172, and thymalfasin.
  • Targeted therapy agents include, for example, monoclonal antibodies and small molecule drugs.
  • targeted therapy agents include signal transduction inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, HER2 inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell-cycle inhibitors, angiogenesis inhibitors, matrix-metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factors (FGF) inhibitors, RAF inhibitor, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, BRAF-inhibitors, RAS inhibitor, gene expression modulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.
  • HDAC histone deacetylase
  • MMP matrix-
  • Non-limiting examples of tyrosine kinase inhibitors include EGFR inhibitors, HER2 inhibitors, JAK inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factors (FGF) inhibitors, RAF inhibitor, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, BRAF- inhibitors, RAS inhibitor, TYK2 inhibitors, c-MET inhibitors, RET inhibitors and ROS1 inhibitors.
  • FGF fibroblast growth factors
  • Non-limiting examples of signal transduction inhibitors include tyrosine kinase inhibitors, multiple-kinase inhibitors, anlotinib, avapritinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, lonidamine, nilotinib, nintedanib, pazopanib, pegvisomant, ponatinib, vandetanib, and EGFR and/or HER2 inhibitory agents (i.e., other than Compound (1) or its salt).
  • tyrosine kinase inhibitors include tyrosine kinase inhibitors, multiple-kinase inhibitors, anlotinib, avapritinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, lonidamine, nilotinib,
  • Non-limiting examples of EGFR inhibitors include small molecule antagonists of EGFR such as afatinib, brigatinib, erlotinib, gefitinib, lapatinib, neratinib, dacomitinib, vandetanib, and osimertinib; and antibody-based EGFR inhibitors, including any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand.
  • Antibody -based EGFR inhibitory agents may include, for example, those described in Modjtahedi, H., et al., 1993, Br. J.
  • HB-8508 or an antibody or antibody fragment having the binding specificity thereof; specific antisense nucleotide or siRNA; afatinib, cetuximab; matuzumab; necitumumab; nimotuzumab; panitumumab; and zalutumumab.
  • Non-limiting examples of HER2 inhibitors include HER2 tyrosine kinase inhibitors such as afatinib, lapatinib, neratinib, and tucatinib; and anti-HER2 antibodies or drug conjugates thereof such as trastuzumab, trastuzumab emtansine (T-DM1), pertuzumab, margetuximab, trastuzumab deruxtecan (DS-8201a), and trastuzumab duocarmazine.
  • T-DM1 trastuzumab
  • T-DM1 trastuzumab emtansine
  • pertuzumab pertuzumab
  • margetuximab pertuzumab
  • trastuzumab deruxtecan DS-8201a
  • trastuzumab duocarmazine trastuzumab duocarmazine.
  • HD AC histone deacetylase
  • Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib.
  • Non-limiting examples of cell-cycle inhibitors include abemaciclib, alvocidib, palbociclib, and riboci clib.
  • Non-limiting examples of anti-angiogenic agents include, but not limited to, matrix-metalloproteinase (MMP) inhibitors; VEGF inhibitors; EGFR inhibitors; TOR inhibitors such as everolimus and temsirolimus; PDGFR kinase inhibitory agents such as crenolanib; HIF-la inhibitors such as PX 478; HIF-2a inhibitors such as belzutifan and the HIF-2a inhibitors described in WO 2015/035223; fibroblast growth factor (FGF) or FGFR inhibitory agents such as B-FGF and RG 13577; hepatocyte growth factor inhibitors; KDR inhibitors; anti-Angl and anti-Ang2 agents; anti-Tie2 kinase inhibitory agents; Tek antagonists (US 2003/0162712; US 6,413,932); anti-TWEAK agents (US 6,727,225); ADAM distintegrin domain to antagonize
  • MMP matrix-metalloproteinas
  • MMP inhibitors include MMP- 2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, prinomastat, RO 32-3555, and RS 13-0830.
  • WO 96/33172 examples include WO 96/27583, EP 1004578 , WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 0606046, EP 0931788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 1999/007675 , EP 1786785, EP 1181017, US 2009/0012085 , US 5,863,949, US 5,861,510, and EP 0780386.
  • MMP -2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP -2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP -4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
  • MMP-1 matrix-metalloproteinases
  • Non-limiting examples of VEGF and VEGFR inhibitory agents include bevacizumab, cediranib, CEP 7055, CP 547632, KRN 633, orantinib, pazopanib, pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAPTM.
  • anti-angiogenic agents may include, but are not limited to, 2-methoxyestradiol, AE 941, alemtuzumab, alpha-D148 Mab (Amgen, US), alphastatin, anecortave acetate, angiocidin, angiogenesis inhibitors, (SUGEN, US), angiostatin, anti-Vn Mab (Crucell, Netherlands), atiprimod, axitinib, AZD 9935, BAY RES 2690 (Bayer, Germany, BC 1 (Genoa Institute of Cancer Research, Italy), beloranib, benefin (Lane Labs, US), cabozantinib, CDP 791 (Celltech Group, UK), chondroitinase AC, cilengitide, combretastatin A4 prodrug, CP 564959 (OSI, US), CV247, CYC 381 (Harvard University, US), E 7820, EHT 0101,
  • the anticancer agent(s) that may be combined with Compound (1) may also be an active agent that disrupts or inhibits RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways or is a PD-1 and/or PD-L1 antagonist.
  • RAF inhibitor examples include, but are not limited to, a RAF inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a AKT inhibitor, a TOR inhibitor, an MCL-1 inhibitor, a BCL-2 inhibitor, a SHP2 inhibitor, a proteasome inhibitor, or an immune therapy, including monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAGl, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.
  • IMDs immunomodulatory imides
  • Non-limiting examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib.
  • Non-limiting examples of MEK inhibitors include binimetinib, CI- 1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and tram etinib.
  • Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, ravoxertinib, ulixertinib, and ASTX029.
  • Non-limiting examples of PI3K inhibitors include 17-hydroxywortmannin analogs (e.g., WO 06/044453); AEZS-136; alpelisib; AS-252424; buparlisib; CAL263; copanlisib; CUDC-907; dactolisib (WO 06/122806); demethoxyviridin; duvelisib; GNE-477; GSK1059615; IC87114; idelalisib; INK1117; LY294002; Palomid 529; paxalisib; perifosine; PI-103; PI-103 hydrochloride; pictilisib (e.g., WO 09/036,082; WO 09/055,730); PIK 90; PWT33597; SF1126; sonolisib; TGI 00-115; TGX-221; XL147; XL-765; wortmann
  • Non-limiting examples of AKT inhibitors include Akt-1-1 (inhibits Aktl) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1, 2 (Barnett et al. (2005) Biochem. J.
  • API-59CJ-Ome e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12
  • 1-H- imidazo[4,5-c]pyridinyl compounds e.g., W005011700
  • indole-3 -carbinol and derivatives thereof e.g., U.S. Patent No. 6,656,963; Sarkar and Li (2004) JNutr. 134(12 Suppl), 3493S- 3498S
  • perifosine Dasmahapatra et al. (2004) Clin. Cancer Res.
  • imidazooxazone compounds including trans-3 -amino- l-methyl-3-[4-(3 -phenyl-5H- imidazo[ 1 ,2-c]pyrido[3 ,4-e] [ 1 ,3 ]oxazin-2-yl)phenyl]-cyclobutanol hydrochloride (W O 2012/137870); afuresertib;; capivasertib; 8-[4-(l-aminocyclobutyl)phenyl]-9-phenyl-l,2,4- triazolo[3,4-f][l,6]naphthyridin-3(2H)-one (MK2206) and pharmaceutically acceptable salts thereof; AZD5363; trans-3 -amino- l-methyl-3-(4-(3 -phenyl-5H-imidazo[l,2-c]pyrido[3, 4- e][l,3]
  • Non-limiting examples of TOR inhibitors include deforolimus; ATP-competitive TORC1/TORC2 inhibitors, including PI- 103, PP242, PP30, and Torin 1; TOR inhibitors in FKBP12 enhancer, rapamycins and derivatives thereof, including temsirolimus, everolimus, WO 9409010; rapalogs, e.g. as disclosed in WO 98/02441 and WO 01/14387, e.g.
  • AP23573, AP23464, or AP23841 40-(2-hydroxyethyl)rapamycin, 40-[3- hydroxy(hydroxymethyl)methylpropanoate]-rapamycin; 40-epi-(tetrazolyl)-rapamycin (also called ABT578); AZD8055; 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin, and other derivatives disclosed in WO 05/005434; derivatives disclosed in US 5,258,389, WO 94/090101, WO 92/05179, US 5,118,677, US 5,118,678, US 5,100,883, US 5,151,413, US 5,120,842, WO 93/111130, WO 94/02136, WO 94/02485, WO 95/14023, WO 94/02136, WO 95/16691, WO 96/41807, WO 96/41807 and US 5,
  • MCL-1 inhibitors include AMG-176, MIK665, and S63845.
  • Non-limiting examples of SHP2 inhibitors include JAB-3068, RMC-4630, TNO155, SHP-099, RMC-4550, and SHP2 inhibitors described in WO 2019/167000, WO 2020/022323 and WO2021/033153.
  • Non-limiting examples of RAS inhibitors include AMG510, MRTX849, LY3499446, JNJ-74699157 (ARS-3248), ARS-1620, ARS-853, RM-007, and RM-008.
  • anticancer agents include, but are not limited to, 2-ethylhydrazide, 2,2',2"-trichlorotriethylamine, ABVD, aceglatone, acemannan, aldophosphamide glycoside, alpharadin, amifostine, aminolevulinic acid, anagrelide, ANCER, ancestim, anti-CD22 immunotoxins, antitumorigenic herbs, apaziquone, arglabin, arsenic trioxide, azathioprine, BAM 002 (Novelos), bcl-2 (Genta), bestrabucil, biricodar, bisantrene, bromocriptine, brostallicin, bryostatin, buthionine sulfoximine, calyculin, cell-cycle nonspecific antineoplastic agents, celmoleukin, clodronate, clotrimazole, cytara
  • Cisplatin can be administered at dose levels of from about 10 mg/m 2 , from about 15 mg/m 2 , from about 20 mg/m 2 , from about 30 mg/m 2 , from about 40 mg/m 2 , from about 50 mg/m 2 , from about 60 mg/m 2 , from about 80 mg/m 2 , from about 90 mg/m 2 and up to about 250 mg/m 2 , up to about 225 mg/m 2 , up to about 200 mg/m 2 , up to about 175 mg/m 2 , up to about 150 mg/m 2 , up to about 125 mg/m 2 , up to about 110 mg/m 2 .
  • the dosing level may be varied within the ranges such as from about 10 mg/m 2 to about 250 mg/m 2 , from about 20 mg/m 2 to about 150 mg/m 2 , preferably from about 50 mg to about 100 mg/m 2 , preferably from about 60 mg to about 90 mg/m 2 , preferably from about 70 mg to about 80 mg/m 2 , more preferably from about 72.5 mg to about 77.5 mg/m 2 , more preferably about 75 mg/m 2 .
  • the administration dose level can be changed during an administration schedule, for example, the administration can begin with low dose for some time and then increased, or, the administration can begin with high dose for some time and then decreased.
  • the dosing of the cisplatin can be continuous (daily; 7 days of administration in a week), intermittent (alternating one or more dosing days with one or more non-dosing days, such as 4 days-on/3 days-off), or once-per-cycle for example, depending the pharmacokinetics and a particular patient’s clearance/accumulation of the drug.
  • the dosing schedule should be selected using sound medical judgement.
  • Once- per-cycle administration of cisplatin is preferred.
  • the once-per-cycle administration occurs on the first day of a treatment cycle.
  • the once-per-cycle administration preferably happens on only the first day (day 1) of the treatment cycle.
  • the once-per-cycle dose may be administered as a single dose or multiple individual divided doses.
  • one intravenous injection containing about 50 to 100 mg/m 2 of cisplatin can be administered on the first day of the treatment cycle.
  • three (3) separate intravenous injections, each containing 20 mg/m 2 of cisplatin, may be administered to the subject in a single day 60 mg/m 2 on that day.
  • the dosing whether continuous, intermittent, or once-per-cycle is continued for a particular treatment cycle typically at least a 21 day cycle, which can be repeated with or without a drug holiday. Longer or shorter cycles can also be used such as 7 days, 14 days, 18 days, 24 days, 28 days, 35 days, 42 days, or any range therebetween.
  • the treatment cycle may be repeated without a drug holiday or with a drug holiday depending upon the subject.
  • Carboplatin can be administered at dose levels of from about AUC 1.0 mg/mL/min, from about AUC 1.5 mg/mL/min, from about AUC 2.0 mg/mL/min, from about AUC 2.5 mg/mL/min, from about AUC 3.0 mg/mL/min, from about AUC 3.5 mg/mL/min, from about AUC 4.0 mg/mL/min, from about AUC 4.5 mg/mL/min and up to about AUC 10.0 mg/mL/min, up to about AUC 9.5 mg/mL/min, up to about AUC 9.0 mg/mL/min, up to about AUC 8.5 mg/mL/min, up to about AUC 8.0 mg/mL/min, up to about AUC 7.5 mg/mL/min, up to about AUC 7.0 mg/mL/min, up to about AUC 6.5 mg/mL/min, up to about AUC 6.0 mg/mL/min, up to about AUC 5.5 mg/mL/
  • the dosing level may be varied within the ranges such as from about AUC 1 mg/mL/min to about AUC 10 mg/mL/min, from about 2.5 mg/mL/min to about AUC 7.5 mg/mL/min, from about 4.5 mg/mL/min to about AUC 5.5 mg/mL/min.
  • carboplatin is administered at a dose level of AUC 5.0 mg/mL/min.
  • the administration dose level can be changed during an administration schedule, for example, the administration can begin with low dose for some time and then increased, or, the administration can begin with high dose for some time and then decreased.
  • the dosing of the carboplatin(or other platinum anticancer agent) can be continuous (daily; 7 days of administration in a week), intermittent (alternating one or more dosing days with one or more non-dosing days, such as 4 days-on/3 days-off), or once-per-cycle for example, depending the pharmacokinetics and a particular patient’s clearance/accumulation of the drug.
  • the dosing schedule should be selected using sound medical judgement.
  • Once- per-cycle administration of cisplatin is preferred.
  • the once-per-cycle administration occurs on the first day of a treatment cycle.
  • the once-per-cycle administration preferably happens on only the first day (day 1) of the treatment cycle.
  • the once-per-cycle dose may be administered as a single dose or multiple individual divided doses. For example, one intravenous injection sufficient to give an AUC 5 mg/mL/min dose is administered over a period of 15 to 60 minutes.
  • the dosing whether continuous, intermittent, or once-per-cycle is continued for a particular treatment cycle typically at least a 21-day cycle, which can be repeated with or without a drug holiday. Longer or shorter cycles can also be used such as 7 days, 14 days, 18 days, 24 days, 28 days, 35 days, 42 days, or any range therebetween.
  • the treatment cycle may be repeated without a drug holiday or with a drug holiday depending upon the subject.
  • Pemetrexed can be administered at dose levels of from about 50 mg/m 2 , from about 75 mg/m 2 , from about 100 mg/m 2 , from about 150 mg/m 2 , from about 200 mg/m 2 , from about 250 mg/m 2 , from about 300 mg/m 2 , from about 350 mg/m 2 , from about 400 mg/m 2 , from about 425 mg/m 2 , from about 450 mg/m 2 , from about 475 mg/m 2 and up to about 1000 mg/m 2 , up to about 950 mg/m 2 , up to about 900 mg/m 2 , up to about 850 mg/m 2 , up to about 800 mg/m 2 , up to about 750 mg/m 2 , up to about 700 mg/m 2 , up to about 650 mg/m 2 , up to about 600 mg/m 2 , up to about 550 mg/m 2 .
  • the dosing level may be varied within the ranges such as from about 50 mg/m 2 to about 100 mg/m 2 , from about 250 mg/m 2 to about 750 mg/m 2 , and from about 450 mg to about 550 mg/m 2 .
  • pemetrexed is administered in an amount of 500 mg/m 2 .
  • the administration dose level can be changed during an administration schedule, for example, the administration can begin with low dose for some time and then increased, or, the administration can begin with high dose for some time and then decreased.
  • the dosing of the pemetrexed can be continuous (daily; 7 days of administration in a week), intermittent (alternating one or more dosing days with one or more non-dosing days, such as 4 days-on/3 days-off), or once-per-cycle for example, depending the pharmacokinetics and a particular patient’s clearance/accumulation of the drug.
  • the dosing schedule should be selected using sound medical judgement.
  • Once-per-cycle administration of pemetrexed is preferred.
  • the once-per-cycle administration occurs on the first day of a treatment cycle.
  • the once-per-cycle administration preferably happens on only the first day (day 1) of the treatment cycle.
  • the once-per-cycle dose may be administered as a single dose or multiple individual divided doses.
  • one intravenous injection containing about 450 to 550 mg/m 2 of pemetrexed can be administered on the first day of the treatment cycle.
  • the dosing whether continuous, intermittent, or once-per-cycle is continued for a particular treatment cycle typically at least a 21 day cycle, which can be repeated with or without a drug holiday. Longer or shorter cycles can also be used such as 7 days, 14 days, 18 days, 24 days, 28 days, 35 days, 42 days, or any range therebetween.
  • the treatment cycle may be repeated without a drug holiday or with a drug holiday depending upon the subject.
  • the additional therapeutic agent is amivantamab.
  • Amivantamab can be administered at dose levels of from about 350 mg, from about 500 mg, from about 700 mg, from about 1000 mg up to about 1050 mg, up to about 1400 mg, up to about 1500 mg, up to about 1750 mg, up to about 1900 mg, up to about 2100 mg.
  • the dosing level may be varied within the ranges such as from about 350 mg to about 700 mg, from about 1050 to about 1400 mg, from about 1400 mg to 1750 mg, and from about 1750 to about 2100 mg.
  • the administration dose level can be changed during an administration schedule, for example, the administration can begin with low dose for some time and then increased, or, the administration can begin with high dose for some time and then decreased.
  • Amivantamab can be administered at an infusion rate of from about 20 mL/hr, from about 35 mL/hr, from about 50 mL/hr, up to about 65 mL/hr, up to about 75 mL/hr, up to about 85 mL/hr, up to about 125 mL/hr, up to about 150 mL/hr.
  • the dosing of the amivantamab can be continuous (daily; 7 days of administration in a week), intermittent (alternating one or more dosing days with one or more non-dosing days, such as 4 days-on/3 days-off, once per week, etc.), or once-per-cycle for example, depending the pharmacokinetics and a particular patient’s clearance/accumulation of the drug.
  • the dosing schedule should be selected using sound medical judgement.
  • Amivantamab may be administered as a single dose or multiple individual divided doses. For example, in a first week of amivantamab treatment, amivantamab may be administered across two doses separated by one or more days but still falling within a 7-day period. For example, on a first day, a first dose of amivantamab can be administered, including, for example, 350 mg or 500 mg, or 700 mg of amivantamab. On a second day, a second dose of amivantamab can be administered, including, for example 700 mg or 1050 mg or 1400 mg of amivantamab.
  • a typical exemplary dosing schedule for amivantamab includes weekly administration of 1050 mg with a first week infusion split into two days, a first day of 350 mg amivantamab administration and a second day of 700 mg amivantamab administration.
  • Another typical exemplary dosing schedule for amivantamab includes weekly administration of 1400 mg with a first week infusion split into two days, a first day of 350 mg amivantamab administration and a second day of 1050 mg amivantamab administration.
  • Typical dosing schedules include weekly administration for 4 weeks or cycles of 4 weeks or weekly administration for 4 weeks followed by administration every 2 or more weeks for an indefinite period (e.g., until disease progression or unacceptable toxicity). Week 5 and/or week 6 may be drug holiday.
  • a subsequent cycle may forego the splitting of the first week administration described above. Subsequent cycles may be repeated indefinitely (e.g., until disease progression or unacceptable toxicity). Onset of adverse reactions may lead to, result in, or be mitigated by dosage reductions in subsequent weeks or treatment cycles. For example, an initial dose of 1050 mg may be reduced to 700 mg, then to 350 mg. An initial dose of 1400 mg may be reduced to 1050 mg, then to 700 mg, then to 350 mg. Amivantamab may be administered according to the drug label.
  • the previous treatment with amivantamab is performed as described above.
  • the term “combination,” “combined,” or a variation thereof is intended to define a therapy involving the use of two or more compound/drug combinations.
  • the term can refer to compounds/drugs that are administered as part of the same overall dosage schedule.
  • the respective dosages of two or more compounds/drugs can be different.
  • the combination therapy is intended to embrace administration of these compounds/drugs in a sequential manner, that is, wherein each compound/drug is administered at a different time, as well as administration of these compounds/drugs, or at least two of the compounds/drugs, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each compound/drug or in multiple, single dosage forms for each of the compounds/drugs.
  • Sequential or substantially simultaneous administration of each compound/drug can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues (e.g., buccal).
  • the compounds/drugs can be administered by the same route or by different routes.
  • a first compound/drug of the combination selected may be administered by intravenous injection while the other compound/drug of the combination may be administered orally.
  • all compounds/drugs may be administered orally or all compounds/drugs may be administered by intravenous injection.
  • Combination therapy also can embrace the administration of the compounds/drugs as described above in further combination with other biologically active ingredients and nondrug therapies (e.g., surgery or radiation treatment).
  • the combination therapy further comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of compound/drug and non-drug treatment is achieved.
  • the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the compound/drug, perhaps by days or even weeks.
  • Radiotherapy refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site.
  • radioactive isotopes e.g., At-211, 1-131, 1 -125, Y-90, Re- 186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu.
  • Suitable radiation sources for use as a cell conditioner of the present disclosure include both solids and liquids.
  • the radiation source can be a radionuclide, such as 1-125, 1 - 131, Yb-169, Ir-192 as a solid source, 1-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays.
  • the radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of 1-125 or I- 131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90.
  • the radionuclide(s) can be embodied in a gel or radioactive microspheres.
  • H1975insSVD was transplanted at 5 ⁇ 106 cells/mouse into the flank of male BALB/cA Jcl-nu mice.
  • TAS6417 was orally administered at 100 mg/kg every day.
  • Carboplatin (CBDCA) was administered intravenously at 50 mg/kg and 70 mg/kg in day 1 and day 8.
  • TAS6417 was mixed in 0.1 mol/L hydrochloric acid to generate a suspension.
  • CBDCA was mixed in saline to generate a suspension.
  • BWC body weight change
  • TAS6417 combination efficacy with CBDCA compared to TAS6417 single agent was examined. H1975ins SVD cells were implanted into the flank of mice. The TAS6417 combination efficacy with CBDCA was observed in this xenograft models (FIG. 1). TAS6417 combined with CBDCA resulted in a significant reduction in tumor growth compared TAS641 single agent (Aspin-welch test, p ⁇ 0.05). The combination setting showed the similar body weight change with TAS6417 single agent (FIG. 2).
  • Table 1 below presents results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin, at various maximum doses of Compound (1) (TAS6417). Plots of the tumor volumes presented in Table 1 below, along with additional time points between days 1 and 15, are presented in FIG. 1.
  • FIG. 2 shows a plot of mean body weight change throughout treatment for the preclinical animal studies. The reasonable stability of the body weight throughout the treatment indicates that none of the regimens involves increased or unacceptable levels of toxicity.
  • Table 1 Results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin, with a maximum dose of Compound (1) (TAS6417) of 200 mg/kg.
  • Compound (1) was administered orally twice a day without food continuously in 21- day treatment cycles. Tumor assessments were performed at baseline, week 6, every 9 weeks until week 42, and every 12 weeks thereafter. Brain imaging was required with each restaging for patients with a history of central nervous system (CNS) metastases. Treatment was continued until disease progression, unacceptable adverse effects, withdrawal of consent, or could be discontinued at the investigator’s discretion. Treatment could be continued beyond radiographic disease progression in patients with continued clinical benefit. Safety evaluations, including clinical and laboratory assessments, were conducted at baseline and at regular intervals during treatment. Adverse event (AE) severity was graded according to the National
  • DLTs Dose-limiting toxi cities
  • TAEs treatment-related AEs
  • Escalation began with a single-patient accelerated titration design with transition to a rolling six design upon the first occurrence of a grade >2 TRAE during cycle 1 (FIG. 6). Successive cohorts were treated with Compound 1 at 30, 45, 65, 100, and 150 mg twice a day; transition to the rolling six design occurred at the 100 mg dose level.
  • the Protocol online only allowed for expanded enrollment of up to six patients in any cohort with an acceptable safety profile. For those cohorts in which at least 1/6 patients achieved a confirmed partial response (PR), enrollment could be expanded to a total of 13 patients, and for those cohorts in which 4/13 patients achieved a confirmed PR, enrollment could be expanded up to 36 total patients.
  • Eligible patients were age 18 years and older and had histologically or cytologically confirmed recurrent and/or metastatic NSCLC with an EGFR ex20ins mutation confirmed on local testing in a Clinical Laboratory Improvement Amendments of 1988, CLIA certified or equivalent laboratory. Central confirmation of the EGFR ex20ins was not required. Archival tumor tissue and circulating tumor deoxyribonucleic acid for molecular profiling were collected during screening.
  • Exclusion criteria included spinal cord compression, history of drug-induced pneumonitis, or active infection.
  • CNS central nervous system
  • ECOG Eastern Cooperative Oncology Group
  • EGFR epidermal growth factor receptor
  • ex20ins Insertions in EGFR exon 20
  • TKIs tyrosine kinase inhibitors
  • TEAEs Treatment-emergent AEs
  • TRAEs Treatment-emergent AEs
  • TRAEs of any grade occurred in 72/73 (99%) patients treated across all dose levels, with grade >3 TRAEs in 17/73 (23%) patients (Table 3).
  • the most common TRAEs of any grade occurring in >15% patients included rash (80%), paronychia (32%), diarrhea (30%), fatigue (21%), anemia (19%), dry skin (18%), and nausea (16%; Table 3).
  • Anemia (10%) was the only grade >3 TRAE observed in >5% patients (Table 7).
  • mPFS Median progression- free survival
  • Response-evaluable patients included those with measurable disease at baseline and either at least one on-treatment tumor assessment or clinical progression before the first on- treatment tumor assessment.
  • Adverse events were coded using the Medical Dictionary for Regulatory Activities, version 24.0.
