[go: up one dir, main page]

WO2024241273A1 - Méthodes de traitement du cancer du poumon non à petites cellules (cpnpc) - Google Patents

Méthodes de traitement du cancer du poumon non à petites cellules (cpnpc) Download PDF

Info

Publication number
WO2024241273A1
WO2024241273A1 PCT/IB2024/055039 IB2024055039W WO2024241273A1 WO 2024241273 A1 WO2024241273 A1 WO 2024241273A1 IB 2024055039 W IB2024055039 W IB 2024055039W WO 2024241273 A1 WO2024241273 A1 WO 2024241273A1
Authority
WO
WIPO (PCT)
Prior art keywords
egfr
seq
lazertinib
bispecific anti
met antibody
Prior art date
Application number
PCT/IB2024/055039
Other languages
English (en)
Inventor
Roland Knoblauch
Original Assignee
Janssen Biotech, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Biotech, Inc. filed Critical Janssen Biotech, Inc.
Publication of WO2024241273A1 publication Critical patent/WO2024241273A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present disclosure provides methods for treating EGFR-positive non-small cell lung cancer (NSCLC) in a subject that is treatment naive.
  • NSCLC non-small cell lung cancer
  • NSCLC neurostyrene-semiconductor kinase
  • EGFR a receptor tyrosine kinase controlling cell growth and division.
  • EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients.
  • EGFR exl9del or EGFR exon 21 L858R mutations are the most common EGFR mutations.
  • EGFR-TKIs EGFR tyrosine kinase inhibitors
  • the five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent.
  • Patients with EGFR exl9del or exon 21 L858R mutations have a real-world five-year overall survival of 19 percent.
  • a method of improving median progression free survival (PFS) in a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naive comprising administering to the subject or the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR/c-Met antibody, and (ii) a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of subjects with NSCLC harboring one or more EGFR mutations who are treatment-naive, the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR/c-Met antibody.
  • PFS median progression free survival
  • a method of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naive comprising administering to the subject or a population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR/c-Met antibody, and (ii) a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a reference subject or a reference population of subjects with NSCLC harboring one or more EGFR mutations who are treatment-naive, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR/c-Met antibody.
  • OS overall survival
  • NSCLC locally advanced or metastatic non-small cell lung cancer
  • EGFR epidermal growth factor
  • the lazertinib, or pharmaceutically acceptable salt or hydrate thereof is lazertinib mesylate. In some embodiments, the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is lazertinib mesylate monohydrate.
  • the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitution, or any combination thereof. In some embodiments, the one or more EGFR mutations comprise one or more exon 19 deletions. In some embodiments, the one or more EGFR mutations comprise exon 21 L858R substitution.
  • the subject has newly diagnosed, locally advanced or metastatic NSCLC that is not amenable to curative therapy including surgical resection or chemoradiation. In some embodiments, the curative therapy includes surgical resection or chemoradiation.
  • the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, in an amount of about 80 mg to about 320 mg orally once daily. In some embodiments, the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, in an amount of about 240 mg orally once daily.
  • the method elicits a clinical response in the subject according to RECIST vl. l criteria. In some embodiments, the method achieves a partial response or better in the subject according to RECIST vl.l criteria. In some embodiments, the clinical response comprises a median duration of response (DOR) of at least 25 months.
  • DOR median duration of response
  • the subject is progression-free after at least 11 months. In some embodiments, the subject is progression-free after at least 23 months. In some embodiments, the method achieves a PFS rate of 87% at 6 months, 73% at 12 months, 60% at 18 months, 48% at 24 months and 41% at 30 months in a population of the treatment naive subjects diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations.
  • EGFR epidermal growth factor receptor
  • the bispecific anti-EGFR/c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 4, a LCDR2 comprising SEQ ID NO: 5, and a LCDR3 comprising SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises a HCDR1 comprising SEQ ID NO: 7, a HCDR2 comprising SEQ ID NO: 8, a HCDR3 comprising SEQ ID NO: 9, a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising SEQ ID NO: 12.
  • HCDR1 heavy chain complementar
  • the first domain that specifically binds EGFR comprises a heavy chain variable region (VH) comprising SEQ ID NO: 13 and a light chain variable region (VL) comprising SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises the VH comprising SEQ ID NO: 15 and a VL comprising SEQ ID NO: 16.
  • the bispecific anti-EGFR/c-Met antibody is an IgGl isotype.
  • the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain (HC1) comprising SEQ ID NO: 17, a first light chain (LC1) comprising SEQ ID NO: 18, a second heavy chain (HC2) comprising SEQ ID NO: 19, and a second light chain (LC2) comprising SEQ ID NO: 20.
  • the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 1% to about 15%.
  • the bispecific anti-EGFR/c-Met antibody is administered intravenously to the subject. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 140 mg to about 2240 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1575 mg, about 1600 mg, about 2100 mg, or about 2240 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of 1050 mg if the subject has a body weight of less than 80 kg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of 1400 mg if the subject has a body weight of greater than or equal to 80 kg.