  • Responses in individual patients were determined on the basis of the assessment of the treating investigator using Response Evaluation Criteria in Solid Tumors, version 1.1.
  • Objective responses were confirmed by at least one sequential tumor assessment obtained at least 4 weeks from the original scan documenting a response. OR rates (ORRs) were calculated as [[(patients with a complete response 1 patients with a partial response [PR]) 4 number of patients] 3 100%].
  • a Simon two-stage design was used to assess efficacy of zipalertinib for all dose levels entering the phase I dose expansion phase.
  • the null hypothesis was an ORR of 10%, which was tested against an alternative hypothesis of ORR > 40%. If 0 responses were observed in the first six patients at given dose level, no further patients would be recruited at that dose level. Otherwise, seven additional patients could be recruited and, if four or more responses are observed in total, the null hypothesis would be rejected.
  • This design yields a one-sided type I error rate of ⁇ 5% and power of >80% when the true response rate is 40%. For dose levels entering the phase 2a dose expansion phase, an additional 23 patients could be recruited.
  • the median duration of response was estimated using the Kaplan-Meier method and defined as the interval between the date of earliest response and the date of disease progression or death for any cause.
  • Median progression-free survival was estimated using the Kaplan-Meier method and defined as the interval between the day of the first dose of study treatment to the first documentation of disease progression or death due to any cause, whichever occurred earlier.
  • the median duration of follow-up was determined by simple frequentist median.
  • grade 3 pneumonitis was initially considered possibly related to zipalertinib, but ultimately deemed to be unrelated to study treatment by the sponsor after the patient was diagnosed and treated for Pneumocystis jirovecii pneumonia on the basis of positive bronchoalveolar lavage.
  • the median number of cycles administered was 11 (range, 2-32), 11 (2-33), and 10 (1-17) for patients treated at doses of 65mg twice a day or less, 100 mg twice a day, and 150 mg twice a day, respectively.
  • PRs were observed across a spectrum of diverse epidermal growth factor receptor exon 20 insertion mutations (ex20ins) mutations.
  • ex20ins epidermal growth factor receptor exon 20 insertion mutations
  • near-loop mutations were the most common mutation subtype, followed by the far-loop mutations and helical region with 52, 9, and 2 patients, respectively.
  • One patient had different ex20ins mutations identified in two different tumor specimens and was included in the unknown group.
  • the response rate was 41.5%, 22%, and 0% in the near-loop, far-loop, and helical region mutations, respectively (FIG. 8).
  • the response rate in the unreported group was 40%.
  • NSCLC non-small-cell lung cancer.
  • CPI checkpoint inhibitor
  • CTCAE Common Terminology Criteria for Adverse Events
  • TEAE treatment-emergent adverse events.
  • v5.0. b 100 mg patient with grade 3 pneumonitis confounded by treatment with CPI and concurrent hydropneumothorax contralateral lung; 150 mg patient with grade 3 pneumonitis confounded by concurrent Pneumocystis infection, had stopped zipalertinib 3 weeks before the event; 100 mg patient with grade 1 (to be upgraded as grade 2) pneumonitis treated with steroids with resolution and continued therapy; 65 mg patient with grade 2 pneumonitis who previously had pneumonitis on osimertinib.
  • AR accumulation ratio
  • AUCLST Area under the plasma-time concentration curve from time zero to the last observed time point
  • AUC TA U Area under the plasma concentration-time curve in a dosing interval of 12 hours
  • CV coefficient of variation
  • GM geometric mean
  • max maximum
  • min minimum
  • NA not applicable
  • TI/ 2 halflife, T m ax, time to C max .
  • H1975insSVD was transplanted at 8* 10 6 cells/mouse into the flank of male BALB/cA Jcl-nu mice.
  • TAS6417 was orally administered at 100 mg/kg every day.
  • CBDCA and pemetrexed were administered intravenously at 60 mg/kg and 50 mg/kg respectively in day 1 and day 15.
  • TAS6417 was mixed in 0.1 mol/L hydrochloric acid to generate a suspension.
  • CBDCA and pemetrexed were mixed in saline to generate a suspension.
  • the percent BWC was calculated for each group by equation below. Then the mean BWC was calculated from the BWC data of the individual animals and was plotted on a graph versus the number of days after grouping.
  • BWC (%) [(body weight on Day n) - (body weight on Day 0)] / (body weight on Day 0) x 100
  • TAS6417 combination efficacy with CBDCA/pemetrexed compared to TAS6417 single agent was examined. H1975ins SVD cells were implanted into the flank of mice. The TAS6417 combination efficacy with CBDCA/pemetrexed was observed in this xenograft models (FIG. 10). TAS6417 combined with CBDCA/pemetrexed resulted in a significant reduction in tumor growth compared TAS641 single agent (Aspin-welch test, p ⁇ 0.05). The combination setting showed the similar body weight change with TAS6417 single agent (Fig. H).
  • Table 10 below presents results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or CBDCA/pemetrexed. Plots of the tumor volumes presented in Table 10 below, along with additional time points between days 1 and 22, are presented in FIG. 10.
  • CBDCA/pemetrexed did not result in inhibition of tumor volume increase.
  • administration of Compound (1) (TAS6417) along or in combination with CBDCA/pemetrexed showed dramatically smaller tumor volume after 22 days.
  • there is a statistically significant decrease in tumor volume (indicated by the bracket and asterisk in FIG. 10) when Compound (1) (TAS6417) is administered at a dosage of 100 mg/kg in combination with CBDCA/pemetrexed.
  • FIG. 11 shows a plot of mean body weight change throughout treatment for the preclinical animal studies. The reasonable stability of the body weight throughout the treatment indicates that none of the regimens involves increased or unacceptable levels of toxicity.
  • Table 10 Results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or CBDCA/PEM (pemetrexed)
  • NIH/3T3 EGFR H773_V774insNPH was transplanted at 5* 10 6 cells/mouse into the flank of male BALB/cA Jcl-nu mice.
  • TAS6417 was orally administered at 100 mg/kg every day.
  • CBDCA and pemetrexed were administered intravenously at 60 mg/kg and 50 mg/kg respectively in day 1.
  • TAS6417 was mixed in 0.1 mol/L hydrochloric acid to generate a suspension.
  • CBDCA and pemetrexed were mixed in saline to generate a suspension.
  • the percent BWC was calculated for each group by equation below. Then the mean BWC was calculated from the BWC data of the individual animals and was plotted on a graph versus the number of days after grouping.
  • BWC (%) [(body weight on Day n) - (body weight on DayO)] / (body weight on DayO) x 100
  • TAS6417 combination efficacy with CBDCA/pemetrexed compared to TAS6417 single agent was examined. H1975ins SVD cells were implanted into the flank of mice. The TAS6417 combination efficacy with CBDCA/pemetrexed was observed in this xenograft models (FIGS. 12-13). TAS6417 combined with CBDCA/pemetrexed resulted in a significant reduction in tumor growth compared TAS641 single agent (Aspin-welch test, p ⁇ 0.05). The combination setting showed the similar body weight change with TAS6417 single agent (FIG. 14).
  • Table 11 below presents results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or CBDCA/pemetrexed, at various maximum doses of Compound (1) (TAS6417). Plots of the tumor volumes presented in Table 11 below, along with additional time points between days 1 and 8, are presented in FIGS. 12- 13.
  • CBDCA/pemetrexed did not result in inhibition of tumor volume increase.
  • administration of Compound (1) (TAS6417) along or in combination with CBDCA/pemetrexed showed dramatically smaller tumor volume after 8 days.
  • there is a statistically significant decrease in tumor volume (indicated by the bracket and asterisk in FIG. 13) when Compound (1) (TAS6417) is administered at a dosage of 100 mg/kg in combination with CBDCA/pemetrexed.
  • FIG. 14 shows a plot of mean body weight change throughout treatment for the preclinical animal studies. The reasonable stability of the body weight throughout the treatment indicates that none of the regimens involves increased or unacceptable levels of toxicity.
  • Table 11 Results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or CBDCA/PEM (pemetrexed) at various maximum doses of Compound (1) (TAS6417).
  • TAS6417 was mixed in 0.1 mol/L hydrochloric acid to generate a suspension.
  • Amivantamab was diluted in saline to generate a suspension.
  • TAS6417 efficacy was examined in the model of Amivantamab pre-treatment. H1975ins SVD cells were implanted into the flank of mice. The Amivantamab was administered intraperitoneally at 10 mg/kg twice a week from the time the tumor volume reaches about 200 mm 3 . The tumor temporarily regressed but re-grew to about 500 mm 3 , Amivantamab-relapsed tumors, were randomly stratified into two groups of five animals per group to ensure uniform mean tumor volume. TAS6417 was administered orally at a dose of 200 mg/kg daily to one mice group, and the other continued to receive Amivantamab as a control group. TAS6417 resulted in a significant reduction in tumor growth compared Amivantamab (Aspin-Welch p-value ⁇ 0.05) (FIG.15).
  • NCT05967689 (REZILIENT2) is a global, open-label, multicohort, phase 2b study designed to evaluate the efficacy and safety of zipalertinib (Compound (1), TAS6417) in adult patients with pathologically confirmed, locally advanced or metastatic NSCLC with EGFR ex20ins and other uncommon single or compound
  • EGFR mutations including in patients with brain metastases and leptomeningeal disease. Eligible patients will be assigned to one of four cohorts depending on prior treatment and type of EGFR mutation.
  • Cohort A Patients with EGFR ex20ins mutations who have progressed on or after first- line platinum-based chemotherapy and prior therapy targeting ex20ins mutations (administered together or separately) for advanced disease. Patients with brain metastases must be neurologically stable.
  • Cohort B Patients with EGFR ex20ins mutations who have not received prior treatment for advanced disease.
  • Cohort C Patients with ex20ins, other uncommon single or compound EGFR mutations, and active brain metastases (including leptomeningeal disease (LMD)) and who may or may not have received prior treatment for advanced disease.
  • LMD leptomeningeal disease
  • Cohort D Patients harboring other, uncommon, non-ex20ins, single or compound EGFR mutations who have progressed on or after standard systemic therapy.
  • Treatment-related Grade > 3 Adverse Events were seen in 6 patients including 1 patient with 4 events (amylase increase, lymphocyte decrease, hypoxia, and pneumonitis), 1 patient with 2 events (anemia and rash), and 4 patients each with 1 event (folliculitis, ILD, hypertension, or rash).
  • zipalertinib demonstrated efficacy similar to that of patients that progressed after platinum-based chemotherapy and had a manageable safety profile.
  • Zipalertinib (CLN-081, TAS6417) is a novel EGFR TKI which demonstrated a confirmed objective response rate (ORR) of 41% and manageable safety in a phase l/2a study in patients with ex20ins NSCLC after prior platinum-containing chemotherapy (JCO 2023).
  • ORR objective response rate
  • JCO 2023 platinum-containing chemotherapy
  • FIG. 16 is a summary of patient demographics module C ami overall.
  • Module C Ami Overall are Patients that progressed on amivantamab with or without prior mobocertinib and/or other ex20ins drugs (excluding patients that received mobocertinib and/or other exon20ins drugs only, but no amivantamab).
  • FIG. 17 depicts a summary of the best overall tumor response based on investigator assessment per RECIST vl.l. This includes all treated patients with measurable disease at baseline who have received at least one dose of zipalertinib and had one of the following: at least two on treatment tumor assessments, death, or discontinuation due to disease progression (either clinical or per RECIST vl.
  • FIG. 18 is a waterfall plot for the best change from baseline in target lesions.
  • Efficacy population includes all treated patients with measurable disease at baseline who received at least one dose of zipalertinib and had one of the following: 1) at least two on treatment tumor assessments, 2) death, or 3) discontinuation due to disease progression (either clinical or per RECIST vl. l based on Investigator Assessment). Positive change in tumor size indicates tumor growth which negative change in tumor size indicates tumor reduction. If the dimension was recorded as “TOO SMAL TO MEASURE”, a default value of 5mm was assigned. If dimension is recorded as “INDTERMINATE”, the value from the previous assessment is assigned.
  • Ami+ex20ins drug includes patients receiving prior amivantamab and mobocertinib or other EGFR exon 20 insertion (ex20ins) targeted tyrosine kinase inhibitors (TKIs).
  • TKIs tyrosine kinase inhibitors
  • FIG. 19 is a swim plot for study treatment duration.
  • the study treatment duration is the end of treatment date - first dose date+1.
  • the study duration is the data cutoff date - the first dose date+1.
  • Ami only includes patients receiving only prior amivantamab
  • Ami+ex20ins drug includes patients receiving prior amivantamab and mobocertinib or other EGFR exon 20 insertion (ex20ins) targeted tyrosine kinase inhibitors (TKIs).
  • FIG. 20 is a Kaplan Meier plot of progression free survival based on RECIST vl.l.
  • Treatment-related AEs occurring in > 10% of patients were rash (38%), paronychia (36%), anemia (24%), dry skin (20%), dermatitis acneiform (16%), nausea (16%), and stomatitis (11%).
  • Grade 3 TRAEs were reported in 14 patients (31%): occurring in >2 patients included anemia (4), rash (3), and pneumonitis/ILD (3). There were no grade 4 or 5 TRAEs. TRAEs leading to dose reductions and discontinuations occurred in 3 patients (7%) each.
  • FIG. 21 is a summary of treatment-related adverse events of any grade observed in > 10% of patients.
  • FIG. 22 is a summary of grade 3 treatment-related adverse events in > 2 patients.
  • NCT05973773 (REZILIENT3) is a global, randomized, controlled, open-label, phase 3 study to compare the efficacy and safety of zipalertinib (Compound (1), TAS6417) plus standard first-line platinum-based chemotherapy with chemotherapy alone in patients with locally advanced or metastatic nonsquamous NSCLC with EGFR ex20ins mutations.
  • Part A safety lead-in
  • Part B randomized phase 3
  • Part A was designed to confirm the recommended dose of zipalertinib in combination with standard chemotherapy (pemetrexed plus carboplatin or cisplatin) to be studied in Part B.
  • the efficacy and safety of zipalertinib plus chemotherapy will be compared with chemotherapy alone.
  • Treatment Regimen Zipalertinib + pemetrexed + carboplatin or cisplatin. N-6-12 patients with EGFR ex20ins or other common single or compound EGFR mutations. Doselimiting toxicity assessment and dose selection for Part B.
  • Study population meet all of the following criteria: 1) Previously untreated, locally advanced or metastatic, nonsquamous NSCLC; 2) EGFR exon20ins mutation by local test; 3) >1 measurable lesion per RECIST vl. l; 4) ECOG PS 0 or 1; 5) Stable brain metastases permitted; and 6) Archival tumor tissue available for submission.
  • Prior EGFR TKI monotherapy (not targeting ex20ins mutations) lasting ⁇ 8 weeks, with documented lack of response and resolved associated toxicities, and >2 weeks/4 halflives before randomization is allowed; alternatively, an approved prior adjuvant/ neoadjuvant treatment >6 months before the first dose of study treatment is allowed for early-stage NSCLC.
  • Patients with previously treated brain metastases and stable central nervous system disease (defined as being neurologically stable and off corticosteroids for >2 weeks before enrollment) are eligible.
  • Asymptomatic brain metastases ⁇ 2 cm in size can be eligible for inclusion if, in the opinion of the investigator, immediate definitive treatment is not indicated. Patients with insufficient tissue may be eligible following discussion with the sponsor.

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Abstract

A method of treating a subject with a cancer having at least one aberration in EGFR, whereby the subject is administered (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (also known as zipalertinib and as TAS6417) or a pharmaceutically acceptable salt thereof, to a subject who has previously been treated with a molecularly targeted therapeutic. The molecularly targeted therapeutic may be an EGFR-targeting therapeutic other than Compound (1) or a non-EGFR-targeting therapeutic. The method may optionally involve administering to the subject an additional therapeutic agent.

Description

TITLE OF THE INVENTION
TREATMENT METHODS FOR SUBJECTS WITH NON-SMALL CELL LUNG CANCER
HAVING AN ABERRATION IN EGER
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority to U.S. Provisional Applications No.
63/523,518, 63/523,572, both filed June 27, 2023, and 63/650,590, filed May 22, 2024, each of which is incorporated by reference in its entirety for all purposes.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
[0001] The present invention relates to methods of treating cancers harboring an aberration in EGFR.
DESCRIPTION OF THE RELATED ART
[0002] In patients with advanced or metastatic NSCLC harboring epiderma! growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations, current lung cancer treatment guidelines recommend standard platinum-based chemotherapy to treat patients in the front- line setting. This regimen is preferred due to low response rates against EGFR ex20ins mutation patients with single agent fust-, second-, and third-generation EGFR-tyrosine kinase inhibitors (TKI). See National Comprehensive Cancer Network. NCCN guidelines. Non-small cell lung cancer version 3.2022. J Natl Compr Cane Netw. 2022;20:497-530. Real world evidence analysis of overall survival (OS) and progression-free survival (PFS) outcomes indicate that patients having advanced NSCLC with EGFR ex20ins mutations have better outcomes with front-line platinum-based chemotherapy as compared to standard EGFR TKIs. However, outcomes for these patients remain poor regardless of treatment in subsequent lines of therapy. See Bazhenova L, Minchom A, Viteri S, et al. Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Lung Cancer. 2021; 162: 154-161. Further, imm uno-oncology therapy does not appear to offer the same benefit in patients with NSCLC harboring EGFR ex20ins mutations, as would be expected in patients with advanced NSCLC without actionable mutations. See Remon J, Hendriks LEL, Cardona AF, Besse B. EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins. Cancer Treat Rev. 2020;90: 102105; Minchom A, Viteri S, Bazhenova L, et al. Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy. Lung Cancer. 2022;168:74-82.
[0003] Despite recent accelerated/conditional approvals for amivantamab (US, EU, and Canada) and mobocertinib (US and China) for EGFR ex20ins patients for whom platinumbased chemotherapy failed to treat their locally advanced or metastatic disease, there continues to be an unmet medical need for tolerable and effective treatment options specifically targeting EGFR ex20ins mutations, particularly in the front-line treatment setting. Further, because of the narrow therapeutic window between inhibition of EGFR ex20ins and wild-type (WT) EGFR, currently available EGFR ex20ins-specific TKIs such as mobocertinib cause frequent rash and diarrhea. Amivantamab, a bispecific antibody targeting EGFR and mesenchymal-epithelial transition factor (MET), requires intravenous administration and causes frequent infusion reactions (IRRs). While more effective for some patients, amivantamab treatment is associated with adverse events including rash, infusion- related reactions, infected skin around the nail, muscle and joint pain, shortness of breath, nausea, fatigue, swelling of hands, ankles, feet, face, or the entire body, sores in the mouth, cough, constipation, vomiting, and changes in certain blood tests (e.g., decreased albumin levels, increased glucose levels, increased liver enzymes) and has the further disadvantage of requiring intravenous administration.
[0004] Hence, despite recent progress in the development of EGFR ex20ins-targeting therapies, there remains a significant need for novel agents that will maximize clinical efficacy while achieving a more favorable safety profile.
[0005] In view of the forgoing, there exists a need for new treatment methods in patients with cancers harboring having an aberration in EGFR, particularly those in patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations.
SUMMARY OF THE INVENTION
[0006] Zipalertinib (CLN-081/TAS6417) is a novel EGFR tyrosine kinase inhibitor (TKI) with broad activity against EGFR mutations (including ex20ins) and increased selectivity for ex20ins versus wild-type (WT) EGFR. In cell-based assays using genetically engineered cell lines, zipalertinib potently inhibited intracellular phosphorylation of mutant EGFRs, including EGFRs harboring a wide spectrum of ex20ins mutations. Its inhibitory activity is more potent against mutant EGFRs than that against WT EGFR, and zipalertinib exerts significant antitumor activity in vivo against cancer xenografts harboring EGFR ex20ins mutations. See Udagawa H, Hasako S, Ohashi A, et al. TAS6417/CLN-081 is a pan- mutation-selective EGFR tyrosine kinase inhibitor with a broad spectrum of preclinical activity against clinically relevant EGFR mutations. Mol Cancer Res. 2019;17:2233-2243. The high specificity and selectivity for mutant EGFR (e.g., ex20ins mutant EGFR) versus wild-type EGFR gives zipalertinib (TAS6417) a more promising side-effect or adverse effect profile. Higher specificity and selectivity can allow for high doses of zipalertinib to be used without widespread adverse effects or administration for longer periods of time. The lower impact on wild-type EGFR not associated with a cancer or tumor and produce a wider therapeutic window for zipalertinib, a distinct advantage over other EGFR-targeting therapeutics. Therefore, zipalertinib represents a significant improvement over existing therapies.
[0007] Accordingly, it is an aspect of the present invention to provide methods of treating a subject with a cancer having an aberration in EGFR.
[0008] It is another aspect of the present invention to provide methods of treating a subject with a cancer having an EGFR exon 20 insertion mutation, including those which are locally advanced and/or which have metastasized.
[0009] It is another aspect of the present invention to provide methods of treating a subject with a cancer having an EGFR exon 20 insertion mutation, which has metastasized to the brain.
[0010] It is another aspect of the present invention to provide methods of treating a subject with a cancer having an EGFR exon 20 insertion mutation who has already been treated with at least one TKI agent.
[0011] These and other aspects, which will become apparent during the following detailed description, have been achieved by the inventors’ finding that a treatment method involving administering to a subject both (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9- dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof in the presence or absence of an additional therapeutic agent to a patient who has previously received treatment with a molecularly targeted therapeutic is active in and can be used for treating cancers harboring EGFR aberrations listed above and in particular non-small cell lung cancers. The present invention has the following aspects:
[0012] A method of treating a subject with a cancer having at least one aberration in EGFR, the method comprising administering to the subject an effective amount of (S)-N-(4-amino-6- methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof. The structure of (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide is depicted below and will be referred to herein as Compound (1):
Figure imgf000006_0001
(1), wherein the subject has previously been treated with a systemic treatment which is at least one selected from the group consisting of a chemotherapeutic agent and a molecularly targeted therapeutic.
[0014] (2) The method of (1), wherein the cancer is a solid tumor.
[0015] (3) The method of any one of (1) to (2), wherein the cancer is a lung cancer.
[0016] (4) The method of any one of (1) to (3), wherein the cancer is a non-small cell lung cancer.
[0017] (5) The method of (4), wherein the non-small cell lung cancer is a nonsquamous non- small cell lung cancer.
[0018] (6) The method of any one of (1) to (5), wherein the cancer is at least one selected from the group consisting of locally advanced and has metastasized to a brain of the subject.
[0019] (7) The method of any one of (1) to (6), wherein the cancer is locally advanced.
[0020] (8) The method of any one of (1) to (7), wherein the cancer is unresectable.
[0021] (9) The method of any one of (1) to (8), wherein the cancer has metastasized to a brain of the subject.
[0022] (10) The method of any one of (1) to (9), wherein the cancer has an EGFR amplification/overexpression.
[0023] (11) The method of any one of (1) to (10), wherein the cancer has an EGFR mutation in at least one exon selected from the group consisting of exon 18, exon 19, exon 20, and exon 21. [0024] (12) The method of any one of (1) to (11), wherein the cancer has an EGFR mutation in exon 20.
[0025] (13) The method of any one of (1) to (12), wherein the cancer has an EGFR exon 20 insertion mutation.
[0026] (14) The method of (13), wherein the EGFR exon 20 insertion mutation is at least one selected from the group consisting of D770_N771insX, V769_D770insX, H773_V774insX, P772_H773insX, N771_P772insX, A763_Y764insX, V774_C775insX, D761_E762insX, A767_S768insX, S768_V769insX, Y764_V765insX, V765_M766insX, A763_Y764insFQEA, A767_S768insTLA, S768_V769insVAS, S768_V769insAWT, V769_D770insGV, V769_D770insCV, V769_D770insDNV, V769_D770insGSV, V769_D770insGVV, V769_D770insMASVD, V769_D770insASV, V769_D770insGE, V769_D770delInsDGEL, D770_N771insSVD, D770_N771insNPG, D770_N771insKH, D770_N771insGNPH, D770_N771insAPW, D770_N771insD, D770_N771insDG, D770delinsGY, D770_N771insGL, D770_N771insN, D770_N771insNPH,
D770_N77 tins SVP, D770_N771insSVQ, D770_N771insMATP, D770_N771insG, D770_N771insY, D770_N771insGF, D770_N771insGT, delD770insGY, N771_P772insH, N771_P772insN, delN771insGY, delN771insGF, N771delinsGY, N771_P772insRH, P772_H773insPR, P772_H773insYNP, P772_H773insDPH, P772_H773insDNP, P772_H773insQV, P772_H773insTPH, P772_H773insN, P772_H773insV, P772_H773insNP, P772_H773insNPH, H773_V774insH, H773_V774insNPH, H773_V774insPH, H773_V774insGNPH, H773_V774insG, H773_V774insGH, H773_V774insAH, H773_V774delInsLM, H773_V774delInsTY, and V774_C775insHV. [0027] (15) The method of any one of (1) to (14), wherein the subject is determined to have the aberration in EGFR prior to the administration.
[0028] (16) The method of any one of (1) to (15), wherein (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered orally to the subject.
[0029] (17) The method of any one of (1) to (16), wherein (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice per day (BID).
[0030] (18) The method of any one of (1) to (17), wherein (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject every day of a treatment cycle lasting 21 days. [0031] (19) The method of any one of (1) to (18), wherein from about 10 to about 500 mg of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8- yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.
[0032] (20) The method of any one of (1) to (19), wherein from about 30 to about 300 mg of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8- yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.
[0033] (21) The method of any one of (1) to (20), wherein the of (S)-N-(4-amino-6-methyl- 5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject orally in the form of at least one selected from the group consisting of a tablet and a capsule.
[0034] (22) The method of (21), wherein the tablet or capsule comprises a pharmaceutically acceptable carrier.
[0035] (23) The method of any one of (1) to (22), further comprising administering to the subject an effective amount of an additional therapeutic agent.
[0036] (24) The method of (23), wherein the additional therapeutic agent is at least one selected from the group consisting of a chemotherapeutic agent, a tyrosine kinase inhibitor, and an immunotherapeutic agent.
[0037] (25) The method of (24), wherein the chemotherapeutic agent is a platinum anticancer agent.
[0038] (26) The method of any one of (1) to (25), wherein the systemic treatment is systemic treatment with a molecularly targeted therapeutic selected from the group consisting of an EGFR-targeting therapeutic other than compound (1) and a non-EGFR-targeting therapeutic. [0039] (27) The method of (26), wherein the EGFR-targeting therapeutic other than Compound (1) is at least one selected from the group consisting of gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, poziotinib, mobocertinib, lazertinib, sunvozertinib, DZD9008, BDTX-189, necitumumab, pembrolizumab, brigatinib, icotinib, neratinib, olmutinib, rociletinib, vandetanib, lapatinib, duligotuzumab, panitumumab, zalutumumab, cetuximab, depatuxizumab, depatuxizumab mafodotin, imgatuzumab, matuzumab, and nimotuzumab.
[0040] (28) The method of (27), wherein the EGFR-targeting therapeutic other than Compound (1) is osimertinib. [0041] (29) The method of any one of (27) to (28), wherein the EGFR-targeting therapeutic other than Compound (1) is afatinib.
[0042] (30) The method of any one of (27) to (29), wherein the EGFR-targeting therapeutic other than Compound (1) is gefitinib.
[0043] (31) The method of any one of (27) to (30), wherein the EGFR-targeting therapeutic other than Compound (1) is poziotinib.
[0044] (32) The method of any one of (27) to (31), wherein the EGFR-targeting therapeutic other than Compound (1) is sunvozertinib.
[0045] (33) The method of any one of (27) to (32), wherein the EGFR-targeting therapeutic other than Compound (1) is amivantamab.
[0046] (34) The method of any one of (26) to (33), wherein the non-EGFR-targeting therapeutic is at least one selected from the group consisting of crizotinib, ceritinib, alectinib, ensartinib, entrectinib, repotrectinib, belizatinib, alkotinib, foritinib, CEP-37440, TQ-B3139, PLB1003, zotizalkiv, lorlatinib, conteltinib, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, bevacizumab, ipilimumab, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine.
[0047] (35) The method of (34), wherein the non-EGFR-targeting therapeutic is nivolumab.
[0048] (36) The method of any one of (34) to (35), wherein the non-EGFR-targeting therapeutic is pembrolizumab.
[0049] (37) The method of any one of (34) to (36), wherein the non-EGFR-targeting therapeutic is cemiplimab.
[0050] (38) The method of any one of (34) to (37), wherein the non-EGFR-targeting therapeutic is atezolizumab.
[0051] (39) The method of any one of (34) to (38), wherein the non-EGFR-targeting therapeutic is durvalumab.
[0052] (40) The method of any one of (1) to (39), wherein the systemic treatment is a systemic treatment with a chemotherapeutic agent selected from the group consisting of carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.
[0053] (41) The method of (40), wherein the chemotherapeutic agent is cisplatin.
[0054] (42) The method of any one of (40) to (41), wherein the chemotherapeutic agent is carboplatin.
[0055] (43) The method of any one of (1) to (42), wherein the subject has previously undergone at least two systemic treatments for the cancer. [0056] (44) The method of any one of (1) to (43), wherein the subject has previously undergone at least three systemic treatments for the cancer.
[0057] (45) The method of any one of (1) to (44), wherein the subject failed to respond to the systemic treatment; or the subject had disease progression after administration of the systemic treatment.
[0058] (46) A method of treating a subject with a cancer having at least one aberration in EGFR, the method comprising administering to the subject an effective amount of (S)-N-(4- amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof and an effective amount of a platinum anticancer agent.
[0059] (47) The method of (46), wherein the cancer is a solid tumor.
[0060] (48) The method of (46) or (47), wherein the cancer is a lung cancer.
[0061] (49) The method of any one of (46) to (48), wherein the cancer is a non-small cell lung cancer.
[0062] (50) The method of (49), wherein the non-small cell lung cancer is a nonsquamous non-small cell lung cancer.
[0063] (51) The method of any one of (46) to (50), wherein the cancer is at least one selected from the group consisting of locally advanced and has metastasized to a brain of the subject.
[0064] (52) The method of any one of (46) to (51), wherein the cancer is locally advanced.
[0065] (53) The method of any one of (46) to (52), wherein the cancer is unresectable.
[0066] (54) The method of any one of (46) to (53), wherein the cancer has metastasized to a brain of the subject.
[0067] (55) The method of any one of (46) to (54), wherein the cancer has an EGFR amplification/overexpression.
[0068] (56) The method of any one of (46) to (55), wherein the cancer has an EGFR mutation in at least one exon selected from the group consisting of exon 18, exon 19, exon 20, and exon 21.
[0069] (57) The method of any one of (46) to (56), wherein the cancer has an EGFR mutation in exon 20.
[0070] (58) The method of any one of (46) to (57), wherein the cancer has an EGFR exon 20 insertion mutation.
[0071] (59) The method of any one of (46) to (58), wherein the subject is determined to have the aberration in EGFR prior to the administering. [0072] (60) The method of any one of (46) to (59), wherein the subject has not previously undergone systemic treatment for the cancer.
[0073] (61) The method of any one of (46) to (60), wherein (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered orally to the subject.
[0074] (62) The method of any one of (46) to (61), wherein (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice per day (BID).
[0075] (63) The method of any one of (46) to (62), wherein (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject every day of a treatment cycle lasting 21 days.
[0076] (64) The method of any one of (46) to (63), wherein the platinum anticancer agent is administered to the subject intravenously.
[0077] (65) The method of any one of (46) to (64), wherein the platinum anticancer agent is administered on only a first day of a treatment cycle lasting 21 days.
[0078] (66) The method of any one of (1) to (65), further comprising administering to the subject an effective amount of pemetrexed.
[0079] (67) The method of (66), wherein the pemetrexed is administered on only a first day of a treatment cycle lasting 21 days.
[0080] (68) The method of any one of (66) to (67), wherein the pemetrexed is administered to the subject intravenously.
[0081] (69) The method of any one of (46) to (68), wherein the (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof and the platinum anticancer agent are administered for one to ten treatment cycles, each treatment cycle lasting 21 days.
[0082] (70) The method of any one of (46) to (69), wherein the (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof and the platinum anticancer agent are administered for four treatment cycles, each treatment cycle lasting 21 days.
[0083] (71) The method of any one of (46) to (70), wherein the pemetrexed is administered for four treatment cycles, each treatment cycle lasting 21 days.
[0084] (72) The method of any one of (46) to (71), wherein from about 10 to about 500 mg of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8- yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.
[0085] (73) The method of any one of (46) to (72), wherein from about 30 to about 150 mg of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8- yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.
[0086] (74) The method of any one of (1) to (73), wherein 100 mg of (S)-N-(4-amino-6- methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or its pharmaceutically acceptable salt there is administered to the subject twice daily(BID), every day of a treatment cycle lasting 21 days.
[0087] (75) The method of any one of (46) to (74), wherein the platinum anticancer agent is at least one selected from the group consisting of cisplatin and carboplatin.
[0088] (76) The method of any one of (46) to (75), wherein the platinum anticancer agent is cisplatin and from about 50 to about 100 mg/m2 of cisplatin is administered to the subject on only a first day of a treatment cycle lasting 21 days.
[0089] (77) The method of any one of (46) to (76), wherein the platinum anticancer agent is carboplatin and from about AUC 2.5 mg/mL/min to about AUC 7.5 mg/mL/min of carboplatin is administered to the subject on only a first day of a treatment cycle lasting 21 days.
[0090] (78) The method of any one of (66) to (77), wherein from about 250 to about 750 mg/m2 of pemetrexed is administered to the subject on only a first day of a treatment cycle lasting 21 days.
[0091] (79) The method of any one of (46) to (78), wherein the of (S)-N-(4-amino-6-methyl- 5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject orally in the form of at least one selected from the group consisting of a tablet and a capsule.
[0092] (80) The method of (79), wherein the tablet or capsule comprises a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
[0093] The foregoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the following claims. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawing, wherein: [0094] FIG. 1 shows a plot of tumor volume over time in preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin, with a maximum dose of Compound (1) (TAS6417) of 200 mg/kg.
[0095] FIG. 2 shows a plot of body weight change over time in preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin, with a maximum dose of Compound (1) (TAS6417) of 200 mg/kg.
[0096] FIGS. 3A and 3B show plots of clinical activity of zipalertinib (Compound (1); TAS6417) in EGFR ex20ins patients with NSCLC with postbaseline target lesion assessments where FIG. 3 A is a waterfall plot for response of target lesions by dose level (* indicates confirmed response, E indicates previous EGFR-targeted Q: 10 treatment), and FIG. 3B is a swimmers plot for time to response and treatment duration by dose level (EGFR, epidermal growth factor receptor; ex20ins, insertions in EGFR exon 20; NSCLC, non-smallcell lung cancer).
[0097] FIG. 4 is a spider plot of percent change from baseline in sum of target lesion diameters over time in the efficacy population (n = 73) by investigator assessment.
[0098] FIGS. 5 A and 5B are images from MRI with gadolinium enhancement before (FIG. 5 A) and after (FIG. 5B) treatment with zipalertinib (EGFR, epidermal growth factor receptor; ex20ins, insertions in EGFR exon 20; NSCLC, non-small-cell lung cancer).
[0099] FIG. 6 shows a schematic depiction of the Phase 1/2 study design. A single-patient accelerated design was used for escalation of doses from 30 to 100 mg twice a day. At the 100 mg dose level, grade 2 toxicity occurred in the first patient, and the study transitioned to a rolling six design. Lower-dose cohorts could be expanded with a rolling six design if the dose level achieved serum drug concentrations that were associated with response in preclinical tumor models. This occurred at the first dose level of 30 mg twice a day. The SRC made decisions about expansion of cohorts at higher dose levels to six patients and chose only to expand the 65 mg twice a day cohort. The 100 and 150 mg dose levels were expanded on the basis of safety considerations. Expansion of a dose level to 13 patients was permitted on the basis of the observation of a single response in the first six patients at any dose level. The SRC chose to expand the 65, 100, and 150 mg dose levels to 13 patients, but not the 30 or 45 mg dose levels. Expansion of the 100 mg dose level from 13 to 36 patients was based on the protocol-defined achievement of four or more responses. Although the 65 mg dose level also met this criterion, it was not expanded at the discretion of the SRC. DLT, doselimiting toxicity; SRC, safety review committee. The 100 mg dose has a good balance between efficacy and adverse events. As the dose is increased there is a tendency for more adverse events.
[00100] FIG. 7 shows Kaplan-Meier curves of PFS by dose level (PFS, progression-free survival).
[00101] FIG. 8 is a waterfall plot displaying best percent change from baseline in sum of target lesion diameters by location of EGFR exon20ins determined by local laboratory testing and investigator response (EGFR, Q: 14 epidermal growth factor receptor; ORR, objective response rate, * indicates response was confirmed).
[00102] FIG. 9 shows a plot of average unbound plasma concentration over time for the 30, 65, 100, and 150 mg dose levels. The 50% growth inhibitory concentration of cell lines expressing wild-type and two exon 20 insertion mutation expressing cell lines (EGFR, epidermal growth factor receptor; WT, wild-type).
[00103] FIG. 10 shows a plot of tumor volume over time in preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin + pemetrexed, with a maximum dose of Compound (1) (TAS6417) of 100 mg/kg.
[00104] FIG. 11 shows a plot of mean body weight change throughout treatment for the preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin + pemetrexed, with a maximum dose of Compound (1) (TAS6417) of 100 mg/kg.
[00105] FIG. 12 shows a plot of tumor volume over time in preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin + pemetrexed, with a maximum dose of Compound (1) (TAS6417) of 50 mg/kg.
[00106] FIG. 13 shows a plot of tumor volume over time in preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin + pemetrexed, with a maximum dose of Compound (1) (TAS6417) of 100 mg/kg.
[00107] FIG. 14 shows a plot of mean body weight change throughout treatment for the preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin + pemetrexed, at various doses of carboplatin + pemetrexed and Compound (1).
[00108] FIG. 15 shows a plot of tumor volume over time in preclinical animal studies of various treatment regimens involving continued treatment with Amivantamab or with Compound (1) (TAS6417), with a dose of Compound (1) (TAS6417) of 200 mg/kg.
[00109] FIG. 16 is a summary of patient demographics module C ami overall. [00110] FIG. 17 is a summary of the best overall tumor response based on investigator assessment per RECITS vl .1.
[00111] FIG. 18 is a waterfall plot for best change from baseline in target lesions.
[00112] FIG. 19 is a swim plot for study treatment duration.
[00113] FIG. 20 is a Kaplan Meier plot of progression free survival based on RECITS vl .1.
[00114] FIG. 21 is a summary of treatment-related adverse events of any grade observed in > 10% of patients.
[00115] FIG. 22 is a summary of grade 3 treatment-related adverse events in > 2 patients.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[00116] In the description above or below of the specification, preferred examples of various definitions included in the scope of the present invention will be described in detail below.
TAS6417
[00117] Compound (1), also known as zipalertinib and TAS6417, is a potent, and highly selective EGFR-tyrosine kinase inhibitor (TKI), as described in W02018079310, which is fully incorporated by reference herein in its entirety and Hasako, S. et al “TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations”, Mol Cancer Ther; 17 (8), 2018, pp.1648-1657). Biochemical assays have shown that Compound (1) inhibited the in vitro phosphorylation activity of EGFR and EGFR mutants that harbor an exon 20 insertion mutation.
[00118] The chemical synthesis and chemical properties have been described in U.S. Patent 9650386, which is fully incorporated by reference herein in its entirety.
[00119] Additional description of Compound (1) can be found in WO2022055895A1 and US 2020253975 and US20220072000, each of which is fully incorporated herein by reference in its entirety.
Activity of TAS6417
[00120] In cell-based assays, Compound (1) showed intensive cellular potency in inhibiting the phosphorylation of mutant EGFRs that possess a wide spectrum of in-frame insertion mutations in exon 20 (A763_Y764insFQEA, V769_D770insASV, D770_N771insG, D770_N771insSVD, H773_V774insNPH, and H773_V774insPH). Compound (1) also showed moderate inhibition against WT EGFR. [00121] Consistent with the intracellular target inhibition, Compound (1) demonstrated a more potent and selective inhibitory effect on the proliferation of the cells expressing EGFR with exon 20 insertion mutations than on cells expressing WT EGFR.
[00122] Furthermore, Compound (1) inhibited the growth of five cell lines out of a panel of seven NSCLC cell lines harboring mutant EGFR (V769_D770insASV for LXF 2478L cells; D770_N771insSVD for NCI-H1975 EGFR D770_N771insSVD cells; delE746_A750 for HCC827 and PC-9 cells; and L858R plus T790M for NCI-H1975) with GI50 values ranging from 1.92 ± 0.21 nmol/L to 86.5 ± 28.5 nmol/L. By contrast, KRAS mutant cell lines, NCI- 1123 cells, and NCI-H460 cells that exhibit EGFR-independent cell growth did not respond to Compound (1) (GI50 > 3000 nmol/L). CLN-081 suppressed the growth of NSCLC cells with EGFR exon 20 insertions (LXF 2478 and NCI-H1975 EGFR D770_N771insSVD cells) through a mechanism associated with the inhibition of the phosphorylation of EGFR and its downstream molecules and the induction of caspase 3/7.
[00123] In vivo antitumor efficacy studies showed that in nude mouse and/or nude rat models bearing subcutaneously-implanted tumors expressing EGFR with exon 20 insertions (V769_D770insASV, D770_N771insSVD, and H773_V774insNPH), Compound (1) exerts striking tumor growth inhibition and tumor regression effects in a dose-dependent manner. Pharmacodynamic (PD) marker analysis revealed that Compound (1) exhibits potent and durable in vivo inhibitory effect on the phosphorylation of EGFR and its downstream effectors in human lung cancer xenografts harboring EGFR exon 20 insertions but spares skin tissue with WT EGFR. The antitumor efficacy of twice-daily Compound (1) administration to nude mice transplanted with the human NSCLC cell line NCI-H1975 EGFR D770_N771insSVD is not inferior to that of once-daily Compound (1) administration.
[00124] In cell-based assays, Compound (1) showed intensive cellular potency in inhibiting the phosphorylation of mutant EGFRs that possess mutations in exon 18 or exon 21 (G719A, G719S, G719C, E709K, E709A, L861Q), and the activity was higher than erlotinib and osimertinib. Compound (1) also showed intensive inhibition against EGFRs harboring a combination of acquired resistance mutation T790M and either exon 18 or exon 21 mutations (G719A+T790M, L861Q+T790M) (W02019045036, incorporated herein by reference in its entirety; Udagawa, H. et al. “TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations” Mol Cancer Res 2019;17:2233-43).
[00125] Furthermore, Compound (1) inhibited the growth of Ba/F3 cell lines harboring EGFR with mutations in exon 18 (G719A, G719A+T790M) or exon 21 (L861Q, L861Q+T790M) with IC50 ranging from 9.0 nmol/L to 37.5 nmol/L, which were significantly lower than the IC50 for inhibiting Ba/F3 harboring wild type EGFR (597.3 nmol/L). The selectivity index, defined as the ratio between IC50 for WT EGFR and mutant EGFR containing cell lines, was much higher for Compound (1) compared to erlotinib and afatinib. When EGFR mutations include T790M in addition to either G719A or L861Q, the selectivity index for Compound (1) is higher than osimertinib.
[00126] In vivo antitumor efficacy studies showed that in nude mouse model bearing subcutaneously-implanted tumors expressing EGFR with G719A+T790M mutations, Compound (1) exerts significant tumor growth inhibition effects in a dose-dependent manner. Importantly, the anti -turn or activity was not effected at a cost of body weight loss, fecal abnormalities, or skin abnormalities.
[00127] In cell-based assays, Compound (1) showed intensive cellular potency in inhibiting the phosphorylation of mutant EGFRs that possess mutations in exon 18 or exon 21 (G719A, G719S, G719C, E709K, E709A, L861Q), and the activity was higher than erlotinib and osimertinib. Compound (1) also showed intensive inhibition against EGFRs harboring a combination of acquired resistance mutation T790M and either exon 18 or exon 21 mutations (G719A+T790M, L861Q+T790M).
[00128] In cell-based assays, Compound (1) showed intensive cellular potency in inhibiting the phosphorylation of mutant EGFRs that possess L718Q mutation in exon 18 in combination with exl9del+T790M or L858R+T790M (i.e., L718Q+ exl9del+T790M or L718Q+ L858R+T790M), and both the absolute activity and the selectivity over baseline mutations (exl9del+T790M or L858R+T790M) was higher than osimertinib, erlotinib and Afatinib (W02020138400, incorporated herein by reference in its entirety).
[00129] In cell-based assays, Compound (1) showed intensive cellular potency in inhibiting the phosphorylation of mutant EGFRs that possess mutations at L792 (L792H, L792F, L792Y) in exon 20 in combination with exl9del+T790M or L858R+T790M (i.e. L792H + exl9del+T790M, L792H + L858R+T790M, L792F + exl9del+T790M, L792F + L858R+T790M, L792Y + exl9del+T790M, L792Y + L858R+T790M), and both the absolute activity and the selectivity over baseline mutations (exl9del+T790M or L858R+T790M) was higher than osimertinib, erlotinib and Afatinib.
[00130] Compound (1) demonstrated favorable safety and tolerability and encouraging preliminary clinical activity among patients with recurrent or metastatic EGFR ex20ins mutant Non-Small-Cell Lung Cancer (NSCLC) previously treated with anti-cancer agents including other TKIs, monoclonal antibodies, ALK (anaplastic lymphoma kinase) agents . Objective responses were observed across the range of dose levels tested and across a diverse spectrum of ex20ins mutations. In a heavily previously-treated patient population, Compound (1) led to rapid and durable tumor regression. Although data from this ongoing study are maturing, it is notable that 24 of 73 (33%) of patients remain on study at the time of the data cutoff.
[00131] While the development of effective therapies targeting EGFR ex20ins has been limited by EGFR-mediated toxicities, the safety profile of Compound (1) observed to date appears consistent with its high in vitro selectivity for ex20ins-mutant versus WT EGFR. TRAEs have generally been reversible and manageable with standard supportive care. Diarrhea was observed in 30% of patients across all dose levels, with only two cases of grade 3 diarrhea, both at the highest dose level tested. Antidiarrheal prophylaxis was not required and symptoms were well managed with standard antidiarrheal therapies. Although dermatologic toxicities were more common, with 80% of patients across all dose levels experiencing rash, these were also predominantly low grade. Only one patient (at the 150 mg dose level) experienced grade 3 rash. Dermatologic toxicities observed with Compound (1) have been well managed with conventional supportive care (topical antibiotics and/or corticosteroids, and in a smaller number of patients, oral antibiotics, antihistamines, or corticosteroids).
[00132] The safety profile of Compound (1) is better than with that of other EGFR ex20ins- directed therapies. Diarrhea occurred in 91% of patients treated with mobocertinib, 92% with poziotinib, and 54% with sunvozertinib, with over 20% of patients experiencing grade >3 diarrhea with mobocertinib and pozotinib.4,6,7 Although amivantamab causes less diarrhea, dermatologic toxicities including rash (84%) are more common and IRRs occur in 64% of patients.
[00133] There were also high rates of skin and gastrointestinal toxicities, with poziotinib with 65% of patients requiring dose reduction from the starting dose of 16 mg daily. This type of EGFR-wild-type side effect profile illustrates the difficulty in obtaining an adequate therapeutic index for TKIs in EGFR ins20 NSCLC, a challenge that has also limited the clinical utility of afatinib and dacomitinib. With mobocertinib similar to poziotinib, the most common side effects were gastrointestinal, with 92% of patients treated at 160 mg having any grade diarrhea (16% grade > 3) and 28% having nausea. Rash was seen in 45%. Treatment- related adverse events led to dose reduction in 21% of patients and treatment discontinuation in 10% of patients. Treatment with Osimertinib 160 mg daily led to higher rates of diarrhea (76% any grade), fatigue (67% any grade), and acneiform rash (38% any grade) than is typical at 80 mg daily, but no cases of grade 3 gastrointestinal or dermatologic toxicides were observed. With amivantamab skin rash was reported as a common side effect in 86% of patients, with only 4% grade 3 rash. Other common treatment-related adverse events were infusion-related reaction (66% with only 3% grade > 3, mostly with the first infusion) and paronychia (42%), A significant disadvantage with amivantamab lies in its requirement for intravenous administration.
[00134] Taken together, the results indicate that Compound (1) represents a more tolerable oral treatment option for patients with EGFR exon 20 insertion mutations than other currently available agents. This promising safety profile may be due to the increased selectivity for mutant EGFR (e.g., ex20ins mutant EGFR) versus wild-type EGFR.
[0100] The ORR (38.4%) and mPFS (10 months) observed with Compound (1), in particular the activity observed in the largest expansion cohort of 100 mg twice a day, suggest that its efficacy may be at least comparable with, if not exceeding, other EGFR ex20ins-targeted agents, including both mobocertinib and amivantamab. Among 81 patients treated with amivantamab on the CHRYSALIS trial, the confirmed ORR was 40% and the mPFS was 8.3 months (95% CI, 6.5 to 10.9). Similarly, mobocertinib led to an ORR of 28% and an mPFS of months. Moreover, responses to Compound (1) in patients previously treated with ex20ins TKI(s) were observed.
[0101] Compound (1), a novel oral irreversible pyrrolo-pyrimidine inhibitor of ex20ins- mutant EGFR, demonstrated encouraging antitumor activity (as evidenced by both the ORR and PFS), with an acceptable safety profile and reduced WT EGFR-related toxicity in previously-treated patients with EGFR ex20ins-mutant NSCLC. The risk-benefit profile of Compound (1) is encouraging and Compound (1) may represent an alternative treatment option for these patients.
[0102] Due to low response rates, the lung cancer clinical practice guidelines 2017 edition discourage use of EGFR-TKIs to treat patients with NSCLC harboring EGFR ex20ins mutations and instead recommend treating these patients with cytotoxic anticancer agents and immune-checkpoint inhibitors. See Ettinger DS, et al., Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology, J. Natl. Compr. Cane. Netw., 2017;15:504-535; Lee CK, et al., Checkpoint Inhibitors in Metastatic EGFR-Mutated NonSmall Cell Lung Cancer-A Meta- Analysis, J. Thorac. Oncol., 2017;12:403-407; and Gainor JF, et al. EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis, Clin. Cancer Res., 2016;22:4585-4593. There are no current approved therapies for patients who have previously received exon20ins targeted therapy. However, the clinical benefit from combinations of these agents has yet to be fully elucidated. There is an unmet medical need for safe and effective therapies for patients with EGFR ex20ins mutations. Nonclinical studies have shown that CLN-081/TAS6417 is not only a potent inhibitor of ex20ins mutations but also shows selectivity over WT EGFR.
Definitions
[0103] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the methods described herein belong. Any reference to standard methods refers to the most recent available version of the method at the time of filing of this disclosure unless otherwise indicated.
[0104] For any method disclosed herein that includes discrete steps, the steps may be conducted in any feasible order. And, as appropriate, any combination of two or more steps may be conducted simultaneously.
[0105] All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.
[0106] The words "preferred" and "preferably" refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the invention.
[0107] The term "comprises" and variations thereof do not have a limiting meaning where these terms appear in the description and claims. Such terms will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.
[0108] By "consisting of' is meant including, and limited to, whatever follows the phrase "consisting of." Thus, the phrase "consisting of' indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of' is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of' indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they materially affect the activity or action of the listed elements.
[0109] The singular form "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. These articles refer to one or to more than one (i.e., to at least one). As used herein, the term "or" is generally employed in its usual sense including "and/or" unless the content clearly dictates otherwise. The term "and/or" means any one or more of the items in the list joined by "and/or". As an example, "x and/or y" means any element of the three-element set {(x), (y), (x, y)}. In other words, "x and/or y" means "one or both of x and y". As another example, "x, y, and/or z" means any element of the seven-element set {(x), (y), (z), (x, y), (x, z), (y, z), (x, y, z) } . In other words, "x, y and/or z" means "one or more of x, y and z".
[0110] Where ranges are given, endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. Herein, "up to" a number (for example, up to 50) includes the number (for example, 50). The term "in the range" or "within a range" (and similar statements) includes the endpoints of the stated range. [OHl] Reference throughout this specification to "one aspect,” "an aspect,” "certain aspects," or "some aspects," etc., means that a particular feature, configuration, composition, or characteristic described in connection with the aspect is included in at least one aspect of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure.
Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more aspects.
[0112] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. All numerical values, however, inherently contain a range necessarily resulting from the standard deviation found in their respective testing measurements.
[0113] The term "exemplary" means serving as a non-limiting example, instance, or illustration. As utilized herein, the terms "e.g.," and "for example" set off lists of one or more non-limiting aspects, examples, instances, or illustrations. [0114] As used herein, the term "substantially" refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. Biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term "substantially" is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena. For example, "substantially" may refer to being within at least about 20%, alternatively at least about 10%, alternatively at least about 5% of a characteristic or property of interest.
[0115] Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." As used herein in connection with a measured quantity, the term "about" refers to that variation in the measured quantity as would be expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring equipment used. The term "about" as used in connection with a numerical value throughout the specification and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art. In general, such interval of accuracy is +/-10%. Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
[0116] In the present specification, “EGFR” refers to a human epidermal growth factor receptor protein and is also referred to as ErbB-1 or HERE
[0117] As used herein, “wild-type EGFR” refers to EGFR that has no somatic mutation and is specifically a protein consisting of the amino acid sequence represented by SEQ ID NO: 1 (GenBank accession number: NP — 005219.2).
[0118] The term "molecularly targeted therapeutic" refers to an anticancer therapeutic that functions by interfering with specific targeted molecules needed for cancer -related functions such as carcinogenesis and tumor growth. Molecularly targeted therapeutics are distinct from chemotherapeutics which interfere with all rapidly dividing cells in a non-specific manner. A molecularly targeted therapeutic may be a small molecule (compound) or an antibody. Examples of the "molecular targeted therapeutics" include, but are not limited to, kinase inhibitors, proteasome inhibitors, monoclonal antibodies, mTOR inhibitors, TNF inhibitors, and T-cell inhibitors.
[0119] As used herein, “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound or agent having the ability to inhibit a biological function of a target protein or polypeptide, such as by inhibiting the activity or expression of the target protein or polypeptide. Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein or polypeptide. While some antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein or polypeptide by interacting with other members of the signal transduction pathway of that target protein or polypeptide are also specifically included within this definition. Non-limiting examples of biological activity inhibited by an antagonist include those associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease.
[0120] As used herein, “anticancer agent”, “antitumor agent” or “chemotherapeutic agent” refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents comprises chemotherapeutic agents. “Chemotherapy” means the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.
[0121] As used herein, “cell proliferation” or “proliferation of the cells” refers to a phenomenon by which the cell number has changed as a result of cell division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.
[0122] As used herein, “selective inhibition” or “selectively inhibit” as applied to a biologically active agent refers to the agent's ability to selectively reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target. For example, a compound that selectively inhibits exon 20 mutant EGFR over wildtype EGFR has an activity of at least about 2* against the mutated EGFR relative to the compound's activity against the wild-type EGFR isoform (e.g., at least about 3*, about 5*, about 10x, about 20*, about 50*, or about 100*).
[0123] As used herein, “in vivo” refers to an event that takes place in a subject's body. In vivo also includes events occurring in rodents, such as rats, mice, guinea pigs, and the like. [0124] As used herein, “in vitro” refers to an event that takes places outside of a subject's body. For example, an in vitro assay encompasses any assay conducted outside of a subject. In vitro assays encompass cell-based assays in which cells, alive or dead, are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.
[0125] As used herein, “therapeutic effect” encompasses a therapeutic benefit as described above. A “prophylactic effect” includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
[0126] Overall response rate (ORR) means the number and percentage of patients whose best overall response (BOR) is either a complete response (CR) or partial response (PR). To qualify as a responder a patient must have a complete or partial visit response confirmed by a second scan performed at least 4 weeks after the criteria for response are first met. ORR will be calculated separately using both investigator assessment of response and independent central review (ICR).
[0127] The invention is defined in the claims. However, below is a non-exhaustive listing of non-limiting exemplary aspects. Any one or more of the features of these aspects may be combined with any one or more features of another example, embodiment, or aspect described herein.
Methods of Treating Certain Cancers
[0128] Compound (1) can be used directly (free form) or in the form of a pharmaceutically acceptable salt. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The pharmaceutically acceptable salt of Compound (1) is not particularly limited, and examples thereof include addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, and the like; salts with alkali metals such as potassium, sodium, and the like; salts with alkaline earth metals such as calcium, magnesium, and the like; and salts with organic bases such as ammonium salts, ethylamine salts, alginate, and the like. The pharmaceutically acceptable salts can be synthesized by conventional chemical methods, generally by reacting Compound (1) with a stoichiometric amount or sub-stoichiometric amount (e.g., 0.5 eq) of the appropriate base or acid in water or in an organic solvent (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile), or in a mixture of the two.
[0129] Compound (1) or a pharmaceutically acceptable salt thereof may be in the form of a “solvate”, which refers to a physical association of a referenced compound with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a nonordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. Solvate encompasses both solution phase and isolable solvates. Exemplary solvent molecules which may form the solvate include, but are not limited to, water, methanol, ethanol, //-propanol, isopropanol, //-butanol, isobutanol, tertbutanol, ethyl acetate, glycerin, acetone, and the like.
[0130] The terms “treat”, “treating”, or the “treatment” of cancers in the present disclosure includes any effect, e.g., lessening, reducing, modulating, stabilizing, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. Specifically, these terms may refer to: (1) a stabilization, reduction (e.g., by more than 10%, 20%, 30%, 40%, 50%, preferably by more than 60% of the population of cancer cells and/or tumor size as compared to prior to administration), or elimination of the cancer cells, (2) inhibiting cancerous cell division and/or cancerous cell proliferation, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by unregulated or aberrant cellular division, (4) an increase in disease-free, relapse-free, progression-free, and/or overall survival, duration, or rate, (5) a decrease in hospitalization rate, (6) a decrease in hospitalization length, (7) eradication, removal, or control of primary, regional and/or metastatic cancer, (8) a stabilization or reduction (e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, preferably at least 80% relative to the initial growth rate) in the growth of a tumor or neoplasm, (9) an impairment in the formation of a tumor, (10) a reduction in mortality, (11) an increase in the response rate, the durability of response, or number of patients who respond or are in remission, (12) the size of the tumor is maintained and does not increase or increases by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%, (13) a decrease in the need for surgery (e.g., colectomy, mastectomy), and/or (14) preventing or reducing the metastasis of cancer cells.
[0131] In some embodiments, the cancers which can be treated herein are EGFR-positive cancers. “EGFR-positive” means a cancer in which an EGFR protein aberration and/or an EGFR gene aberration is detected/detectable. The EGFR protein/gene may be detected/detectable as wild-type or in altered form (e.g., mutated).
[0132] Examples of types of cancers which can be treated include, but are not limited to, glandular tumors, carcinoid tumors, undifferentiated carcinomas, angiosarcoma, adenocarcinoma, gastrointestinal cancers (e.g., colorectal cancers (“CRC”) including colon cancer and rectal cancer, biliary cancers including gall bladder cancer and bile duct cancer (cholangiocarcinoma), anal cancer, esophageal cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor(s), gastrointestinal stromal tumor(s) (“GIST”), liver cancer, duodenal cancer and small intestine cancer), lung cancers (e.g., non-small cell lung cancer (“NSCLC”), squamous-cell lung carcinoma, large-cell lung carcinoma, small cell lung carcinoma, invasive mucinous adenocarcinoma, mesothelioma and other lung cancers such as bronchial tumors and pleuropulmonary blastoma), urological cancers (e.g., kidney (renal) cancer, transitional cell cancer (“TCC”) of kidney, TCC of the renal pelvis and ureter (“PDQ”), bladder cancer, urethral cancer and prostate cancer), head and neck cancers (e.g., eye cancer, retinoblastoma, intraocular melanoma, hypopharyngeal cancer, pharyngeal cancer, laryngeal cancer, laryngeal papillomatosis, metastatic squamous neck cancer with occult primary, sinonasal squamous cell carcinoma (SNSCC), oral (mouth) cancer, lip cancer, throat cancer, oropharyngeal cancer, esthesioneuroblastoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, and salivary gland cancer), endocrine cancers (e.g., thyroid cancer, parathyroid cancer, multiple endocrine neoplasia syndromes, thymoma and thymic carcinoma, pancreatic cancers including pancreatic ductal adenocarcinoma (“PDAC”), pancreatic neuroendocrine tumors and islet cell tumors), breast cancers (extrahepatic ductal carcinoma in situ (“DCIS”), lobular carcinoma in situ (“LCIS”), triple negative breast cancer, and inflammatory breast cancer), male and female reproductive cancers (e.g., cervical cancer, ovarian cancer, endometrial cancer, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, gestational trophoblastic tumor (“GTD”), extragonadal germ cell tumor, extracranial germ cell tumor, germ cell tumor, testicular cancer and penile cancer), brain and nervous system cancers (e.g., astrocytomas, brain stem glioma, brain tumor, glioblastoma (GBM), craniopharyngioma, central nervous system (“CNS”) cancer, chordomas, ependymoma, embryonal tumors, neuroblastoma, paraganglioma, atypical teratoid, oligodendroma, oligodendroastrocytoma, oligodendroglioma, anaplastic oligodendroastrocytoma, ganglioglioma, central neurocytoma, medulloblastoma, germinoma, meningioma, neurilemmoma, GH secreting pituitary adenoma, PRL-secreting pituitary adenoma, ACTH- secreting pituitary adenoma, nonfunctional pituitary adenoma, hemangioblastoma, and epidermoid tumor), skin cancers (e.g., basal cell carcinoma (“BCC”), squamous cell skin carcinoma (“SCC”), Merkel cell carcinoma and melanoma), tissue and bone cancers (e.g., soft-tissue sarcoma, rhabdomyosarcoma, fibrous histiocytoma of bone, Ewing sarcoma, malignant fibrous histiocytoma of bone (“MFH”), osteosarcoma and chondrosarcoma), cardiovascular cancers (e.g., heart cancer and cardiac tumors), appendix cancers, childhood and adolescent cancers (e.g., adrenocortical carcinoma childhood, midline tract carcinoma, hepatocellular carcinoma (“HCC”), hepatoblastoma and Wilms’ tumor) and viral-induced cancers (e.g., HHV-8 related cancers (Kaposi sarcoma) and HIV/AIDS related cancers). [0133] Cancers also suitable for treatment may include, but are not limited to, hematological and plasma cell malignancies (e.g., cancers that affect blood, bone marrow and/or lymph nodes) such as multiple myeloma, leukemias and lymphomas, myelodysplastic syndromes and myeloproliferative disorders. Leukemias include, without limitation, acute lymphoblastic leukemia (“ALL”), acute myelogenous (myeloid) leukemia (“AML”), chronic lymphocytic leukemia (“CLL”), chronic myelogenous leukemia (“CML”), acute monocytic leukemia (“AMoL”), hairy cell leukemia, and/or other leukemias. Lymphomas include, without limitation, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (“NHL”). In some embodiments, NHL is B-cell lymphomas and/or T-cell lymphomas. In some embodiments, NHL includes, without limitation, diffuse large B-cell lymphoma (“DLBCL”), small lymphocytic lymphoma (“SLL”), chronic lymphocytic leukemia (“CLL”), mantle cell lymphoma (“MCL”), Burkitt’s lymphoma, cutaneous T-cell lymphoma including mycosis fungoides and Sezary syndrome, AIDS-related lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia (“WM”)), primary central nervous system (CNS) lymphoma, central nervous system malignant lymphoma, and/or other lymphomas.
[0134] Compound (1) or its pharmaceutically acceptable salt forms also may possess brain penetrability. Therefore, the cancers which can be treated also include metastatic brain tumors, for example, brain metastases of any of the above cancer types, e.g., lung cancers, breast cancers, gastric (stomach) cancer, bladder cancer, or biliary cancers including gall bladder cancer and bile duct cancer, etc., which have metastasized to the brain. [0135] The treatment methods of the present disclosure are particularly useful in the treatment of solid cancers (e.g., cancers having solid tumors) such as lung cancer (e.g., nonsmall cell lung cancer (“NSCLC”), invasive mucinous adenocarcinoma, etc.), breast cancer (e.g., extrahepatic ductal carcinoma in situ (“DCIS”), lobular carcinoma in situ (“LCIS”), etc.), gastric cancer, bladder cancer, biliary cancer, brain cancer (e.g., glioblastoma), colorectal cancer, pancreatic cancer, and ovarian cancer, as well as any of the above which have metastasized to the brain. NSCLC is the most common form of lung cancer and is histologically divided into adenocarcinoma, squamous cell carcinoma (SCC) and large cell carcinoma. Of particular interest to the present disclosure is lung cancer, specifically NSCLC. Of special interest to the present disclosure is nonsquamos NSCLC.
[0136] The methods disclosed herein may also be used as a tumor-agnostic treatment for malignancies having an aberration in EGFR, for example, where EGFR aberrations are found in the form of constitutive ErbB-mediated pathway activation due to aberrant ligand binding, for example NRG1 fusion-driven tumors.
[0137] Subjects harboring one or more aberrations in EGFR are candidates for treatment herein. EGFR aberrations are key oncogenic drivers for certain types of cancers. For example, EGFR aberrations can cause activation of a variety of signaling pathways, including Ras and phosphoinositide 3 -kinase (PI3K), which in turn contributes to various tumorigenic processes.
[0138] In the present disclosure, an “aberration” in EGFR refers to gain-of-function changes such as protein overexpression, gene amplification (e.g., copy-number alterations), activating gene mutation/activating protein mutation (e.g., insertion, point, or deletion mutations), activating protein overexpression, activating chromosomal translocation/insertion/inversion, activating gene rearrangement or gene fusion (a subset of gene rearrangements), misregulation/dysregulation, and the like, including combinations thereof, that result in or contributes to cancer formation and/or development. For example, cancers harboring EGFR aberrations may express (i) amplified or overexpressed EGFR, including those of the wildtype variety; (ii) constitutively activated EGFR (including those of the wild-type variety) due to aberrant ligand binding, such as through an aberrancy in NRG1, e.g., NRG1 fusion-driven binding; (iii) altered EGFR, for example, via activating gene and/or protein mutation(s); or (iv) a combination of aberrations, for example where EGFR is amplified/overexpressed and altered e.g., via mutation(s) in the EGFR gene and/or protein.
[0139] Unless specified otherwise, any reference to EGFR amino acid sequence information is based on human wild-type EGFR isoform a, which is accessible from the National Center for Biotechnology Information (NCBI) Protein Database as Accession No. NP_ 005219.2, P00533.2, etc.
[0140] Isoforms of EGFR are also known by those of ordinary skill in the art, and the present disclosure also encompasses those isoforms. With regard to alterations (e.g., mutations) in EGFR discussed herein, it should be understood that the alteration in the isoform may be located in a different position from the position identified for EGFR due to deletion or insertion of an amino acid(s) in the isoform, but that the alteration in the isoform nevertheless corresponds to the position identified for EGFR.
[0141] Aberrations in EGFR may be in the form of gene amplification and/or protein overexpression.
[0142] Aberrations in EGFR may be in the form of one or more mutations in the EGFR protein. EGFR mutations may be located in the tyrosine kinase domain of EGFR, including, but are not limited to, one or more of: exon 18 (in the region of 688-728); exon 19 (in the region of 729-761); exon 20 (in the region of 762-823); and exon 21 (in the region of 824- 875).
[0143] EGFR exon 18 mutations may include, but are not limited to, point mutations such as E709X or G719X (where X is an arbitrary amino acid), exemplified by E709K, E709A, E709G, G719A, G719S, and G719C, deletion mutations, and deletion insertion mutations, for example deletion of glutamic acid at position 709 and threonine at position 710 and insertion of aspartic acid (DelE709_T710insD), and the like.
[0144] EGFR exon 19 mutations may include, but are not limited to, “classical” Exon 19 deletion mutations of at least three amino acid residues, as well as deletion insertion mutations, for example DelE746_A750 (deletion of glutamic acid at position 746 to alanine at position 750), DelL747_P753insS (deletion of leucine at position 747 to proline at position 753 and insertion of serine), DelE746_T751insA, DelE746_S752insD, DelL747 T751, DelL747_A750insP, and the like.
[0145] EGFR exon 20 mutations may include, but are not limited to, point mutations such as T790M, S768I, V769M, and H773R, deletion mutations, and insertion mutations. In particular, compound (1) or its pharmaceutically acceptable salts have been found to be surprisingly active in cancers harboring one or more EGFR exon 20 insertion mutations. EGFR exon 20 insertion mutations are found with relatively high prevalence in non-small lung cancer (NSCLC) as well as sinonasal squamous cell carcinoma (SNSCC), are associated with de novo resistance to current clinically available EGFR inhibitors and are therefore preferred targets for treatment herein. [0146] EGFR exon 20 insertion mutations may be heterogeneous in-frame insertions of between 1-7 amino acids (indicated as “insX”) across a span of about 15 amino acids (D761- C775) in exon 20, for example D761_E762insX (insertion of between 1-7 amino acid residues “X” in between aspartic acid at position 761 and glutamic acid at position 762), A763_Y764insX, Y764_V765insX, V765_M766insX, A767_S768insX, S768_V769insX, V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, H773_V774insX, and V774_C775insX. Also included are deletion insertion mutations, such as DelD770insX (deletion of aspartic acid at position 770 and insertion of 1-7 amino acids “X”) and DelN771insX (Simon Vyse and Paul H. Huang, Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther. 2019 Mar 8;4:5). Specific examples of EGFR exon 20 insertion mutations include, but are not limited to, A763_Y764insFQEA, A763_Y764insTLA, Y764_V765insHH, A767_S768insASV, A767_S768insTLA, S768dupSVD, S768_V769insVAS, S768_V769insAWT, V769_D770insGV, V769_D770insCV, V769_D770insDNV, V769_D770insGSV, V769_D770insGVV, V769_D770insMASVD, V769_D770insASV, V769_D770insGE, V769_D770delInsDGEL, V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insKH, D770_N771insGNPH, D770_N771insAPW, D770_N771insD, D770_N771insDG, D770delinsGY, D770_N771insGL, D770_N771insN, D770_N771insNPH, D770_N771insSVP, D770_N771insSVQ, D770_N771insMATP, D770_N771insG, D770_N771insY, D770_N771insGF, D770_N771insGT,
D770_N77 tins SVG, DelD770insGY, DelD770insVG, N771_P772insH, N771_P772insV, N771_P772insN, DelN771insGY, DelN771insTH, delN771insGF, N771delinsGY, N771_P772insRH, P772_H773insPR, P772_H773insYNP, P772_H773insDPH, P772_H773insQV, P772_H773insTPH, P772_H773insN, P772_H773insV, P772_H773insNP, P772_H773insDNP, P772_H773insPNP, P772_H773insNPH, H773_V774insNPH, H773_V774insPH, H773_V774insGNPH, H773_V774insG, H773_V774insGH, H773_V774insAH, H773_V774insH, H773_V774delInsLM, H773_V774delInsTY, and V774_C775insHV (Takayuki Kosaka et al. Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors. Cancer Res. 2017 May;77(10):2712-2721).
[0147] A preferred embodiment of the present disclosure involves treating a subject with a cancer, specific mention being made to non-small lung cancer (NSCLC), harboring an EGFR exon 20 insertion mutation, particularly in cases where such cancers are locally advanced or where such cancers have metastasized to the brain. [0148] EGFR exon 21 mutations may include, but are not limited to, point mutations such as L858X and L861X (where X is an arbitrary amino acid), such as the “classical” exon 20 activating mutation L858R, as well as L833V, H835L, L838V, A839T, K846R, and L861Q. [0149] Exemplary EGFR proteins which contain multiple mutations, and can be treated herein, may include, but are not limited to, DelE746_A750/T790M and T790M/L858R.
[0150] Mutations in the EGFR protein may be those set forth in Japanese Patent Application No. 2020-121525, the contents of which are incorporated herein by reference in their entirety. [0151] Aberrations in EGFR may also be in the form of gene amplification and/or one or more genetic alterations in EGFR, such as EGFR gene rearrangements, and resultant mutations in EGFR in which particular exons or exon parts are deleted. Examples of which include, but are not limited to, EGFR variant I (EGFRvI; deletion of N-terminal part), EGFR variant II (EGFRvII; deletion of exons 14 and 15), EGFR variant III (EGFRvIII; deletion of exons 2-7), EGFR variant IV (EGFRvIV; deletion of exons 25-27), and EGFR variant V (EGFRvV; deletion of exons 25-28).
[0152] Of these, gene rearrangements resulting in expression of EGFRvIII is found with high prevalence in glioblastoma (GBM), with expression being identified in other cancers as well, such as breast carcinoma, and lung carcinoma (e.g., NSCLC). EGFRvIII results from the inframe deletion of 801 base pairs spanning exons 2-7, with this deletion removing 267 amino acids from the extracellular domain, thereby creating a junction site between exons 1 and 8 and a new glycine residue. These alterations confer enhanced tumorgenicity, such as increased rates of proliferation, reduced apoptosis, increased angiogenesis, and increased invasiveness compared to unaltered EGFR, mediated by several downstream signaling pathways, including PI3K/Akt, Ras/Raf/MAPK, signal transducer and activator of transcriptase 3 (Stat3), and nuclear factor kappa-B (NF-KB).
[0153] Given the high prevalence of EGFR amplification and EGFRvIII mutations in GBM, the lack of approved drugs targeting GBM harboring these EGFR genetic alterations, and the high brain penetrability of compound (1) or its pharmaceutically acceptable salts, a preferred embodiment of the present disclosure involves treating a subject with GBM harboring an EGFR amplification and/or an EGFRvIII mutation.
[0154] Aberrations in EGFR may also be in the form of constitutively activated EGFR (including those of the wild-type variety) due to aberrant ligand binding. One example of which is cancers having an aberration in NRG1. An “aberration” in NRG1 refers to gain-of- function changes such as protein overexpression, gene amplification (e.g., copy-number alterations), activating gene mutation/activating protein mutation (e.g., insertion, point, or deletion mutations), activating chromosomal translocation/insertion/inversion, activating gene rearrangement or gene fusion (a subset of gene rearrangements), misregulation/dysregulation, and the like, including combinations thereof, that result in or contributes to cancer formation and/or development.
[0155] For example, aberrations in NRG1 may be in the form of NRG1 overexpression. NRG1 overexpression has been found to be associated with aggressive tumor features and poor prognosis in gastric cancer patients (Yun, S. et al. Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients; Gastric Cancer (2018) 21 :225-236).
[0156] Another example of which is cancers harboring oncogenic gene fusions in NRG1. NRG1 gene fusions result in irregular expression of the epidermal growth factor (EGF)-like domain of NRG1 on the cell surface, which serves as a ligand for ErbB3 (HER3) and induces the formation of heterodimers, most frequently ErbB2-ErbB3, but also with EGF receptor (EGFR; ErbBl) and ErbB4. This leads to pathologic activation of the phosphoinositide 3- kinase-protein kinase B (PI3K-Akt), mitogen-activated protein kinase (MAPK), and other signaling pathways, resulting in abnormal cell proliferation. This binding event may take place in an autocrine or juxtacrine fashion. Alternatively, in some cases, the EGF-like domain of NRG1 can be cleaved from its surface tether where it binds to ErbB3 (HER3) in a paracrine fashion. In any event, NRG1 fusion-positive cancers cause aberrant activation of EGFR and/or HER2, and thus in a preferred embodiment, the present disclosure involves treating a subject with an NRG1 fusion-driven tumor.
[0157] Cancers driven by one or more aberrations in NRG1 may include, but are not limited to, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, biliary cancer, ovarian cancer, and gastric cancer.
[0158] Cancers driven by NRG1 gene fusions may include, but are not limited to, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, biliary cancer, and ovarian cancer. [0159] NRG1 fusions may be formed from various fusion partners (listed below as X in X- NRG1), the selection of fusion partner is not particularly limiting. Examples of NRG1 fusions include, but are not limited to, DOC4-NRG1, CD74-NRG1, SLC3A2-NRG1, SDC4- NRG1, RBPMS-NRG1, WRN-NRG1, VAMP2-NRG1, ATP1B1-NRG1, ROCK1-NRG1, RALGAPA1-NRG1, TNC-NRG1, MDK-NRG1, DIP2B-NRG1, MRPL13-NRG1, DPYSL2- NRG1, PARP8-NRG1, ITGB1-NRG1, P0MK-NRG1, APP-NRG1, CDH6-NRG1, ATP1B1- NRG1, and CLU-NRG1 (J. Laskin et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol. 2020 Dec;31(12): 1693-1703).
[0160] Other growth factors that activate ErbB receptors that may lead to aberrant ErbB- mediated constitutive pathway activation include, but are not limited to, EGF, TGF-a, HB- EGF, amphiregulin, betacellulin, epigen, and epiregulin. Thus, cancers harboring activating aberrations in any of these growth factors that result in aberrant activation of ErbB family receptors and downstream ErbB-mediated signaling pathways, contributing to oncogenesis, may be treated herein.
[0161] While cancers at various stages and resectabilities may respond to the disclosed treatment, the methods herein may be particularly useful in the treatment of unresectable or advanced (stage III, “locally advanced”) and metastatic (stage IV) disease, “recurrent,” “resistant”, and “refractory” cancers — cancer that heretofore has failed to respond to medical treatment. “Recurrent” cancers are cancers that have recurred (come back), usually after a period of time during which the cancer could not be detected. The cancer may come back to the same place as the original (primary ) tumor or to another place in the body. “Refractory” cancers may present as resistance/intractability from the start. “Resistant” cancers may present following the acquisition of resistance/intractability by the cancer cells during the course of prior therapy, and thus can include relapsed cancer that responds initially to treatment, but returns, often in a more aggressive/resistant form. Resistant cancers may also be described as having “secondary resistance”, “acquired resistance”, or similar term. For example, the cancer may be a recurrent, resistant, or refractory EGFR-positive cancer, preferably a recurrent, resistant, or refractory cancer in which EGFR is genetically amplified and/or overexpressed. Example cancer types may include, but are not limited to, recurrent, resistant, or refractory EGFR-positive NSCLC. Particularly relevant to the present disclosure at cancers which are locally advanced and/or which have metastasized to the brain of the subject.
[0162] Subjects with a recurrent, resistant, or refractory cancer who have previously undergone at least one treatment regimen with one or more anticancer agents may be treated with Compound (1) or its pharmaceutically acceptable salt and the platinum anticancer agent. In some cases, the recurrent, resistant, or refractory cancer may have acquired resistance to, or intractability from, the prior treatment regimen(s). For example, a subject with an EGFR- positive cancer treated previously with one or more anticancer agents, and that failed to respond to or relapsed from the prior treatment(s) with the anticancer agent(s), may develop resistance/intractability as a result of exposure of the cancer to the anticancer agent(s). Resistance/intractability may manifest in the cancer in the form of EGFR aberrations e.g., overexpression and/or mutations, or any other cancer driver alterations that result in loss-of- function of tumor suppressor genes/proteins or gain-of-function alterations in oncogenes/oncogene-encoded proteins.
[0163] Prior treatment regimen(s) may have been performed with a variety of anticancer agents, examples of such anticancer agents will be discussed hereinafter. An embodiment of the present disclosure involves administering Compound (1) or its pharmaceutically acceptable salt to a subject with EGFR-positive cancer that has not previously undergone at least one systemic treatment with a molecularly targeted therapeutic. An embodiment of the present disclosure involves administering Compound (1) or its pharmaceutically acceptable salt to a subject with EGFR-positive cancer that has previously undergone at least one systemic treatment with a molecularly targeted therapeutic. In some embodiments, administration of Compound (1) or its pharmaceutically acceptable salt to a subject with EGFR-positive cancer that has previously undergone at least one systemic treatment is initiated following the systemic treatment decreasing in efficacy or effectiveness, following a disease relapse, following a disease progression, following a failure of the subject to respond to treatment, or a combination of these. Examples of systemic treatments with a molecularly targeted therapeutic include, but are not limited to, treatment with one or more EGFR inhibitor(s) (i.e., EGFR inhibitors other than Compound (1), such as gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, poziotinib, mobocertinib, lazertinib, sunvozertinib, furmonertinib amivantamab, DZD9008, BDTX-189, necitumumab, pembrolizumab, brigatinib, icotinib, neratinib, olmutinib, rociletinib, vandetanib, lapatinib, duligotuzumab, panitumumab, zalutumumab, cetuximab, depatuxizumab, depatuxizumab mafodotin, imgatuzumab, matuzumab, and nimotuzumab), non-EGFR-targeting agents such as ALK inhibitors (such as crizotinib, ceritinib, alectinib, ensartinib, entrectinib, repotrectinib, belizatinib, alkotinib, foritinib, CEP-37440, TQ-B3139, PLB1003, zotizalkiv, lorlatinib, and conteltinib), PD-1/PD-L1 Inhibitors (such as nivolumab, pembrolizumab, and cemiplimab), PD-L1 inhibitors (such as atezolizumab and durvalumab), VEGF inhibitors (such as bevacizumab), CLTA-4 inhibitors (such as ipilimumab), patrit umab, deruxtecan, datopotamab, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, or combinations of these. Systemic treatment does not include local treatment such as localized or limited tumor rescission.
[0164] Before commencing treatment, determination may be made as to whether the subject has one or more aberrations in EGFR, as described above. Thus, the methods may involve a pre-screening step to determine whether the subject has an aberration in EGFR and is a good candidate for treatment. The aberration(s) may be determined from family history of cancers involving the aberration(s), by genotyping the subject or analyzing any biological sample from the subject including blood or tumor samples taken from the subject using assays such as those described hereinafter, or from historical records or previous testing performed on the subject. If the subject is determined to be EGFR-positive, and to harbor one or more aberrations therein such as those described in the present disclosure, treatment with Compound (1) or its pharmaceutically acceptable salt is appropriate.
[0165] In one embodiment of the present invention, prior to the administration of Compound (1), a step of detecting that the EGFR expressed by the malignant tumor patient has an exon 20 insertion mutation can be performed.
[0166] Predictive biomarkers which may be used to identify individuals who are likely to be responsive to treatment herein, include, but are not limited to, EGFR overexpression/amplification or other gene alterations at DNA, RNA or protein level, for example, in breast cancer; EGFR exon 20 insertions and other activating mutations, for example, in lung cancer (e.g., NSCLC); EGFRvIII mutation, EGFR amplification and/or O6- methylguanine-DNA methyltransferase (MGMT) promoter methylation, for example, in brain cancer (e.g., GBM). A companion diagnostic (CDx) test may be developed to analyze biological samples.
[0167] The presence of EGFR aberrations (including aberrations that cause protein activation via aberrant ligand binding, e.g., NRG1 fusion-driven EGFR as described above) may be determined, e.g., during subject pre-screening or from previous testing performed on the subject, or otherwise confirmed according to known assays, including cleared or approved in vitro diagnostic (IVD) assays or assays for this purpose. Examples of which include, but are not limited to, testing by next generation sequencing (NGS)-based gene panel, whole exome profiling, polymerase chain reaction (PCR), in situ hybridization (ISH), immunohistochemistry (IHC), flow cytometry, or other assays that can determine EGFR aberrations on tumor tissues or circulating tumor DNA (ctDNA), RNA, protein, etc. For example, subjects who do not have archival tumor tissue samples can be biopsied and the fresh tumor biopsy can be analyzed for confirmation of existing aberrations.
[0168] A sample used for detection of the EGFR aberration is not particularly limited as long as it is a biological sample derived from a malignant tumor patient, such as a sample collected from a malignant tumor patient and containing malignant tumor cells. Examples of biological samples include body fluids (blood, urine, etc.), tissues, extracts thereof, and cultures of collected tissues. Moreover, the collection method of a biological sample can be suitably selected according to the kind of biological sample.
[0169] The biological sample is prepared by appropriate processing depending on the detection method. Moreover, the reagent (for example, reagent containing a primer or a probe) used for detection can be adjusted by a commonly used method according to the detection method.
[0170] The term "effective amount" is a therapeutically effective or pharmaceutically effective amount. The effective amount of the compound according to an embodiment of the present invention refers to an amount of the compound which is sufficient to achieve a biological response or therapeutic response of a subject, such as causing reduction or prevention of an activity of enzyme or protein; or improving a symptom, alleviating a medical state, delaying or retarding progression of disorder, or preventing a disease.
[0171] The term “pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic bases or acids.
[0172] The terms “administer”, “administering”, “administration”, and the like, refer to the methods that may be used to enable delivery of the active ingredient to the desired site of biological action. Routes or modes of administration are as set forth herein. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical/transdermal, and rectal/vaginal administration. Those of ordinary skill in the art are familiar with administration techniques that can be employed. For Compound (1), oral administration is preferred. For the platinum anticancer agent, intravenous injection is preferred. For the optional pemetrexed, intravenous injection is preferred.
[0173] As used herein, “co-admini strati on,” “administered in combination with,” and their grammatical equivalents, as used herein, encompasses administration of two or more agents to a subject such that both agents and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a single fixed dose composition in which both agents are present.
[0174] In the present disclosure, the term “administration schedule” is a plan in which the type, amount, period, procedure, etc. of the drug in the drug treatment are shown in time series, and the dosage, administration method, administration order, administration date, and the like of each drug are indicated. The date specified to be administered is determined before the start of the drug administration. The administration is continued by repeating the course with the set of administration schedules as “courses”.
[0175] Regarding the administration schedule in the present application, “continuous” means administration every day without interruption during the treatment course. If the administration schedule follows an “intermittent” administration schedule, then one or more days of administration may be followed by one or more “rest days” or days of nonadministration of drug within the course.
[0176] A “drug holiday” indicates that the drug is not administered in a predetermined administration schedule. For example, after undergoing several courses of treatment, a subject may be prescribed a regulated drug holiday as part of the administration schedule, e.g., prior to re-recommencing active treatment.
[0177] The dosage amount and treatment duration are dependent on factors, such as bioavailability of a drug, administration mode, toxicity of a drug, gender, age, lifestyle, body weight, the use of other drugs and dietary supplements, the disease stage, tolerance and resistance of the body to the administered drug, etc., and then determined and adjusted accordingly. An appropriate dosage amount may differ from one individual to another. An appropriate dosage amount in any individual case may be determined using techniques, such as dose escalation. An appropriate dosage can include an amount of Compound (1). An appropriate dosage can also include an amount of an additional therapeutic agent (e.g., a platinum anticancer agent), as described below. These amounts can be varied independently or can be jointly varied (e.g., a single dosage can be varied to maintain a specific ratio of the amount of Compound (1) to the amount of the additional therapeutic agent).
[0178] The subject having a cancer with at least one aberration in EGFR can be treated with Compound (1) or its pharmaceutically acceptable salt at dose levels of from about 10 mg/day, from about 15 mg/day, from about 20 mg/day, from about 30 mg/day, from about 40 mg/day, from about 50 mg/day, from about 60 mg/day, from about 80 mg/day, from about 100 mg/day, from about 125 mg/day, from about 140 mg/day and up to about 500 mg/day, up to about 480 mg/day, up to about 450 mg/day, up to about 400 mg/day, up to about 350 mg/day, up to about 300 mg/day, up to about 250 mg/day, up to about 240 mg/day, up to about 200 mg/day, up to about 150 mg/day. The dosing level may be varied within the ranges such as from about 10 mg/day to about 500 mg/day, from about 20 mg/day to about 300 mg/day, and from about 30 mg to about 150 mg/day. In one embodiment, the dosing level is about 100 mg/day. The administration dose level can be changed during an administration schedule, for example, the administration can begin with low dose for some time and then increased, or, the administration can begin with high dose for some time and then decreased. The administration dosage can be reduced, but is not limited. The dosage may, for example, be decreased from 300 mg/day to 150 mg/day, from 300 mg/day to 100 mg/day, and from 100 mg/day to 50 mg/day.
[0179] The dosing can be continuous (daily; 7 days of administration in a week) or intermittent (alternating one or more dosing days with one or more non-dosing days, such as 4 days-on/3 days-off), for example, depending the pharmacokinetics and a particular patient’s clearance/accumulation of the drug. The dosing schedule should be selected using sound medical judgement. Dosage can be adjusted depending on the occurrence of side effects and symptoms. For example, reduction from twice per day(BID) to once per day(QD). Daily administration is preferred. The dosing can be performed every other day (QOD), once per day (QD), twice per day (BID) or more than twice per day (TID, etc.), with doses of about 60 to 300 mg/day being preferred, with dosed of about 200mg/day being most preferred.
[0180] If a patient experiences a clinically significant adverse event, such as CTCAE V5.0 Grade 3 or higher, and/or otherwise unacceptable toxicity, CLN-081 dosing should be interrupted and supportive therapy should be administered as described in Table 11 . Study treatment may be discontinued or resumed with or without dose reduction based upon the severity and/or resolution of the adverse event according to the criteria detailed in Table 11. Recommended dose reductions are presented in Table 12.
[0181] The daily dose may be administered as a single dose or multiple individual divided doses. For example, one (1) tablet, containing 50 mg of Compound (1) or its pharmaceutically acceptable salt, may be administered to the patient once per day (QD) for a total dose of 50 mg/day. In another example, two (2) tablets, each containing 50 mg of Compound (1) or its pharmaceutically acceptable salt, may be administered to the patient once per day (QD) for a total dose of 100 mg/day. In another example, one (1) tablet, containing 50 mg of Compound (1) or its pharmaceutically acceptable salt, may be administered to the patient twice per day (BID) for a total dose of 100 mg/day. In another example, two (2) tablets, each containing 50 mg of Compound (1) or its pharmaceutically acceptable salt, may be administered to the patient twice per day (BID) for a total dose of 200 mg/day. In another example, three (3) tablets, each tablet containing 10 mg of Compound (1) or its pharmaceutically acceptable salt, may be administered to the subject once per day (QD) for a total dose of 30 mg/day. In another example, three (3) tablets, each tablet containing 20 mg of Compound (1) or its pharmaceutically acceptable salt, may be administered to the subject twice per day (BID) for a total dose of 120 mg/day. The multiple individual divided doses can be equal in terms of the amount of Compound (1) or its pharmaceutically acceptable salt or can contain different amounts of Compound (1) or its pharmaceutically acceptable salt. For example, one (1) tablet, containing 50 mg of Compound (1) or its pharmaceutically acceptable salt, may be administered to the patient as a first dose in a day and two (2) tablets, each containing 50 mg of Compound (1) or its pharmaceutically acceptable salt, may be administered to the patient as a second dose in a day, for a total dose of 150 mg/day.
[0182] The dosing whether continuous or intermittent is continued for a particular treatment cycle, typically at least a 21 -day cycle, which can be repeated with or without a drug holiday. Longer or shorter cycles can also be used such as 7 days, 14 days, 18 days, 24 days, 28 days, 35 days, 42 days, or any range therebetween. The treatment cycle may be repeated without a drug holiday or with a drug holiday depending upon the subject. A treatment cycle of alternating and consecutive days can be used. For instance, a dosing schedule of sequential 7- day periods may be used where each period comprises alternating 4 days-on and 3 days-off Here, this schedule would involve dosing on days 1, 3, 5, 7, 8, 10, 12, 14, 15, 17, 19, 21, and so on. Other schedules are possible depending upon the presence or absence of adverse events, response of the cancer to the treatment, patient convenience, and the like. An “adverse event” refers to any unfavorable or unintended illness or symptom thereof occurring in a patient to whom a drug has been administered. It does not matter whether there is a causal relationship with the drug or not.
[0183] The larger doses are usually given intermittently with doses up to about 500 mg usually given continuously (daily). Compound (1) may be dosed using an up-titration regimen, whereby a subject is started with a low dose for a certain period of time (e.g., 2 weeks) and then the dose is escalated. The dose may be up-titrated until either a target or maximum dose is reached or the subject experiences adverse events at which point the escalation is stopped and the drug dosing is reduced to a previous dose where the adverse event was not experienced or was not serious enough to require stoppage of the treatment. A subject that experiences an adverse event may also be managed with dosing interruptions (e.g., a drug holiday), if deemed appropriate. Typical dosing for the continuous regimen may be 30, 45, 50, 60, 75, 100, 150, 200, 250, 300, 350, or 400 mg/day but higher or lower doses may be used depending on the subject’s response to the treatment and presence or absence of adverse events. If a dose is well-tolerated, the dose can be increased. The continuous administration may be continued for one treatment cycle, e.g., 21 days, the treatment cycle may then be repeated, as desired. In some embodiments, only one treatment cycle is performed. In some embodiments, up to 10 treatment cycles are performed. In general, any number of treatment cycles can be performed, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 treatment cycles can be performed. A drug holiday can be included in between any treatment cycles. A treatment regimen can include treatment cycles between which a drug holiday is included and treatment cycles between which a drug holiday is not included.
[0184] Such continuous or intermittent administration is applicable also to combination therapies where Compound (1) or its pharmaceutical acceptable salt is administered in combination with one or more additional therapeutic agents (e.g., other anticancer agents) as described below.
[0185] The treatment methods of the present disclosure may involve administration of Compound (1) or pharmaceutically acceptable salt thereof. The treatment may also involve administration as a post-operative auxiliary chemotherapy that is performed to prevent recurrence of tumors after surgically removing tumors, as well as pre-operative auxiliary chemotherapy prior to surgery to surgically remove tumors. In some cases, such as with breast cancer, surgery may include a lumpectomy, a mastectomy, a breast reconstruction, and the like. In some cases, such as with lung cancer, surgery may include pneumonectomy, lobectomy, wedge resection, sleeve resection, thoracoscopy, and the like. In some cases, such as with brain cancer, surgery may include craniotomy, ventriculoperitoneal shunt, endoscopic third ventriculostomy, surgery to put in a ventricular access catheter, and the like. The treatment may also include administration of Compound (1) or pharmaceutically acceptable salt thereof during or after radiation therapy or as an adjuvant therapy to prevent recurrence of the tumor in a patient where other treatments such as surgery have rendered the patient cancer-free.
[0186] Subjects may be treated whom have previously undergone a treatment regimen with one or more with a molecularly targeted therapeutic, i.e., Compound (1) or its pharmaceutically acceptable salt is administered as second-, third-, fourth-, etc. line therapy. Subjects may be treated whom have been previously treated with an EGFR-targeted therapeutic such as an EGFR inhibitor. EGFR inhibitors may be categorized as an EGFR tyrosine kinase inhibitor or an anti-EGFR antibody, such as those set forth herein, examples of which include, but are not limited to, afatinib, gefitinib, erlotinib, osimertinib, poziotinib, lazertinib, sunvozertinib, furmonertinib, mobocertinib, lapatinib, neratinib, cetuximab, dacomitinib, panitumumab, vandetanib, DZD9008, BDTX-189, amivantamab, pembrolizumab, brigatinib, icotinib, olmutinib, rociletinib, duligotuzumab, zalutumumab, depatuxizumab, depatuxizumab mafodotin, imgatuzumab, matuzumab, nimotuzumab, and necitumumab. The subjects treated with Compound (1) or its pharmaceutically acceptable salt as described herein may, or may not, have been previously treated with an anticancer agent(s) besides an EGFR inhibitor(s), examples of which will be discussed hereinafter.
[0187] As described below, Compound (1) or its pharmaceutically acceptable salt may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets or capsules, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained release formulation; (3) topical application/transdermal administration, for example, as a cream, ointment, or a controlled release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) nasally. In the case of Compound (1) or its pharmaceutically acceptable salt, an oral formulation is preferable. [0188] Formulations can be prepared using a pharmaceutically acceptable carrier or the like by using known formulation methods. Pharmaceutically acceptable carriers are those materials, compositions, or vehicles, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations, such as cyclodextrins, liposomes, and micelle forming agents, e.g., bile acids, just to name a few.
[0189] Pharmaceutically acceptable carriers may be categorized as various general-purpose agents such as excipients, binders, disintegrating agents, lubricants, diluents, dissolution aids, suspending agents, swelling agents, isotonic agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, corrigents, and the like.
[0190] Examples of excipients include, but are not limited to, lactose, sucrose, D-mannitol, glucose, starch (corn starch), calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid anhydride.
[0191] Examples of binders include, but are not limited to, water, ethanol, 1 -propanol, 2- propanol, simple syrup, liquid glucose, liquid a-starch, liquid gelatin, D-mannitol, carboxymethyl cellulose, hydroxypropyl cellulose (e.g., low viscosity hydroxypropyl cellulose), hydroxypropyl methylcellulose (hypromellose), hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone.
[0192] Examples of disintegrants include, but are not limited to, low-substituted hydroxypropyl cellulose, dry starch, partially pregelatinized starch, crystalline cellulose, carmellose sodium, carmellose calcium, D-mannitol, crospovidone, croscarmellose sodium, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
[0193] Examples of lubricants include, but are not limited to, hydrogenated oil, sucrose fatty acid ester, sodium lauryl sulfate, stearic acid, purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol.
[0194] Examples of colorants include, but are not limited to, edible yellow No. 5 dye, edible blue No. 2 dye, edible lake dye, iron sesquioxide, yellow sesquioxide, and titanium dioxide. [0195] Examples of sweetening/flavoring agents include, but are not limited to, aspartame, saccharin (as sodium, potassium or calcium saccharin), cyclamate (as a sodium, potassium or calcium salt), sucralose, acesulfame-K, thaumatin, neohisperidin, dihydrochalcone, ammoniated glycyrrhizin, dextrose, maltodextrin, fructose, levulose, sucrose, glucose, wild orange peel, citric acid, tartaric acid, oil of wintergreen, oil of peppermint, oil of spearmint, oil of sassafras, oil of clove, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol, lemon, lime, and lemon-lime.
[0196] If desired, an enteric coating or a coating to increase the persistence of effects can be provided by methods desirable for oral preparations. Examples of such coating agents include hydroxypropyl methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, and Tween 80 (registered trademark).
[0197] Compound (1) or its pharmaceutically acceptable salt are preferably formulated in solid dosage form for oral administration, such as in the form of capsules, tablets, pills, dragees, powders, granules, troches, and the like, with preference given to film-coated tablets. Compound (1) or its pharmaceutically acceptable salt may be mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants (e.g., fatty acid esters of sorbitan and polyalkolyated fatty acid esters of sorbitan such as Tween 80 (registered trademark); (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the formulations may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
[0198] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. One example coating formulation may include hypromellose, polyethylene glycol, titanium dioxide, and optionally a coloring agent. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These formulations may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
[0199] Compound (1) or its pharmaceutically acceptable salt may be formulated for parenteral administration, for intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion administration, by combining Compound (1) or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers which may be employed include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, pH regulators, stabilizers, local anesthetics, etc. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. [0200] Compound (1) or its pharmaceutically acceptable salt can be combined with one or more additional therapeutic agents. Examples of additional therapeutic agents include chemotherapeutic agents (e.g., cytotoxic agents), immunotherapeutic agents, hormonal and anti-hormonal agents, targeted therapy agents, and anti-angiogenesis agents. The additional therapeutic agent can be an anti-cancer agent. Many anti-cancer agents can be classified within one or more of these groups. While certain anticancer agents have been categorized within a specific group(s) or subgroup(s) herein, many of these agents can also be listed within one or more other group(s) or subgroup(s), as would be presently understood in the art. It should be understood that, as used here, “combined with” may refer to simultaneous treatment (e.g., co-administration with the same or different regimens), overlapping treatment, sequential treatment, or a combination of these. Sequential treatment may include treatment first with Compound (1) or its pharmaceutically acceptable salt followed by treatment with one or more anticancer agents or treatment first with one or more anticancer agents followed by Compound (1) or its pharmaceutically acceptable salt. In sequential treatment, there may be a treatment gap, i.e., a period of time following a conclusion or cessation of a first treatment prior to initiation of a second treatment.
[0201] The anticancer agent is not particularly limited, and examples thereof include, but are not limited to, a chemotherapeutic agent, a mitotic inhibitor, a plant alkaloid, an alkylating agent, an anti-metabolite, a platinum anticancer agent, an enzyme, a topoisomerase inhibitor, a retinoid, an aziridine, an antibiotic, a hormonal agent, an anti-hormonal agent, an antiestrogen, an anti-androgen, an anti-adrenal, an androgen, a targeted therapy agent, an immunotherapeutic agent, a biological response modifier, a cytokine inhibitor, a tumor vaccine, a monoclonal antibody, an immune checkpoint inhibitor, an anti-PD-1 agent, an anti- PD-L1 agent, a colony-stimulating factor, an immunomodulator, an immunomodulatory imide (IMiD), an anti-CTLA4 agent, an anti-LAGl agent, an anti-OX40 agent, a GITR agonist, a CAR-T cell, a bispecific T-cell engager (BiTE), a signal transduction inhibitor, a growth factor inhibitor, a tyrosine kinase inhibitor, an EGFR inhibitor, a HER2 inhibitor, a histone deacetylase (HD AC) inhibitor, a proteasome inhibitor, a cell-cycle inhibitor, an antiangiogenesis agent, a matrix-metalloproteinase (MMP) inhibitor, a hepatocyte growth factor inhibitor, a TOR inhibitor, a KDR inhibitor, a VEGF inhibitor, a HIF-la inhibitor a HIF-2a inhibitor, a fibroblast growth factor (FGF) inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, an AKT inhibitor, an MCL-1 inhibitor, a BCL-2 inhibitor, an SHP2 inhibitor, a BRAF-inhibitor, a RAS inhibitor, a gene expression modulator, an autophagy inhibitor, an apoptosis inducer, an antiproliferative agent, and a glycolysis inhibitor.
[0202] Non-limiting examples of chemotherapeutic agents include mitotic inhibitors and plant alkaloids, alkylating agents, anti-metabolites, platinum anticancer agents, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.
[0203] Non-limiting examples of mitotic inhibitors and plant alkaloids include taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel; demecolcine; epothilone; eribulin; etoposide (VP- 16); etoposide phosphate; navelbine; noscapine; teniposide; thaliblastine; vinblastine; vincristine; vindesine; vinflunine; and vinorelbine. [0204] Non-limiting examples of alkylating agents include nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, cytophosphane, estramustine, ifosfamide, mannomustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, tris(2-chloroethyl)amine, trofosfamide, and uracil mustard; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, streptozotocin, and TA-07; ethylenimines and methylamelamines such as altretamine, thiotepa, triethylenemelamine, triethylenethiophosphaoramide, trietylenephosphoramide, and trimethylolomelamine; ambamustine; bendamustine; dacarbazine; cyclophosphamide; etoglucid; irofulven; mafosfamide; mitobronitol; mitolactol; pipobroman; procarbazine; temozolomide; treosulfan; and triaziquone.
[0205] Non-limiting examples of anti-metabolites include folic acid analogues such as aminopterin, denopterin, edatrexate, methotrexate, pteropterin, raltitrexed, trimetrexate, and pemetrexed, of these, pemetrexed is preferable; purine analogs such as 6-mercaptopurine, 6- thioguanine, fludarabine, forodesine, thiamiprine, and thioguanine; pyrimidine analogs such as 5 -fluorouracil (5-FU), tegafur/gimeracil/oteracil potassium, tegafur/uracil, trifluridine, trifluridine/tipiracil hydrochloride, 6-azauridine, ancitabine, azacytidine, capecitabine, carmofur, cytarabine, decitabine, dideoxyuridine, doxifiuridine, doxifluridine, enocitabine, floxuridine, galocitabine, gemcitabine, and sapacitabine; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; broxuridine; cladribine; cyclophosphamide; cytarabine; emitefur; hydroxyurea; mercaptopurine; nelarabine; pentostatin; tegafur; and troxacitabine.
[0206] Non-limiting examples of platinum anticancer agent such as oxaliplatin, cisplatin, carboplatin, and nedaplatin. Of these, carboplatin is preferable.
[0207] Non-limiting examples of enzymes include asparaginase and pegaspargase. [0208] Non-limiting examples of topoisomerase inhibitors include acridine carboxamide, amonafide, amsacrine, belotecan, elliptinium acetate, exatecan, indolocarbazole, irinotecan, lurtotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.
[0209] Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin.
[0210] Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa.
[0211] Non-limiting examples of antibiotics include intercalating antibiotics; anthracenediones; anthracycline antibiotics such as aclarubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, nogalamycin, pirarubicin, and valrubicin; 6-diazo-5-oxo-L-norleucine; aclacinomysins; actinomycin; authramycin; azaserine; bleomycins; cactinomycin; calicheamicin; carabicin; carminomycin; carzinophilin; chromomycins; dactinomycin; detorubicin; esorubicin; esperamicins; geldanamycin; marcellomycin; mitomycins; mitomycin C; mycophenolic acid; olivomycins; novantrone; peplomycin; porfiromycin; potfiromycin; puromycin; quelamycin; rebeccamycin; rodorubicin; streptonigrin; streptozocin; lanespimycin: tubercidin; ubenimex; zinostatin; zinostatin stimalamer; and zorubicin.
[0212] Non-limiting examples of hormonal and anti-hormonal agents include anti-androgens such as abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, goserelin, leuprolide, and nilutamide; anti-estrogens such as 4-hydroxy tamoxifen, aromatase inhibiting 4(5)-imidazoles, EM-800, fosfestrol, fulvestrant, keoxifene, LY 117018, onapristone, raloxifene, tamoxifen, toremifene, and trioxifene; anti-adrenals such as aminoglutethimide, dexaminoglutethimide, mitotane, and trilostane; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; abarelix; anastrozole; cetrorelix; deslorelin; exemestane; fadrozole; finasteride; formestane; histrelin (RL 0903); human chorionic gonadotropin; lanreotide; LDI 200 (Milkhaus); letrozole; leuprorelin; mifepristone; nafarelin; nafoxidine; osaterone; prednisone; thyrotropin alfa; and triptorelin.
[0213] Non-limiting examples of immunotherapeutic agents (i.e., immunotherapy) include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony-stimulating factors, and immunomodulators.
[0214] Non-limiting examples of biological response modifiers, including cytokine inhibitors (cytokines) such as interferons and interleukins, include interferon alfa/interferon alpha such as interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon alfacon-1, peginterferon alfa-2a, peginterferon alfa-2b, and leukocyte alpha interferon; interferon beta such as interferon beta-la, and interferon beta-lb; interferon gamma such as natural interferon gamma- la, and interferon gamma- lb; aldesleukin; interleukin- 1 beta; interleukin-2; oprelvekin; sonermin; tasonermin; and virulizin.
[0215] Non-limiting examples of tumor vaccines include APC 8015, AVICINE, bladder cancer vaccine, cancer vaccine (Biomira), gastrin 17 immunogen, Maruyama vaccine, melanoma lysate vaccine, melanoma oncolysate vaccine (New York Medical College), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), TICE® BCG (Bacillus Calmette-Guerin), and viral melanoma cell lysates vaccine (Royal Newcastle Hospital).
[0216] Non-limiting examples of monoclonal antibodies include abagovomab, adecatumumab, aflibercept, alemtuzumab, blinatumomab, brentuximab vedotin, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), daclizumab, daratumumab, denosumab, edrecolomab, gemtuzumab zogamicin, HER-2 and Fc MAb (Medarex), ibritumomab tiuxetan, idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), ipilimumab, lintuzumab, LYM-1 -iodine 131 MAb (Techni clone), mitumomab, moxetumomab, ofatumumab, polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), ranibizumab, rituximab, veltuzumab, patritumab deruxtecan, datopotamab and trastuzumab.
[0217] Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 agents or antibodies such as cemiplimab, nivolumab, and pembrolizumab; anti-PD-Ll agents or antibodies such as atezolizumab, avelumab, and durvalumab; anti-CTLA-4 agents or antibodies such as ipilumumab and tremelimumab; anti-LAGl agents; and anti-OX40 agents. [0218] Non-limiting examples of colony-stimulating factors include darbepoetin alfa, epoetin alfa, epoetin beta, filgrastim, granulocyte macrophage colony stimulating factor, lenograstim, leridistim, mirimostim, molgramostim, nartograstim, pegfilgrastim, and sargramostim.
[0219] Non-limiting examples of additional immunotherapeutic agents include BiTEs, CAR- T cells, GITR agonists, imiquimod, immunomodulatory imides (IMiDs), mismatched double stranded RNA (Ampligen), resiquimod, SRL 172, and thymalfasin.
[0220] Targeted therapy agents include, for example, monoclonal antibodies and small molecule drugs. Non-limiting examples of targeted therapy agents include signal transduction inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, HER2 inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell-cycle inhibitors, angiogenesis inhibitors, matrix-metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factors (FGF) inhibitors, RAF inhibitor, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, BRAF-inhibitors, RAS inhibitor, gene expression modulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.
[0221] Non-limiting examples of tyrosine kinase inhibitors include EGFR inhibitors, HER2 inhibitors, JAK inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factors (FGF) inhibitors, RAF inhibitor, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, BRAF- inhibitors, RAS inhibitor, TYK2 inhibitors, c-MET inhibitors, RET inhibitors and ROS1 inhibitors.
[0222] Non-limiting examples of signal transduction inhibitors include tyrosine kinase inhibitors, multiple-kinase inhibitors, anlotinib, avapritinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, lonidamine, nilotinib, nintedanib, pazopanib, pegvisomant, ponatinib, vandetanib, and EGFR and/or HER2 inhibitory agents (i.e., other than Compound (1) or its salt).
[0223] Non-limiting examples of EGFR inhibitors include small molecule antagonists of EGFR such as afatinib, brigatinib, erlotinib, gefitinib, lapatinib, neratinib, dacomitinib, vandetanib, and osimertinib; and antibody-based EGFR inhibitors, including any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Antibody -based EGFR inhibitory agents may include, for example, those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al, 1995, Clin. Cancer Res. 1 : 1311-1318; Huang, S. M., et al., 1999, Cancer Res. 15:59(8): 1935-40; and Yang, X., et al., 1999, Cancer Res. 59: 1236-1243; monoclonal antibody Mab E7.6.3 (Yang, 1999 supra); Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof; specific antisense nucleotide or siRNA; afatinib, cetuximab; matuzumab; necitumumab; nimotuzumab; panitumumab; and zalutumumab.
[0224] Non-limiting examples of HER2 inhibitors include HER2 tyrosine kinase inhibitors such as afatinib, lapatinib, neratinib, and tucatinib; and anti-HER2 antibodies or drug conjugates thereof such as trastuzumab, trastuzumab emtansine (T-DM1), pertuzumab, margetuximab, trastuzumab deruxtecan (DS-8201a), and trastuzumab duocarmazine. [0225] Non-limiting examples of histone deacetylase (HD AC) inhibitors include belinostat, panobinostat, romidepsin, and vorinostat.
[0226] Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib.
[0227] Non-limiting examples of cell-cycle inhibitors, including CDK inhibitors, include abemaciclib, alvocidib, palbociclib, and riboci clib.
[0228] Non-limiting examples of anti-angiogenic agents (or angiogenesis inhibitors) include, but not limited to, matrix-metalloproteinase (MMP) inhibitors; VEGF inhibitors; EGFR inhibitors; TOR inhibitors such as everolimus and temsirolimus; PDGFR kinase inhibitory agents such as crenolanib; HIF-la inhibitors such as PX 478; HIF-2a inhibitors such as belzutifan and the HIF-2a inhibitors described in WO 2015/035223; fibroblast growth factor (FGF) or FGFR inhibitory agents such as B-FGF and RG 13577; hepatocyte growth factor inhibitors; KDR inhibitors; anti-Angl and anti-Ang2 agents; anti-Tie2 kinase inhibitory agents; Tek antagonists (US 2003/0162712; US 6,413,932); anti-TWEAK agents (US 6,727,225); ADAM distintegrin domain to antagonize the binding of integrin to its ligands (US 2002/0042368); anti-eph receptor and/or anti-ephrin antibodies or antigen binding regions (US 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; and 6,057,124); and anti-PDGF-BB antagonists as well as antibodies or antigen binding regions specifically binding to PDGF-BB ligands.
[0229] Non-limiting examples of matrix-metalloproteinase (MMP) inhibitors include MMP- 2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, prinomastat, RO 32-3555, and RS 13-0830. Examples of useful matrix metalloproteinase inhibitors are described, for example, in WO 96/33172, WO 96/27583, EP 1004578 , WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 0606046, EP 0931788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 1999/007675 , EP 1786785, EP 1181017, US 2009/0012085 , US 5,863,949, US 5,861,510, and EP 0780386. Preferred MMP -2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP -2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP -4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
[0230] Non-limiting examples of VEGF and VEGFR inhibitory agents include bevacizumab, cediranib, CEP 7055, CP 547632, KRN 633, orantinib, pazopanib, pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAP™. [0231] Other anti-angiogenic agents may include, but are not limited to, 2-methoxyestradiol, AE 941, alemtuzumab, alpha-D148 Mab (Amgen, US), alphastatin, anecortave acetate, angiocidin, angiogenesis inhibitors, (SUGEN, US), angiostatin, anti-Vn Mab (Crucell, Netherlands), atiprimod, axitinib, AZD 9935, BAY RES 2690 (Bayer, Germany, BC 1 (Genoa Institute of Cancer Research, Italy), beloranib, benefin (Lane Labs, US), cabozantinib, CDP 791 (Celltech Group, UK), chondroitinase AC, cilengitide, combretastatin A4 prodrug, CP 564959 (OSI, US), CV247, CYC 381 (Harvard University, US), E 7820, EHT 0101, endostatin, enzastaurin hydrochloride, ER-68203-00 (IV AX, US), fibrinogen-E fragment, Flk-1 (ImClone Systems, US), forms of FLT 1 (VEGFR 1), FR-111142, GCS-100, GW 2286 (GlaxoSmithKline, UK), IL-8, ilomastat, IM-862, irsogladine, KM-2550 (Kyowa Hakko, Japan), lenalidomide, lenvatinib, MAb alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, US), MAb VEGF (Xenova, UK), marimastat, maspin (Sosei, Japan), metastatin, motuporamine C, M-PGA, ombrabulin, 0X14503, PI 88, platelet factor 4, PPI 2458, ramucirumab, rBPI 21 and BPLderived anti angiogenic (XOMA, US), regorafenib, SC-236, SD-7784 (Pfizer, US), SDX 103 (University of California at San Diego, US), SG 292 (Telios, US), SU-0879 (Pfizer, US), TAN-1120, TBC-1635, tesevatinib, tetrathiomolybdate, thalidomide, thrombospondin 1 inhibitor, Tie-2 ligands (Regeneron, US), tissue factor pathway inhibitors (EntreMed, US), tumor necrosis factor-alpha inhibitors, tumstatin, TZ 93, urokinase plasminogen activator inhibitors, vadimezan, vandetanib, vasostatin, vatalanib, VE-cadherin-2 antagonists, xanthorrhizol, XL 784 (Exelixis, US), ziv-aflibercept, and ZD 6126.
[0232] The anticancer agent(s) that may be combined with Compound (1) may also be an active agent that disrupts or inhibits RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways or is a PD-1 and/or PD-L1 antagonist. Examples of which include, but are not limited to, a RAF inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a AKT inhibitor, a TOR inhibitor, an MCL-1 inhibitor, a BCL-2 inhibitor, a SHP2 inhibitor, a proteasome inhibitor, or an immune therapy, including monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAGl, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.
[0233] Non-limiting examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib.
[0234] Non-limiting examples of MEK inhibitors include binimetinib, CI- 1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and tram etinib. [0235] Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, ravoxertinib, ulixertinib, and ASTX029.
[0236] Non-limiting examples of PI3K inhibitors include 17-hydroxywortmannin analogs (e.g., WO 06/044453); AEZS-136; alpelisib; AS-252424; buparlisib; CAL263; copanlisib; CUDC-907; dactolisib (WO 06/122806); demethoxyviridin; duvelisib; GNE-477; GSK1059615; IC87114; idelalisib; INK1117; LY294002; Palomid 529; paxalisib; perifosine; PI-103; PI-103 hydrochloride; pictilisib (e.g., WO 09/036,082; WO 09/055,730); PIK 90; PWT33597; SF1126; sonolisib; TGI 00-115; TGX-221; XL147; XL-765; wortmannin; taselisib (GDC-0032); and ZSTK474.
[0237] Non-limiting examples of AKT inhibitors include Akt-1-1 (inhibits Aktl) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1, 2 (Barnett et al. (2005) Biochem. J.
385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); 1-H- imidazo[4,5-c]pyridinyl compounds (e.g., W005011700); indole-3 -carbinol and derivatives thereof (e.g., U.S. Patent No. 6,656,963; Sarkar and Li (2004) JNutr. 134(12 Suppl), 3493S- 3498S); perifosine, Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogues e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); triciribine (Yang et al. (2004) Cancer Res. 64, 4394-9); imidazooxazone compounds including trans-3 -amino- l-methyl-3-[4-(3 -phenyl-5H- imidazo[ 1 ,2-c]pyrido[3 ,4-e] [ 1 ,3 ]oxazin-2-yl)phenyl]-cyclobutanol hydrochloride (W O 2012/137870); afuresertib;; capivasertib; 8-[4-(l-aminocyclobutyl)phenyl]-9-phenyl-l,2,4- triazolo[3,4-f][l,6]naphthyridin-3(2H)-one (MK2206) and pharmaceutically acceptable salts thereof; AZD5363; trans-3 -amino- l-methyl-3-(4-(3 -phenyl-5H-imidazo[l,2-c]pyrido[3, 4- e][l,3]oxazin-2-yl)phenyl)cyclobutanol (TAS117) and pharmaceutically acceptable salts thereof; and patasertib.
[0238] Non-limiting examples of TOR inhibitors include deforolimus; ATP-competitive TORC1/TORC2 inhibitors, including PI- 103, PP242, PP30, and Torin 1; TOR inhibitors in FKBP12 enhancer, rapamycins and derivatives thereof, including temsirolimus, everolimus, WO 9409010; rapalogs, e.g. as disclosed in WO 98/02441 and WO 01/14387, e.g. AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3- hydroxy(hydroxymethyl)methylpropanoate]-rapamycin; 40-epi-(tetrazolyl)-rapamycin (also called ABT578); AZD8055; 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin, and other derivatives disclosed in WO 05/005434; derivatives disclosed in US 5,258,389, WO 94/090101, WO 92/05179, US 5,118,677, US 5,118,678, US 5,100,883, US 5,151,413, US 5,120,842, WO 93/111130, WO 94/02136, WO 94/02485, WO 95/14023, WO 94/02136, WO 95/16691, WO 96/41807, WO 96/41807 and US 5,256,790; and phosphorus-containing rapamycin derivatives (e.g., WO 05/016252).
[0239] Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845.
[0240] Non-limiting examples of SHP2 inhibitors include JAB-3068, RMC-4630, TNO155, SHP-099, RMC-4550, and SHP2 inhibitors described in WO 2019/167000, WO 2020/022323 and WO2021/033153.
[0241] Non-limiting examples of RAS inhibitors include AMG510, MRTX849, LY3499446, JNJ-74699157 (ARS-3248), ARS-1620, ARS-853, RM-007, and RM-008.
[0242] Additional non-limiting examples of anticancer agents that may be suitable for use include, but are not limited to, 2-ethylhydrazide, 2,2',2"-trichlorotriethylamine, ABVD, aceglatone, acemannan, aldophosphamide glycoside, alpharadin, amifostine, aminolevulinic acid, anagrelide, ANCER, ancestim, anti-CD22 immunotoxins, antitumorigenic herbs, apaziquone, arglabin, arsenic trioxide, azathioprine, BAM 002 (Novelos), bcl-2 (Genta), bestrabucil, biricodar, bisantrene, bromocriptine, brostallicin, bryostatin, buthionine sulfoximine, calyculin, cell-cycle nonspecific antineoplastic agents, celmoleukin, clodronate, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong- A), defofamine, denileukin diftitox, dexrazoxane, diaziquone, di chloroacetic acid, dilazep, discodermolide, docosanol, doxercalciferol, edelfosine, eflomithine, EL532 (Elan), elfomithine, elsamitrucin, eniluracil, etanidazole, exisulind, ferruginol, folic acid replenisher such as frolinic acid, gacytosine, gallium nitrate, gimeracil/oteracil/tegafur combination (S-l), glycopine, histamine dihydrochloride, HIT diclofenac, HLA-B7 gene therapy (Vical), human fetal alpha fetoprotein, ibandronate, ibandronic acid, ICE chemotherapy regimen, imexon, iobenguane, IT-101 (CRLX101), laniquidar, LC 9018 (Yakult), leflunomide, lentinan, levamisole + fluorouracil, lovastatin, lucanthone, masoprocol, melarsoprol, metoclopramide, miltefosine, miproxifene, mitoguazone, mitozolomide, mopidamol, motexafin gadolinium, MX6 (Galderma), naloxone + pentazocine, nitracrine, nolatrexed, NSC 631570 octreotide (Ukrain), olaparib, P-30 protein, PAC-1, palifermin, pamidronate, pamidronic acid, pentosan polysulfate sodium, phenamet, picibanil, pixantrone, platinum, podophyllinic acid, porfimer sodium, PSK (Polysaccharide-K), rabbit antithymocyte polyclonal antibody, rasburi embodiment, retinoic acid, rhenium Re 186 etidronate, romurtide, samarium (153 Sm) lexidronam, sizofiran, sodium phenylacetate, sparfosic acid, spirogermanium, strontium-89 chloride, suramin, swainsonine, talaporfin, tariquidar, tazarotene, tegafur-uracil, temoporfin, tenuazonic acid, tetrachlorodecaoxide, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, TLC ELL-12, tositumomab-iodine 131, trifluridine and tipiracil combination, troponin I (Harvard University, US), urethan, valspodar, verteporfin, zoledronic acid, and zosuquidar. [0243] Cisplatin can be administered at dose levels of from about 10 mg/m2, from about 15 mg/m2, from about 20 mg/m2, from about 30 mg/m2, from about 40 mg/m2, from about 50 mg/m2, from about 60 mg/m2, from about 80 mg/m2, from about 90 mg/m2 and up to about 250 mg/m2, up to about 225 mg/m2, up to about 200 mg/m2, up to about 175 mg/m2, up to about 150 mg/m2, up to about 125 mg/m2, up to about 110 mg/m2. The dosing level may be varied within the ranges such as from about 10 mg/m2 to about 250 mg/m2, from about 20 mg/m2 to about 150 mg/m2, preferably from about 50 mg to about 100 mg/m2, preferably from about 60 mg to about 90 mg/m2, preferably from about 70 mg to about 80 mg/m2, more preferably from about 72.5 mg to about 77.5 mg/m2, more preferably about 75 mg/m2. The administration dose level can be changed during an administration schedule, for example, the administration can begin with low dose for some time and then increased, or, the administration can begin with high dose for some time and then decreased.
[0244] The dosing of the cisplatin (or other platinum anticancer agent) can be continuous (daily; 7 days of administration in a week), intermittent (alternating one or more dosing days with one or more non-dosing days, such as 4 days-on/3 days-off), or once-per-cycle for example, depending the pharmacokinetics and a particular patient’s clearance/accumulation of the drug. The dosing schedule should be selected using sound medical judgement. Once- per-cycle administration of cisplatin is preferred. Preferably, the once-per-cycle administration occurs on the first day of a treatment cycle. For a 21-day treatment cycle, the once-per-cycle administration preferably happens on only the first day (day 1) of the treatment cycle.
[0245] The once-per-cycle dose may be administered as a single dose or multiple individual divided doses. For example, one intravenous injection containing about 50 to 100 mg/m2 of cisplatin can be administered on the first day of the treatment cycle. In another example, three (3) separate intravenous injections, each containing 20 mg/m2 of cisplatin, may be administered to the subject in a single day 60 mg/m2 on that day.
[0246] The dosing whether continuous, intermittent, or once-per-cycle is continued for a particular treatment cycle, typically at least a 21 day cycle, which can be repeated with or without a drug holiday. Longer or shorter cycles can also be used such as 7 days, 14 days, 18 days, 24 days, 28 days, 35 days, 42 days, or any range therebetween. The treatment cycle may be repeated without a drug holiday or with a drug holiday depending upon the subject. [0247] Carboplatin can be administered at dose levels of from about AUC 1.0 mg/mL/min, from about AUC 1.5 mg/mL/min, from about AUC 2.0 mg/mL/min, from about AUC 2.5 mg/mL/min, from about AUC 3.0 mg/mL/min, from about AUC 3.5 mg/mL/min, from about AUC 4.0 mg/mL/min, from about AUC 4.5 mg/mL/min and up to about AUC 10.0 mg/mL/min, up to about AUC 9.5 mg/mL/min, up to about AUC 9.0 mg/mL/min, up to about AUC 8.5 mg/mL/min, up to about AUC 8.0 mg/mL/min, up to about AUC 7.5 mg/mL/min, up to about AUC 7.0 mg/mL/min, up to about AUC 6.5 mg/mL/min, up to about AUC 6.0 mg/mL/min, up to about AUC 5.5 mg/mL/min. The dosing level may be varied within the ranges such as from about AUC 1 mg/mL/min to about AUC 10 mg/mL/min, from about 2.5 mg/mL/min to about AUC 7.5 mg/mL/min, from about 4.5 mg/mL/min to about AUC 5.5 mg/mL/min. Preferably carboplatin is administered at a dose level of AUC 5.0 mg/mL/min. The administration dose level can be changed during an administration schedule, for example, the administration can begin with low dose for some time and then increased, or, the administration can begin with high dose for some time and then decreased.
[0248] The dosing of the carboplatin(or other platinum anticancer agent) can be continuous (daily; 7 days of administration in a week), intermittent (alternating one or more dosing days with one or more non-dosing days, such as 4 days-on/3 days-off), or once-per-cycle for example, depending the pharmacokinetics and a particular patient’s clearance/accumulation of the drug. The dosing schedule should be selected using sound medical judgement. Once- per-cycle administration of cisplatin is preferred. Preferably, the once-per-cycle administration occurs on the first day of a treatment cycle. For a 21-day treatment cycle, the once-per-cycle administration preferably happens on only the first day (day 1) of the treatment cycle.
[0249] The once-per-cycle dose may be administered as a single dose or multiple individual divided doses. For example, one intravenous injection sufficient to give an AUC 5 mg/mL/min dose is administered over a period of 15 to 60 minutes.
[0250] The dosing whether continuous, intermittent, or once-per-cycle is continued for a particular treatment cycle, typically at least a 21-day cycle, which can be repeated with or without a drug holiday. Longer or shorter cycles can also be used such as 7 days, 14 days, 18 days, 24 days, 28 days, 35 days, 42 days, or any range therebetween. The treatment cycle may be repeated without a drug holiday or with a drug holiday depending upon the subject. [0251] Pemetrexed can be administered at dose levels of from about 50 mg/m2, from about 75 mg/m2, from about 100 mg/m2, from about 150 mg/m2, from about 200 mg/m2, from about 250 mg/m2, from about 300 mg/m2, from about 350 mg/m2, from about 400 mg/m2, from about 425 mg/m2, from about 450 mg/m2, from about 475 mg/m2 and up to about 1000 mg/m2, up to about 950 mg/m2, up to about 900 mg/m2, up to about 850 mg/m2, up to about 800 mg/m2, up to about 750 mg/m2, up to about 700 mg/m2, up to about 650 mg/m2, up to about 600 mg/m2, up to about 550 mg/m2. The dosing level may be varied within the ranges such as from about 50 mg/m2 to about 100 mg/m2, from about 250 mg/m2 to about 750 mg/m2, and from about 450 mg to about 550 mg/m2. Preferably, pemetrexed is administered in an amount of 500 mg/m2. The administration dose level can be changed during an administration schedule, for example, the administration can begin with low dose for some time and then increased, or, the administration can begin with high dose for some time and then decreased.
[0252] The dosing of the pemetrexed can be continuous (daily; 7 days of administration in a week), intermittent (alternating one or more dosing days with one or more non-dosing days, such as 4 days-on/3 days-off), or once-per-cycle for example, depending the pharmacokinetics and a particular patient’s clearance/accumulation of the drug. The dosing schedule should be selected using sound medical judgement. Once-per-cycle administration of pemetrexed is preferred. Preferably, the once-per-cycle administration occurs on the first day of a treatment cycle. For a 21-day treatment cycle, the once-per-cycle administration preferably happens on only the first day (day 1) of the treatment cycle.
[0253] The once-per-cycle dose may be administered as a single dose or multiple individual divided doses. For example, one intravenous injection containing about 450 to 550 mg/m2 of pemetrexed can be administered on the first day of the treatment cycle.
[0254] The dosing whether continuous, intermittent, or once-per-cycle is continued for a particular treatment cycle, typically at least a 21 day cycle, which can be repeated with or without a drug holiday. Longer or shorter cycles can also be used such as 7 days, 14 days, 18 days, 24 days, 28 days, 35 days, 42 days, or any range therebetween. The treatment cycle may be repeated without a drug holiday or with a drug holiday depending upon the subject. [0255] In some embodiments, the additional therapeutic agent is amivantamab.
Amivantamab can be administered at dose levels of from about 350 mg, from about 500 mg, from about 700 mg, from about 1000 mg up to about 1050 mg, up to about 1400 mg, up to about 1500 mg, up to about 1750 mg, up to about 1900 mg, up to about 2100 mg. The dosing level may be varied within the ranges such as from about 350 mg to about 700 mg, from about 1050 to about 1400 mg, from about 1400 mg to 1750 mg, and from about 1750 to about 2100 mg. The administration dose level can be changed during an administration schedule, for example, the administration can begin with low dose for some time and then increased, or, the administration can begin with high dose for some time and then decreased. Amivantamab can be administered at an infusion rate of from about 20 mL/hr, from about 35 mL/hr, from about 50 mL/hr, up to about 65 mL/hr, up to about 75 mL/hr, up to about 85 mL/hr, up to about 125 mL/hr, up to about 150 mL/hr.
[0256] The dosing of the amivantamab can be continuous (daily; 7 days of administration in a week), intermittent (alternating one or more dosing days with one or more non-dosing days, such as 4 days-on/3 days-off, once per week, etc.), or once-per-cycle for example, depending the pharmacokinetics and a particular patient’s clearance/accumulation of the drug. The dosing schedule should be selected using sound medical judgement.
[0257] Amivantamab may be administered as a single dose or multiple individual divided doses. For example, in a first week of amivantamab treatment, amivantamab may be administered across two doses separated by one or more days but still falling within a 7-day period. For example, on a first day, a first dose of amivantamab can be administered, including, for example, 350 mg or 500 mg, or 700 mg of amivantamab. On a second day, a second dose of amivantamab can be administered, including, for example 700 mg or 1050 mg or 1400 mg of amivantamab.
[0258] A typical exemplary dosing schedule for amivantamab includes weekly administration of 1050 mg with a first week infusion split into two days, a first day of 350 mg amivantamab administration and a second day of 700 mg amivantamab administration. Another typical exemplary dosing schedule for amivantamab includes weekly administration of 1400 mg with a first week infusion split into two days, a first day of 350 mg amivantamab administration and a second day of 1050 mg amivantamab administration. Typical dosing schedules include weekly administration for 4 weeks or cycles of 4 weeks or weekly administration for 4 weeks followed by administration every 2 or more weeks for an indefinite period (e.g., until disease progression or unacceptable toxicity). Week 5 and/or week 6 may be drug holiday. A subsequent cycle may forego the splitting of the first week administration described above. Subsequent cycles may be repeated indefinitely (e.g., until disease progression or unacceptable toxicity). Onset of adverse reactions may lead to, result in, or be mitigated by dosage reductions in subsequent weeks or treatment cycles. For example, an initial dose of 1050 mg may be reduced to 700 mg, then to 350 mg. An initial dose of 1400 mg may be reduced to 1050 mg, then to 700 mg, then to 350 mg. Amivantamab may be administered according to the drug label.
[0259] In some embodiments, the previous treatment with amivantamab is performed as described above. [0260] As used in the present disclosure, the term “combination,” “combined,” or a variation thereof is intended to define a therapy involving the use of two or more compound/drug combinations. The term can refer to compounds/drugs that are administered as part of the same overall dosage schedule. The respective dosages of two or more compounds/drugs can be different. The combination therapy is intended to embrace administration of these compounds/drugs in a sequential manner, that is, wherein each compound/drug is administered at a different time, as well as administration of these compounds/drugs, or at least two of the compounds/drugs, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each compound/drug or in multiple, single dosage forms for each of the compounds/drugs. Sequential or substantially simultaneous administration of each compound/drug can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues (e.g., buccal). The compounds/drugs can be administered by the same route or by different routes. For example, a first compound/drug of the combination selected may be administered by intravenous injection while the other compound/drug of the combination may be administered orally. Alternatively, for example, all compounds/drugs may be administered orally or all compounds/drugs may be administered by intravenous injection.
[0261] Combination therapy also can embrace the administration of the compounds/drugs as described above in further combination with other biologically active ingredients and nondrug therapies (e.g., surgery or radiation treatment). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of compound/drug and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the compound/drug, perhaps by days or even weeks.
[0262] Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of Compound (1) in this combination therapy can be determined as described herein. Radiation therapy can be administered through one of several methods, or a combination of methods, including, without limitation, external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachytherapy. The term “brachytherapy,” as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, 1-131, 1 -125, Y-90, Re- 186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present disclosure include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as 1-125, 1 - 131, Yb-169, Ir-192 as a solid source, 1-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of 1-125 or I- 131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive microspheres.
[0263] The presently described technology and its advantages will be better understood by reference to the following examples. These examples are provided to describe specific implementations of the present technology. By providing these specific examples, it is not intended limit the scope and spirit of the present technology. It will be understood by those skilled in the art that the full scope of the presently described technology encompasses the subject matter defined by the claims appending this specification, and any alterations, modifications, or equivalents of those claims.
EXAMPLES
Example 1:
[0264] Evaluation of TAS6417 efficacy in xenograft model harboring EGFR exon20 insertion mutation (insSVD).
[0265] Method: H1975insSVD was transplanted at 5^ 106 cells/mouse into the flank of male BALB/cA Jcl-nu mice. TAS6417 was orally administered at 100 mg/kg every day. Carboplatin (CBDCA) was administered intravenously at 50 mg/kg and 70 mg/kg in day 1 and day 8.
[0266] Vehicles and compounds: TAS6417 was mixed in 0.1 mol/L hydrochloric acid to generate a suspension. CBDCA was mixed in saline to generate a suspension.
Example 2:
[0267] Body weight change [0268] As an indicator of toxicity, the percent body weight change (BWC) was calculated for each group by equation below. Then the mean BWC was calculated from the BWC data of the individual animals and was plotted on a graph versus the number of days after grouping. BWC (%) = [(body weight on Day n) - (body weight on Day 0)] / (body weight on Day 0) x 100
[0269] The TAS6417 combination efficacy with CBDCA compared to TAS6417 single agent was examined. H1975ins SVD cells were implanted into the flank of mice. The TAS6417 combination efficacy with CBDCA was observed in this xenograft models (FIG. 1). TAS6417 combined with CBDCA resulted in a significant reduction in tumor growth compared TAS641 single agent (Aspin-welch test, p < 0.05). The combination setting showed the similar body weight change with TAS6417 single agent (FIG. 2).
[0270] Table 1 below presents results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin, at various maximum doses of Compound (1) (TAS6417). Plots of the tumor volumes presented in Table 1 below, along with additional time points between days 1 and 15, are presented in FIG. 1.
[0271] As can be seen, carboplatin alone did not result in inhibition of tumor volume increase. However, administration of Compound (1) (TAS6417) along or in combination with carboplatin showed dramatically smaller tumor volume after 15 days. Further, there is a statistically significant decrease in tumor volume (indicated by the bracket and asterisk in FIG. 1) when Compound (1) (TAS6417) is administered at a dosage of 100 mg/kg in combination with carboplatin. These data indicate a remarkable effect when both are administered together. There is no significant difference between TAS6414+CBDCA for 50 mg CBDCA vs for 70 mg CBDCA. Each combination shows the remarkable effect compared to a single agent.
[0272] FIG. 2 shows a plot of mean body weight change throughout treatment for the preclinical animal studies. The reasonable stability of the body weight throughout the treatment indicates that none of the regimens involves increased or unacceptable levels of toxicity.
Figure imgf000061_0001
[0273] Table 1. Results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or carboplatin, with a maximum dose of Compound (1) (TAS6417) of 200 mg/kg.
Example 3:
[0274] Phase l/2a study
[0275] Study Design
[0276] This international, multicenter, phase l/2a study (Clinical-Trials.gov identifier: NCT04036682) assessed the safety, tolerability, antitumor activity, and PK of Compound (1) in patients with recurrent or metastatic NSCLC harboring EGFR ex20ins mutations. This study was sponsored by Cullinan Pearl Corporation, a Cullinan Oncology Inc portfolio company.
[0277] Compound (1) was administered orally twice a day without food continuously in 21- day treatment cycles. Tumor assessments were performed at baseline, week 6, every 9 weeks until week 42, and every 12 weeks thereafter. Brain imaging was required with each restaging for patients with a history of central nervous system (CNS) metastases. Treatment was continued until disease progression, unacceptable adverse effects, withdrawal of consent, or could be discontinued at the investigator’s discretion. Treatment could be continued beyond radiographic disease progression in patients with continued clinical benefit. Safety evaluations, including clinical and laboratory assessments, were conducted at baseline and at regular intervals during treatment. Adverse event (AE) severity was graded according to the National
[0278] Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dose-limiting toxi cities (DLTs) were defined on the basis of treatment-related AEs (TRAEs) observed during the first 21 -day treatment cycle, although delayed events could be adjudicated as dose-limiting by the safety review committee (SRC).
[0279] Escalation began with a single-patient accelerated titration design with transition to a rolling six design upon the first occurrence of a grade >2 TRAE during cycle 1 (FIG. 6). Successive cohorts were treated with Compound 1 at 30, 45, 65, 100, and 150 mg twice a day; transition to the rolling six design occurred at the 100 mg dose level. The Protocol (online only) allowed for expanded enrollment of up to six patients in any cohort with an acceptable safety profile. For those cohorts in which at least 1/6 patients achieved a confirmed partial response (PR), enrollment could be expanded to a total of 13 patients, and for those cohorts in which 4/13 patients achieved a confirmed PR, enrollment could be expanded up to 36 total patients.
[0280] Eligibility Criteria
[0281] Eligible patients were age 18 years and older and had histologically or cytologically confirmed recurrent and/or metastatic NSCLC with an EGFR ex20ins mutation confirmed on local testing in a Clinical Laboratory Improvement Amendments of 1988, CLIA certified or equivalent laboratory. Central confirmation of the EGFR ex20ins was not required. Archival tumor tissue and circulating tumor deoxyribonucleic acid for molecular profiling were collected during screening.
[0282] Previous platinum-based chemotherapy was required, unless it was contraindicated or declined by the patient, with no restrictions on the number of previous therapies. Previous EGFR inhibitors were allowed, but previous ex20ins-specific TKIs were only allowed in the accelerated titration cohorts. Other requirements included the presence of measurable disease by Response Evaluation Criteria in Solid Tumors, 11 Eastern Cooperative Oncology Group performance status of 0-1, and adequate renal, hepatic, cardiac, and hematologic function.
Patients with radiographically stable, asymptomatic brain metastases were eligible. Exclusion criteria included spinal cord compression, history of drug-induced pneumonitis, or active infection.
[0283] Pharmacokinetic Analysis
[0284] Blood was collected to quantitate Compound 1 plasma concentrations after the first dose on cycle 1 day 1 (C1D1) and on cycle 1 day 15 (C1D15) in the dose-escalation cohorts. In dose-expansion, blood was collected on CID 1. PK data are included as of a PK data cutoff of November 2021. Compound 1 concentrations were determined using a validated liquid chromatography tandem mass spectrometry assay; details of PK analyses are available below. [0285] Statistical Analysis
[0286] All patients treated with Compound 1 as of the data cutoff are included in the safety population. All enrolled patients who were considered evaluable for response at the data cutoff are included in the efficacy population. Patients who received at least one dose of Compound 1 were included in PK analyses.
[0287] Study Oversight
[0288] All patients provided written informed consent for study participation. The study was conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was reviewed and approved by the institutional review board at each participating site. Study conduct was overseen by an SRC composed of study investigators, independent reviewers, and sponsor representatives.
[0289] RESULTS
[0290] Patients
[0291] A total of 91 patients were screened and 73 patients were enrolled and treated with Compound 1 as of the data cutoff on May 9, 2022. All 73 patients are included in both the safety and efficacy population. All patients began Compound 1 treatment between December 23, 2019, and October 21, 2021.
[0292] During dose escalation, eight patients were treated at 30 mg twice a day, one at 45 mg twice a day, 14 at 65 mg twice a day, 13 at 100 mg twice a day, and 11 at 150 mg twice a day. Enrollment at 150 mg twice a day was stopped by the SRC after the first 11 patients treated at this dose had an excess number of dose reductions (three patients) and drug discontinuations (three patients), as well as events meeting DLT criteria outside the 21 -day DLT evaluation period. The 100 mg twice a day dose level then entered phase 2a expansion with 36 patients planned per protocol. Three additional patients originally in screening for the 150 mg dose level were enrolled into the 100 mg dose level after closure of the 150 mg dose level, for a total of 39 patients treated at 100 mg twice a day.
[0293] Demographic information is summarized in Table 2. Enrolled T1 patients (32 [44%] male, 41 [56%] female) had a median age of 64 years (range, 36-82) and a median of two previous systemic therapies (range, 1-9), with 66% having >2 previous regimens (Table 2). All patients had adenocarcinoma histology and a documented EGFR ex20ins mutation, with a broad spectrum of distinct ex20ins mutations represented (Table 5 below). Seventy of 73 (96%) patients had received previous platinum-based chemotherapy; three patients were previously untreated (ineligible for or declined chemotherapy). Twenty-nine of 73 (40%) patients had received a previous EGFR inhibitor, including 13/73 (18%) with previous osimertinib and 3/73 (4%) with previous poziotinib or mobocertinib (Table 2). None had received amivantamab. Forty (55%) patients had received an immune checkpoint inhibitor (ICI); the ICI was part of the most recent treatment regimen in 22 (30%) patients.
Figure imgf000065_0001
[0294] TABLE 2. Summary of Patient Demographics. Abbreviations: CNS, central nervous system, ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; ex20ins, Insertions in EGFR exon 20; TKIs, tyrosine kinase inhibitors; aThree patients with no previous therapy (declined chemotherapy).
[0295] Safety
[0296] Treatment-emergent AEs (TEAEs) of any grade were observed in 73/73 (100%) patients treated across all dose levels, with grade >3 TEAEs in 39/73 (53%) patients (see details in Table 6). TRAEs of any grade occurred in 72/73 (99%) patients treated across all dose levels, with grade >3 TRAEs in 17/73 (23%) patients (Table 3). The most common TRAEs of any grade occurring in >15% patients included rash (80%), paronychia (32%), diarrhea (30%), fatigue (21%), anemia (19%), dry skin (18%), and nausea (16%; Table 3). Anemia (10%) was the only grade >3 TRAE observed in >5% patients (Table 7). [0297]
Figure imgf000066_0001
[0298] TABLE 3. Treatment-Related AEs Observed in >10% of Subjects Overall. Abbreviations: AEs, adverse events; CTCAE, Common Terminology Criteria for Adverse Events. aCTCAE v5.0.
[0299] Fifty-eight (80%) of patients had treatment-related rash, which was grade 1 in 70%, grade 2 in 28%, and grade 3 in 2%. Diarrhea occurred in 22 patients (30%) and was grade 1 in 68%, grade 2 in 23%, and grade 3 in 9%. No patients treated at Compound 1 doses of 100 mg twice a day or lower experienced grade >3 diarrhea or rash. Prophylactic antidiarrheal treatment was not required, and both diarrhea and rash were generally managed with conventional supportive medications.
[0300] There were 0/8, 0/1, 1/14, 1/39, and 4/11 DLTs at the 30, 45, 65, 100, and 150 mg dose levels, respectively (Table 8). Ten of 73 (14%) patients required dose reduction and 6/78 (8%) discontinued Compound 1 because of a drug-related AE. The six treatment-related discontinuations, two each at 65, 100, and 150 mg, were due to pneumonitis (n = 2), hepatic toxicity, 2 fatigue, 1 and allergic reaction. In total, there were four cases of pneumonitis deemed possibly related to Compound 1. There were 2/13, 5/39, and 3/11 dose reductions at the 65, 100, and 150 mg twice a day doses, respectively. Reasons for dose reduction included rash in three patients, and one patient each for to treatment). No drug-related deaths were observed. Forty-nine of 73 (67%) patients had discontinued treatment at the time of data cutoff, while 24/73 (33%) remained on treatment.
[0301] Efficacy
[0302] Objective responses (ORs) were observed across the full range of Compound 1 doses tested, including the starting dose of 30 mg twice a day (Table 4, FIGS. 3A-3B). Confirmed ORs occurred in T3; Fl 28/73 (38.4%; 95% CI, 27 to 49) patients across all dose levels, and in 16/39 (41%; 95% CI, 25 to 56) patients treated at 100 mg twice a day. The median time to response was 1.5 months (range, 1.5-6.2). Fifty-four of 73 (74%) patients experienced tumor regression at their initial 6-week disease assessment (FIG. 4), including 24/73 (33%) patients with an OR, and 43/73 F2 (59%) patients with stable disease (SD) at their first scan.
[0303]
Figure imgf000067_0001
PD, progressive disease; PR, partial response: RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. Ter RECIST v 1.1. [0305] With a median duration of follow-up of 11 months, the median duration of response (mDOR) was 10 months (95% CI, 6 to not calculable [NC]) across all dose levels. At the time of the data cutoff, the mDOR had not been reached for the 16 patients treated at 100 mg twice a day or for the 12 patients treated at doses <65 mg twice a day. Median progression- free survival (mPFS) was 10 months (95% CI, 6 to 12) across all dose levels, 12 months (95% CI, 5 to NC) at 100 mg twice a day, and 8 months (95% CI, 5 to 13) for patients treated at doses of 65 mg twice a day or less (FIG. 7).
[0306] Among 26 patients who received Compound 1 after a previous EGFR (non-ex20ins) inhibitor, eight (31%) experienced a PR, 13 (50%) had SD, and two (8%) had progressive disease (FIGS. 3A-3B). Among the three patients previously treated with another ex20ins- directed TKI (poziotinib, mobocertinib, or both), there were two PRs and one SD (FIGS. 3 A- 3B). In an exploratory analysis, the OR rate (ORR) was 41.5% among patients with near-loop exon 20 insertions (n = 52) and 22% among those with far-loop insertions (n = 9; FIG. 8).
[0307] Although preclinical studies suggest that Compound 1 may not efficiently cross the normal rodent blood-barrier, anecdotal examples of intracranial activity were observed in patients with CNS target lesions. Eighteen patients had nontarget CNS involvement and three had CNS target lesions. Among the three patients with measurable target CNS lesions, one had both systemic and intracranial PR (FIGS. 5 A and 5B), one had systemic and intracranial F3 SD, and one had CNS progression as the best response (details below).
[0308] Pharmacokinetics
[0309] Forty-seven patients were evaluable for PK after the first dose on C1D1 and 24 patients were evaluable for PK on CID 15 (FIG. 9 and Table 9). After fasting administration of Compound 1, median time to Cmax (Tmax) was in the range of 0.5-1.5 hours after the C1D1 or CID 15 dose. Both Cmax and area under the plasma concentration-time curve (AUC) increased in a dose-related manner and exhibited moderate to high variability, with intersubject variability (% coefficient of variation) in the range of 24%-86% across both days. The elimination half-life of Compound 1 is 3-4 hours after repeat twice-a-day dosing for 14 days. No notable accumulation was observed after 14 days on the basis of D15/D1 ratios of AUCTAU; mean values ranged from 1.05 to 1.25.
[0310] Response-evaluable patients included those with measurable disease at baseline and either at least one on-treatment tumor assessment or clinical progression before the first on- treatment tumor assessment. Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities, version 24.0. Responses in individual patients were determined on the basis of the assessment of the treating investigator using Response Evaluation Criteria in Solid Tumors, version 1.1. Objective responses (ORs) were confirmed by at least one sequential tumor assessment obtained at least 4 weeks from the original scan documenting a response. OR rates (ORRs) were calculated as [[(patients with a complete response 1 patients with a partial response [PR]) 4 number of patients] 3 100%]. A Simon two-stage design was used to assess efficacy of zipalertinib for all dose levels entering the phase I dose expansion phase.
[0311] The analysis included patients dosed in both the dose escalation and phase I dose expansion cohorts at a given dose level. The null hypothesis was an ORR of 10%, which was tested against an alternative hypothesis of ORR > 40%. If 0 responses were observed in the first six patients at given dose level, no further patients would be recruited at that dose level. Otherwise, seven additional patients could be recruited and, if four or more responses are observed in total, the null hypothesis would be rejected. This design yields a one-sided type I error rate of <5% and power of >80% when the true response rate is 40%. For dose levels entering the phase 2a dose expansion phase, an additional 23 patients could be recruited.
With a total of 36 patients enrolled at a dose level, the lower and upper 90% confidence limits for ORR would be within 15% of the point estimate.
[0312] The median duration of response was estimated using the Kaplan-Meier method and defined as the interval between the date of earliest response and the date of disease progression or death for any cause. Median progression-free survival was estimated using the Kaplan-Meier method and defined as the interval between the day of the first dose of study treatment to the first documentation of disease progression or death due to any cause, whichever occurred earlier. The median duration of follow-up was determined by simple frequentist median.
[0313] PK Analyses
[0314] Pharmacokinetic parameters (maximum observed plasma concentration [Cmax], area under the plasma-time concentration curve from time zero to the last observed time point [AUClast], area under the plasma concentration-time curve in a dosing interval of 12 hours [AUCTAU], terminal half-life [t 1/2], and accumulation ratio [AR]) were estimated by noncompartmental analysis Q: 11 (Phoenix WinNonlin Build 8.0.0.3176; ICON pic, Dublin, Ireland).
[0315] Safety
[0316] Treatment-related serious AEs included pneumonitis (n = 2), diarrhea (n = 1), and hypersensitivity reaction (n = 1). [0317] By investigator assessment, there were four cases of pneumonitis possibly related to zipalertinib (one at 65 mg twice a day, one at 150 mg twice a day, and two at 100 mg twice a day). One case of grade 1 pneumonitis resolved after a dose hold and corticosteroids with zipalertinib treatment resumed at the same dose, another patient with a history of pneumonitis with osimertinib also experienced grade 2 pneumonitis on zipalertinib, and one patient who had discontinued pembrolizumab and chemotherapy for progressive disease (PD) about 1 month before enrolling on the study experienced grade 3 pneumonitis on zipalertinib. In a fourth patient, grade 3 pneumonitis was initially considered possibly related to zipalertinib, but ultimately deemed to be unrelated to study treatment by the sponsor after the patient was diagnosed and treated for Pneumocystis jirovecii pneumonia on the basis of positive bronchoalveolar lavage.
[0318] There were four cases of grade 3 or 4 ALT/AST increase (one at <65 mg twice a day, two at 100 mg twice a day, and one at 150 mg twice a day), all in patients who had stopped pembrolizumab therapy within 50 days of initiation of zipalertinib therapy. Only one had measurable hepatic metastases. Two of the four patients discontinued zipalertinib because of AST/ALT elevation.
[0319] Reasons for treatment discontinuation included PD (30/49; 61%), AEs (12/49; 25%), withdrawal of consent (3/49; 6%) and other (2/49; 4%), and declining performance status and death (4/49; 8%).
[0320] Clinical Activity
[0321] The median number of cycles administered was 11 (range, 2-32), 11 (2-33), and 10 (1-17) for patients treated at doses of 65mg twice a day or less, 100 mg twice a day, and 150 mg twice a day, respectively.
[0322] PRs were observed across a spectrum of diverse epidermal growth factor receptor exon 20 insertion mutations (ex20ins) mutations. In this study, near-loop mutations were the most common mutation subtype, followed by the far-loop mutations and helical region with 52, 9, and 2 patients, respectively. There were 10 patients whose site of mutation was not reported by polymerase chain reaction testing. One patient had different ex20ins mutations identified in two different tumor specimens and was included in the unknown group. In an exploratory analysis of response rate by mutation subtype, the response rate was 41.5%, 22%, and 0% in the near-loop, far-loop, and helical region mutations, respectively (FIG. 8). The response rate in the unreported group was 40%.
[0323] Eighteen patients had nontarget central nervous system (CNS) involvement and three patients had CNS target lesions. Among the three patients with measurable target lesions in the brain, one patient (treated at the 100 mg dose level) achieved both a systemic and intracranial response at cycle 6, and remained in PR at cycle 16 at the time of the data cutoff (FIGS. 5A-5B). The second patient (treated at Q: 12 100 mg) had stable disease both systemically and intracranially after 1 year on treatment. The third patient (treated at 150mg) progressed with new lesions in the CNS at cycle 3.
Figure imgf000072_0001
[0324] TABLE 5. Summary of Specific Observed EGFR ex20ins Mutations in 73 Patients
With NSCLC. Abbreviations: EGFR, epidermal growth factor receptor; ex20ins, insertions in EGFR exon 20; NSCLC, non-small-cell lung cancer.
Figure imgf000073_0001
[0325] TABLE 6. TEAEs Regardless of Grade Observed in >10% of Subjects Overall (safety analysis set). Abbreviations: AE, adverse event;
CPI, checkpoint inhibitor; CTCAE, Common Terminology Criteria for Adverse Events; TEAE, treatment-emergent adverse events. aCTCAE
v5.0. b100 mg patient with grade 3 pneumonitis confounded by treatment with CPI and concurrent hydropneumothorax contralateral lung; 150 mg patient with grade 3 pneumonitis confounded by concurrent Pneumocystis infection, had stopped zipalertinib 3 weeks before the event; 100 mg patient with grade 1 (to be upgraded as grade 2) pneumonitis treated with steroids with resolution and continued therapy; 65 mg patient with grade 2 pneumonitis who previously had pneumonitis on osimertinib.
[0326]
Figure imgf000074_0001
Common Terminology Criteria for Adverse Events; TEAE, treatment-emergent adverse events. aCTCAE v5.0.
Figure imgf000075_0001
[0328] TABLE 8. Dose-Limiting Toxicities. Abbreviations: DLT, dose-limiting toxicity; EOT, End of Treatment
Figure imgf000075_0002
AR, accumulation ratio; AUCLST, Area under the plasma-time concentration curve from time zero to the last observed time point; AUCTAU, Area under the plasma concentration-time curve in a dosing interval of 12 hours; C1D1, cycle 1 day 1; C1D15, cycle 1 day 15; Cmax, maximum observed plasma concentration; CV, coefficient of variation; GM, geometric mean; max, maximum; min, minimum; NA, not applicable; TI/2, halflife, Tmax, time to Cmax.
Example 4:
[0330] Evaluation of TAS6417 combination efficacy in xenograft model harboring EGFR exon20 insertion mutation (insSVD).
[0331] Method: H1975insSVD was transplanted at 8* 106 cells/mouse into the flank of male BALB/cA Jcl-nu mice. TAS6417 was orally administered at 100 mg/kg every day. CBDCA and pemetrexed were administered intravenously at 60 mg/kg and 50 mg/kg respectively in day 1 and day 15.
[0332] Vehicles and compounds: TAS6417 was mixed in 0.1 mol/L hydrochloric acid to generate a suspension. CBDCA and pemetrexed were mixed in saline to generate a suspension.
Example 5:
[0333] Body weight change in xenograft model harboring EGFR exon20 insertion mutation (insSVD).
[0334] As an indicator of toxicity, the percent BWC was calculated for each group by equation below. Then the mean BWC was calculated from the BWC data of the individual animals and was plotted on a graph versus the number of days after grouping.
BWC (%) = [(body weight on Day n) - (body weight on Day 0)] / (body weight on Day 0) x 100
[0335] The TAS6417 combination efficacy with CBDCA/pemetrexed compared to TAS6417 single agent was examined. H1975ins SVD cells were implanted into the flank of mice. The TAS6417 combination efficacy with CBDCA/pemetrexed was observed in this xenograft models (FIG. 10). TAS6417 combined with CBDCA/pemetrexed resulted in a significant reduction in tumor growth compared TAS641 single agent (Aspin-welch test, p < 0.05). The combination setting showed the similar body weight change with TAS6417 single agent (Fig. H).
[0336] Table 10 below presents results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or CBDCA/pemetrexed. Plots of the tumor volumes presented in Table 10 below, along with additional time points between days 1 and 22, are presented in FIG. 10.
[0337] As can be seen, CBDCA/pemetrexed did not result in inhibition of tumor volume increase. However, administration of Compound (1) (TAS6417) along or in combination with CBDCA/pemetrexed showed dramatically smaller tumor volume after 22 days. Further, there is a statistically significant decrease in tumor volume (indicated by the bracket and asterisk in FIG. 10) when Compound (1) (TAS6417) is administered at a dosage of 100 mg/kg in combination with CBDCA/pemetrexed. These data indicate a remarkable effect when both are administered together.
[0338] FIG. 11 shows a plot of mean body weight change throughout treatment for the preclinical animal studies. The reasonable stability of the body weight throughout the treatment indicates that none of the regimens involves increased or unacceptable levels of toxicity.
Figure imgf000078_0001
[0339] Table 10. Results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or CBDCA/PEM (pemetrexed)
Example 6:
[0340] Evaluation of TAS6417 combination efficacy in allograft model harboring EGFR exon20 insertion mutation (insNPH).
[0341] Method: NIH/3T3 EGFR H773_V774insNPH was transplanted at 5* 106 cells/mouse into the flank of male BALB/cA Jcl-nu mice. TAS6417 was orally administered at 100 mg/kg every day. CBDCA and pemetrexed were administered intravenously at 60 mg/kg and 50 mg/kg respectively in day 1.
[0342] Vehicles and compounds: TAS6417 was mixed in 0.1 mol/L hydrochloric acid to generate a suspension. CBDCA and pemetrexed were mixed in saline to generate a suspension.
Example 7:
[0343] Body weight change in allograft model harboring EGFR exon20 insertion mutation (insNPH).
[0344] As an indicator of toxicity, the percent BWC was calculated for each group by equation below. Then the mean BWC was calculated from the BWC data of the individual animals and was plotted on a graph versus the number of days after grouping.
BWC (%) = [(body weight on Day n) - (body weight on DayO)] / (body weight on DayO) x 100
[0345] The TAS6417 combination efficacy with CBDCA/pemetrexed compared to TAS6417 single agent was examined. H1975ins SVD cells were implanted into the flank of mice. The TAS6417 combination efficacy with CBDCA/pemetrexed was observed in this xenograft models (FIGS. 12-13). TAS6417 combined with CBDCA/pemetrexed resulted in a significant reduction in tumor growth compared TAS641 single agent (Aspin-welch test, p < 0.05). The combination setting showed the similar body weight change with TAS6417 single agent (FIG. 14).
[0346] Table 11 below presents results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or CBDCA/pemetrexed, at various maximum doses of Compound (1) (TAS6417). Plots of the tumor volumes presented in Table 11 below, along with additional time points between days 1 and 8, are presented in FIGS. 12- 13.
[0347] As can be seen, CBDCA/pemetrexed did not result in inhibition of tumor volume increase. However, administration of Compound (1) (TAS6417) along or in combination with CBDCA/pemetrexed showed dramatically smaller tumor volume after 8 days. Further, there is a statistically significant decrease in tumor volume (indicated by the bracket and asterisk in FIG. 13) when Compound (1) (TAS6417) is administered at a dosage of 100 mg/kg in combination with CBDCA/pemetrexed. These data indicate a remarkable effect when both are administered together.
[0348] FIG. 14 shows a plot of mean body weight change throughout treatment for the preclinical animal studies. The reasonable stability of the body weight throughout the treatment indicates that none of the regimens involves increased or unacceptable levels of toxicity.
Figure imgf000081_0001
[0349] Table 11. Results from preclinical animal studies of various treatment regimens involving Compound (1) (TAS6417) and/or CBDCA/PEM (pemetrexed) at various maximum doses of Compound (1) (TAS6417).
Example 8:
[0350] Evaluation of TAS6417 efficacy in xenograft model harboring EGFR exon20 insertion mutation (insSVD) after recurrent of Amivantamab 10 mg/kg/day treatment [0351] Method: NCI-H1975 EGFR D770_N771 insSVD (H1975insSVD) was transplanted at 5* 106 cells/mouse into the flank of male BALB/cA Jcl-nu mice. Amivantamab was administered intraperitoneally at 10 mg/kg twice a week. TAS6417 was orally administered at 200 mg/kg every day.
[0352] Vehicles and compounds: TAS6417 was mixed in 0.1 mol/L hydrochloric acid to generate a suspension. Amivantamab was diluted in saline to generate a suspension.
[0353] The TAS6417 efficacy was examined in the model of Amivantamab pre-treatment. H1975ins SVD cells were implanted into the flank of mice. The Amivantamab was administered intraperitoneally at 10 mg/kg twice a week from the time the tumor volume reaches about 200 mm3. The tumor temporarily regressed but re-grew to about 500 mm3, Amivantamab-relapsed tumors, were randomly stratified into two groups of five animals per group to ensure uniform mean tumor volume. TAS6417 was administered orally at a dose of 200 mg/kg daily to one mice group, and the other continued to receive Amivantamab as a control group. TAS6417 resulted in a significant reduction in tumor growth compared Amivantamab (Aspin-Welch p-value < 0.05) (FIG.15).
Example 9:
[0354] Phase 2b Study
[0355] NCT05967689 (REZILIENT2) is a global, open-label, multicohort, phase 2b study designed to evaluate the efficacy and safety of zipalertinib (Compound (1), TAS6417) in adult patients with pathologically confirmed, locally advanced or metastatic NSCLC with EGFR ex20ins and other uncommon single or compound
[0356] EGFR mutations, including in patients with brain metastases and leptomeningeal disease. Eligible patients will be assigned to one of four cohorts depending on prior treatment and type of EGFR mutation.
[0357] Cohort A: Patients with EGFR ex20ins mutations who have progressed on or after first- line platinum-based chemotherapy and prior therapy targeting ex20ins mutations (administered together or separately) for advanced disease. Patients with brain metastases must be neurologically stable.
[0358] Cohort B : Patients with EGFR ex20ins mutations who have not received prior treatment for advanced disease.
[0359] Cohort C: Patients with ex20ins, other uncommon single or compound EGFR mutations, and active brain metastases (including leptomeningeal disease (LMD)) and who may or may not have received prior treatment for advanced disease.
[0360] Cohort D: Patients harboring other, uncommon, non-ex20ins, single or compound EGFR mutations who have progressed on or after standard systemic therapy.
[0361] The study has the following endpoints.
[0362] Primary: Investigator-assessed Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) vl.l
[0363] Secondary: Disease Control Rate (DCR), Duration of Response (DOR), Progression- Free Survival (PFS), Overall Survival (OS), Intracranial efficacy (ORR, DOR, DCR) per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) (Cohort C), safety and tolerability, pharmacokinetics (PK)
[0364] Exploratory: Population PK parameters and association with safety and efficacy, EGFR mutations/biomarkers from tumor samples and circulating tumor DNA (ctDNA).
Example 10:
[0365] Study to characterize anti-tumor activity of anEGFR ex20ins TKI in patients who have received prior amivantamab.
[0366] 31 patients had been enrolled as of January 2024. Patient data was as follows: median age: 62.5 years (39-77), median lines of prior therapy: 3 (1-6), prior PD1/L1 : 16 (51.6%), history of brain metastasis: 15 (48.4%).
[0367] Treatment-related Adverse Events occurring in > 10% of patients were: rash (38.7%), anemia (25.8%), paronychia (22.6%), dry skin (19.4%), nausea (19.4%), stomatitis (12.9%), pruritis (12.9%), and folliculitis (12.9%).
[0368] Treatment-related Grade > 3 Adverse Events were seen in 6 patients including 1 patient with 4 events (amylase increase, lymphocyte decrease, hypoxia, and pneumonitis), 1 patient with 2 events (anemia and rash), and 4 patients each with 1 event (folliculitis, ILD, hypertension, or rash).
[0369] Treatment-related AEs leading to dose reductions and discontinuations occurred in 2 patients (6.5%) and 2 patients (6.5%), respectively. At DCO, 18 patients were evaluable for response (at least 2 on treatment assessments or PD/death), of which 7 patients (38.9%) had partial response (PR), 9 (50.0%)stable disease (SD), and 1 (5.6%) unconfirmed partial response (uPR, pending confirmatory assessment). The disease control rate (CR + PR/uPR + SD) was 94.4%. Median duration of response and progression-free survival were not yet estimable.
[0370] In patients with heavily pretreated, advanced EGFR ex20ins mutant NSCLC who received prior amivantamab, zipalertinib demonstrated efficacy similar to that of patients that progressed after platinum-based chemotherapy and had a manageable safety profile.
Example 11:
[0371] Safety and Antitumor Activity of Zipalertinib in NSCLC Patients with EGFR Exon 20 Insertion (ex20ins) Mutations Who Received Prior Amivantamab
[0372] Zipalertinib (CLN-081, TAS6417) is a novel EGFR TKI which demonstrated a confirmed objective response rate (ORR) of 41% and manageable safety in a phase l/2a study in patients with ex20ins NSCLC after prior platinum-containing chemotherapy (JCO 2023). Here we present data from the phase 2b REZILIENT1 study of zipalertinib module C patients with EGFR ex20ins mutant NSCLC that progressed after prior amivantamab.
[0373] Methods: Patients that had progressed after at least 1 prior treatment including amivantamab were enrolled to receive zipalertinib at 100 mg oral twice daily. Tumor response was assessed by the investigator per RECIST vl .1. Stable, asymptomatic, or treated brain metastases were allowed.
[0374] Results: As of the 29 March 2024 data cut-off (DCO), 45 patients had been enrolled with median age of 62 years (33-85), median lines of prior therapy 3 (1-6), prior platinumbased chemotherapy 43 patients (96%), prior anti-PDl/Ll 20 patients (44%), prior EGFR TKIs 22 patients (49%), and history of brain metastasis 22 patients (49%).
[0375] FIG. 16 is a summary of patient demographics module C ami overall. Module C Ami Overall are Patients that progressed on amivantamab with or without prior mobocertinib and/or other ex20ins drugs (excluding patients that received mobocertinib and/or other exon20ins drugs only, but no amivantamab). FIG. 17 depicts a summary of the best overall tumor response based on investigator assessment per RECIST vl.l. This includes all treated patients with measurable disease at baseline who have received at least one dose of zipalertinib and had one of the following: at least two on treatment tumor assessments, death, or discontinuation due to disease progression (either clinical or per RECIST vl. l based on Investigator Assessment) NE=not evaluable, NA=Not applicable. FIG. 18 is a waterfall plot for the best change from baseline in target lesions. Efficacy population includes all treated patients with measurable disease at baseline who received at least one dose of zipalertinib and had one of the following: 1) at least two on treatment tumor assessments, 2) death, or 3) discontinuation due to disease progression (either clinical or per RECIST vl. l based on Investigator Assessment). Positive change in tumor size indicates tumor growth which negative change in tumor size indicates tumor reduction. If the dimension was recorded as “TOO SMAL TO MEASURE”, a default value of 5mm was assigned. If dimension is recorded as “INDTERMINATE”, the value from the previous assessment is assigned. Ami only includes patients receiving only prior amivantamab, Ami+ex20ins drug includes patients receiving prior amivantamab and mobocertinib or other EGFR exon 20 insertion (ex20ins) targeted tyrosine kinase inhibitors (TKIs).
[0376] FIG. 19 is a swim plot for study treatment duration. The study treatment duration is the end of treatment date - first dose date+1. For subjects still ongoing, the study duration is the data cutoff date - the first dose date+1. Ami only includes patients receiving only prior amivantamab, Ami+ex20ins drug includes patients receiving prior amivantamab and mobocertinib or other EGFR exon 20 insertion (ex20ins) targeted tyrosine kinase inhibitors (TKIs). FIG. 20 is a Kaplan Meier plot of progression free survival based on RECIST vl.l. Ami only includes patients receiving only prior Amivantamab, Ami+ex20ins drug includes patients receiving prior amivantamab and mobocertinib or other EGFR exon 20 insertion (ex20ins) targeted tyrosine kinase inhibitors (TKIs), Ami overall includes both patient populations (excluding patients that received mobocertinib and/or other ex20ins drugs only, but no amivantamab).
Treatment-related AEs (TRAEs) occurring in > 10% of patients were rash (38%), paronychia (36%), anemia (24%), dry skin (20%), dermatitis acneiform (16%), nausea (16%), and stomatitis (11%). Grade 3 TRAEs were reported in 14 patients (31%): occurring in >2 patients included anemia (4), rash (3), and pneumonitis/ILD (3). There were no grade 4 or 5 TRAEs. TRAEs leading to dose reductions and discontinuations occurred in 3 patients (7%) each. At DCO, 30 patients were evaluable for response (at least 2 on treatment assessments or PD/death), of which 1 pt (3%) had CR, 11 patients (37%) had partial response (PR), and 15 (50%) had stable disease (SD). The ORR was 40% and disease control rate (CR + PR + SD) was 90%. Median duration of response was not yet estimable and median PFS was 9.7 months. FIG. 21 is a summary of treatment-related adverse events of any grade observed in > 10% of patients. FIG. 22 is a summary of grade 3 treatment-related adverse events in > 2 patients. Example 12:
[0377] Phase 3 Study
[0378] NCT05973773 (REZILIENT3) is a global, randomized, controlled, open-label, phase 3 study to compare the efficacy and safety of zipalertinib (Compound (1), TAS6417) plus standard first-line platinum-based chemotherapy with chemotherapy alone in patients with locally advanced or metastatic nonsquamous NSCLC with EGFR ex20ins mutations.
[0379] The study was designed in 2 parts: safety lead-in (Part A) and randomized phase 3 (Part B). Part A was designed to confirm the recommended dose of zipalertinib in combination with standard chemotherapy (pemetrexed plus carboplatin or cisplatin) to be studied in Part B. In Part B, the efficacy and safety of zipalertinib plus chemotherapy will be compared with chemotherapy alone.
[0380] Part A
[0381] Treatment Regimen: Zipalertinib + pemetrexed + carboplatin or cisplatin. N-6-12 patients with EGFR ex20ins or other common single or compound EGFR mutations. Doselimiting toxicity assessment and dose selection for Part B.
[0382] Part B
[0383] Study population meet all of the following criteria: 1) Previously untreated, locally advanced or metastatic, nonsquamous NSCLC; 2) EGFR exon20ins mutation by local test; 3) >1 measurable lesion per RECIST vl. l; 4) ECOG PS 0 or 1; 5) Stable brain metastases permitted; and 6) Archival tumor tissue available for submission.
[0384] Prior EGFR TKI monotherapy (not targeting ex20ins mutations) lasting <8 weeks, with documented lack of response and resolved associated toxicities, and >2 weeks/4 halflives before randomization is allowed; alternatively, an approved prior adjuvant/ neoadjuvant treatment >6 months before the first dose of study treatment is allowed for early-stage NSCLC. Patients with previously treated brain metastases and stable central nervous system disease (defined as being neurologically stable and off corticosteroids for >2 weeks before enrollment) are eligible. Asymptomatic brain metastases <2 cm in size can be eligible for inclusion if, in the opinion of the investigator, immediate definitive treatment is not indicated. Patients with insufficient tissue may be eligible following discussion with the sponsor.
[0385] The study has the following endpoints:
[0386] Primary endpoint: PFS by Blinded Independent Center Review (BICR)
[0387] Secondary endpoints: PFS, ORR, DCR, and DOR by investigator assessment per RECIST vl.l; ORR, DOR, and DCR by BICR per RECIST vl.l; intracranial ORR, DCR, and DOR; Adverse events per Common Terminology Criteria for Adverse Events (CTCAE) v5.0; OS; safety; PK; and Patient Reported Outcomes (PROs).
[0388] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

CLAIMS:
1. A method of treating a subject with a cancer having at least one aberration in EGFR, the method comprising: administering to the subject an effective amount of (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof, wherein the subject has previously been treated with a systemic treatment which is at least one selected from the group consisting of a chemotherapeutic agent and a molecularly targeted therapeutic.
2. The method of claim 1, wherein the cancer is at least one selected from the group consisting of locally advanced and has metastasized to a brain of the subject.
3. The method of claim 1, wherein the cancer is locally advanced.
4. The method of any one of claims 1 to 3, wherein the cancer is unresectable.
5. The method of any one of claims 1 to 3, wherein the at least one aberration in EGFR is an EGFR mutation in at least one exon selected from the group consisting of exon 18, exon 19, exon 20, and exon 21.
6. The method of claim 5, wherein the at least one aberration in EGFR is an EGFR mutation in exon 20.
7. The method of any one of claims 1 to 3, wherein the at least one aberration in EGFR is an EGFR exon 20 insertion mutation.
8. The method of claim 7, wherein the EGFR exon 20 insertion mutation is at least one selected from the group consisting of D770_N771insX, V769_D770insX, H773_V774insX, P772_H773insX, N771_P772insX, A763_Y764insX, V774_C775insX, D761_E762insX, A763_Y764insTLA, Y764_V765insHH, A767_S768insASV, S768dupSVD, A767_S768insX, S768_V769insX, Y764_V765insX, V765_M766insX, A763_Y764insFQEA, A767_S768insTLA, S768_V769insVAS, S768_V769insAWT, V769_D770insGV, V769_D770insCV, V769_D770insDNV, V769_D770insGSV, V769_D770insGVV, V769_D770insMASVD, V769_D770insASV, V769_D770insGE, V769_D770delInsDGEL, D770_N771insSVD, D770_N771insNPG, D770_N771insKH, D770_N771insGNPH, D770_N771insAPW, D770_N771insD, D770_N771insDG, D770delinsGY, D770_N771insGL, D770_N771insN, D770_N771insNPH, D770_N77 tins SVP, D770_N771insSVQ, D770_N771insMATP, D770_N771insG, D770_N771insY, D770_N771insGF, D770_N771insGT, delD770insGY, N771_P772insH, N771_P772insN, delN771insGY, delN771insGF, N771delinsGY, N771_P772insRH, P772_H773insPR, P772_H773insYNP, P772_H773insDPH, P772_H773insDNP, P772_H773insQV, P772_H773insTPH, P772_H773insN, P772_H773insV, P772_H773insNP, P772_H773insNPH, H773_V774insH, H773_V774insNPH, H773_V774insPH, H773_V774insGNPH, H773_V774insG, H773_V774insGH, H773_V774insAH, H773_V774delInsLM, H773_V774delInsTY, and V774_C775insHV.
9. The method of any one of claims 1 to 3, wherein from about 10 to about 500 mg of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8- yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.
10. The method of any one of claims 1 to 3, wherein from about 30 to about 300 mg of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8- yljacrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.
11. The method of any one of claims 1 to 3, wherein (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice per day (BID).
12. The method of any one of claims 1 to 3, wherein (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject every day of a treatment cycle lasting 21 days.
13. The method of any one of claims 1 to 3, wherein lOOmg of (S)-N-(4-amino-6- methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or its pharmaceutically acceptable salt there is administered to the subject twice daily(BID), every day of a treatment cycle lasting 21 days.
14. The method of any one of claims 1 to 3, further comprising administering to the subject an effective amount of an additional therapeutic agent.
15. The method of claim 14, wherein the additional therapeutic agent is at least one selected from the group consisting of a chemotherapeutic agent, a tyrosine kinase inhibitor, and an immunotherapeutic agent.
16. The method of any one of claims 1 to 3, wherein the systemic treatment is a systemic treatment with a molecularly targeted therapeutic selected from the group consisting of an EGFR-targeting therapeutic other than Compound (1) and a non-EGFR-targeting therapeutic.
17. The method of claim 16, wherein the EGFR-targeting therapeutic other than Compound (1) is at least one selected from the group consisting of gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, poziotinib, mobocertinib, lazertinib, sunvozertinib, DZD9008, BDTX-189, necitumumab, pembrolizumab, brigatinib, icotinib, neratinib, olmutinib, rociletinib, vandetanib, lapatinib, duligotuzumab, panitumumab, zalutumumab, cetuximab, depatuxizumab, depatuxizumab mafodotin, imgatuzumab, matuzumab, and nimotuzumab.
18. The method of claim 17, wherein the EGFR-targeting therapeutic other than Compound (1) is osimertinib.
19. The method of claim 17, wherein the EGFR-targeting therapeutic other than Compound (1) is mobocertinib.
20. The method of claim 17, wherein the EGFR-targeting therapeutic other than Compound (1) is afatinib.
21. The method of claim 17, wherein the EGFR-targeting therapeutic other than Compound (1) is gefitinib.
22. The method of claim 17, wherein the EGFR-targeting therapeutic other than Compound (1) is poziotinib.
23. The method of claim 16, wherein the EGFR-targeting therapeutic other than Compound (1) is sunvozertinib.
24. The method of claim 16, wherein the non-EGFR-targeting therapeutic is at least one selected from the group consisting of crizotinib, ceritinib, alectinib, ensartinib, entrectinib, repotrectinib, belizatinib, alkotinib, foritinib, CEP-37440, TQ-B3139, PLB1003, zotizalkiv, conteltinib, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, bevacizumab, ipilimumab, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine.
25. The method of claim 24, wherein the non-EGFR-targeting therapeutic is nivolumab.
26. The method of claim 24, wherein the non-EGFR-targeting therapeutic is pembrolizumab.
27. The method of claim 24, wherein the non-EGFR-targeting therapeutic is cemiplimab.
28. The method of claim 24, wherein the non-EGFR-targeting therapeutic is atezolizumab.
29. The method of claim 24, wherein the non-EGFR-targeting therapeutic is durvalumab.
30. The method of any one of claims 1 to 3, wherein the subject failed to respond to the systemic treatment; or the subject had disease progression after the systemic treatment.
31. The method of any one of claims 1 to 3, wherein the systemic treatment is a systemic treatment with a chemotherapeutic agent selected from the group consisting of carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.
32. The method of claim 31, wherein the chemotherapeutic agent is cisplatin.
33. The method of claim 31, wherein the chemotherapeutic agent is carboplatin.
34. The method of any one of claims 1 to 3, wherein the subject has previously undergone at least two systemic treatments for the cancer.
35. The method of any one of claims 1 to 3, wherein the subject has previously undergone at least three systemic treatments for the cancer.
36. A method of treating a subject with a cancer having at least one aberration in EGFR, the method comprising: administering to the subject: an effective amount of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9- dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof; and an effective amount of a platinum anticancer agent.
37. The method of claim 36, wherein the cancer is a solid tumor.
38. The method of claim 36, wherein the cancer is a lung cancer.
39. The method of claim 36, wherein the cancer is a non-small cell lung cancer.
40. The method of claim 39, wherein the non-small cell lung cancer is a nonsquamous non-small cell lung cancer.
41. The method of claim 36, wherein the cancer is at least one selected from the group consisting of locally advanced and has metastasized to a brain of the subject.
42. The method of claim 36, wherein the cancer is locally advanced.
43. The method of claim 36, wherein the cancer is unresectable.
44. The method of claim 36, wherein the cancer has metastasized to a brain of the subject.
45. The method of claim 36, wherein the cancer has an EGFR amplification/overexpression.
46. The method of claim 36, wherein the cancer has an EGFR mutation in at least one exon selected from the group consisting of exon 18, exon 19, exon 20, and exon 21.
47. The method of claim 36, wherein the cancer has an EGFR mutation in exon 20.
48. The method of claim 36, wherein the cancer has an EGFR exon 20 insertion mutation.
49. The method of claim 36, wherein the subject is determined to have the aberration in EGFR prior to the administering.
50. The method of claim 36, wherein the subject has not previously undergone systemic treatment for the cancer.
51. The method of claim 36, wherein (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9- dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered orally to the subject.
52. The method of claim 36, wherein (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9- dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice per day (BID).
53. The method of claim 36, wherein (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9- dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject every day of a treatment cycle lasting 21 days.
54. The method of claim 36, wherein the platinum anticancer agent is administered to the subject intravenously.
55. The method of claim 36, wherein the platinum anticancer agent is administered on only a first day of a treatment cycle lasting 21 days.
56. The method of claim 1, further comprising administering to the subject an effective amount of pemetrexed.
57. The method of claim 56, wherein the pemetrexed is administered on only a first day of a treatment cycle lasting 21 days.
58. The method of claim 56, wherein the pemetrexed is administered to the subject intravenously.
59. The method of claim 36, wherein the (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)- 8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof and the platinum anticancer agent are administered for one to ten treatment cycles, each treatment cycle lasting 21 days.
60. The method of claim 36, wherein the (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)- 8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof and the platinum anticancer agent are administered for four treatment cycles, each treatment cycle lasting 21 days.
61. The method of claim 56, wherein the pemetrexed is administered for four treatment cycles, each treatment cycle lasting 21 days.
62. The method of claim 36, wherein from about 10 to about 500 mg of (S)-N-(4- amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.
63. The method of claim 36, wherein from about 30 to about 150 mg of (S)-N-(4- amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.
64. The method of any one of claims 1 to 3, wherein lOOmg of (S)-N-(4-amino-6- methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or its pharmaceutically acceptable salt there is administered to the subject twice daily(BID), every day of a treatment cycle lasting 21 days.
65. The method of claim 36, wherein the platinum anticancer agent is at least one selected from the group consisting of cisplatin and carboplatin.
66. The method of claim 36, wherein the platinum anticancer agent is cisplatin and from about 50 to about 100 mg/m2 of cisplatin is administered to the subject on only a first day of a treatment cycle lasting 21 days.
67. The method of claim 36, wherein the platinum anticancer agent is carboplatin and from about AUC 2.5 mg/mL/min to about AUC 7.5 mg/mL/min of carboplatin is administered to the subject on only a first day of a treatment cycle lasting 21 days.
68. The method of claim 56, wherein from about 250 to about 750 mg/m2 of pemetrexed is administered to the subject on only a first day of a treatment cycle lasting 21 days.
69. The method of claim 36, wherein the of (S)-N-(4-amino-6-methyl-5-(quinolin-3- yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject orally in the form of at least one selected from the group consisting of a tablet and a capsule.
70. The method of claim 69, wherein the tablet or capsule comprises a pharmaceutically acceptable carrier.
PCT/US2024/035743 2023-06-27 2024-06-27 Treatment methods for subjects with non-small cell lung cancer having an aberration in egfr WO2025006697A1 (en)

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