  • the bispecific anti-EGFR/c-Met antibody is administered subcutaneously or intradermally to the subject. In some embodiments, the bispecific anti- EGFR/c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.
  • the bispecific anti-EGFR/c-Met antibody is administered twice a week, once a week, once in two weeks, once in three weeks or once in four weeks.
  • the subject or population of subjects has a baseline brain metastasis, baseline liver metastasis, TP53 co-mutation, detectable baseline EGFRm ctDNA, or is without EGFRm ctDNA clearance at C3D1.
  • FIG. 1 shows an exemplary schematic overview of the MARIPOSA clinical study.
  • FIG. 2 shows Kaplan-Meier estimates of progression-free survival as assessed by blinded independent central review in the efficacy population of amivantamab-lazertinib versus osimertinib including the lazertinib monotherapy arm. PFS is shown by BICR results. The dashed lines indicate the median progression-free survival in the two groups and the tick marks indicate censoring of data. The median progression-free survival in the lazertinib group was 18.5 months (95% CI, 14.8 to 20.1).
  • FIG. 3 shows Kaplan-Meier estimates of progression-free survival as assessed by blinded independent central review in the efficacy population of amivantamab-lazertinib versus Osimertinib.
  • the dashed lines indicate the median progression-free survival in the two groups and the tick marks indicate censoring of data.
  • PFS by BICR is prolonged by 7. 1 months for Amivantamab+Lazertinib vs Osimertinib.
  • FIG. 4 shows PFS by subgroup.
  • FIG. 5 shows a Kaplan-Meier estimate of interim overall survival.
  • the efficacy population included all patients who had undergone randomization. Tick marks indicate censoring of data.
  • FIG. 6 shows a Consolidated Standards of Reporting Trials (CONSORT) diagram of patient disposition. 1375 patients were screened and 1074 underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib monotherapy, and 216 to lazertinib monotherapy); 1062 received at least one dose of trial treatment.
  • CONSORT Consolidated Standards of Reporting Trials
  • FIG. 7 shows Kaplan-Meier estimates of progression-free survival as assessed by blinded independent central review in patients with EGFR Exon 19 deletions (top) and in patients with EGFR Exon 21 L858R (bottom).
  • the efficacy population included all patients who had undergone randomization. In both panels, the hazard ratio for disease progression or death was obtained is from an unstratified proportional hazards model; tick marks indicate censoring of data. 95% confidence interval (CI) widths have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects.
  • EGFR denotes epidermal growth factor receptor.
  • FIG. 8 shows Kaplan-Meier estimates of progression-free survival as assessed by blinded independent central review in patients who are of Asian race (top) and in patients who are of non- Asian race (bottom).
  • the efficacy population included all patients who had undergone randomization.
  • the hazard ratio (HR) for disease progression or death was obtained is from an unstratified proportional hazards model; tick marks indicate censoring of data. 95% CI widths have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects.
  • FIG. 9 shows Kaplan-Meier estimates of progression-free survival as assessed by blinded independent central review in patients with a history of brain metastases (top) and in patients without history of brain metastases (bottom).
  • the efficacy population included all patients who had undergone randomization.
  • the hazard ratio for disease progression or death was obtained from an unstratified proportional hazards model; tick marks indicate censoring of data. 95% CI widths have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects.
  • FIG. 10 shows Kaplan-Meier estimates of extracranial progression-free survival as assessed by blinded independent central review in the efficacy population.
  • the efficacy population included all patients who had undergone randomization.
  • Extracranial progression- free survival was defined as time from randomization to disease progression (detected by extracranial scans) or death. If first progression was detected solely in the CNS, these patients were censored at the time of CNS disease progression.
  • the dashed lines indicate the median extracranial progression-free survival in the two groups; tick marks indicate censoring of data. 95% CI widths have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects.
  • CNS denotes central nervous system.
  • FIG. 11 shows waterfall plots of the best percent change from baseline in target lesions in the amivantamab-lazertinib group (top) and in the osimertinib group (bottom).
  • the number of patients with measurable disease at baseline was 421 in amivantamab-lazertinib group and 414 in the osimertinib group, as determined by blinded independent central review.
  • Target lesions were measured as the sum of the diameters.
  • the objective response rate was 86% (95% CI, 83 to 89) in the amivantamab-lazertinib group and 85% (95% CI, 81 to 88) in the osimertinib group.
  • FIG. 12 shows a Kaplan-Meier estimate of response duration among confirmed responders in the efficacy population.
  • the efficacy population included all patients who had undergone randomization. Included in this analysis were the 336 confirmed responders (out of the 421 patients with measurable disease at baseline by blinded independent central review) in the amivantamab-lazertinib group and the 314 confirmed responders (out of 414 patients) in the osimertinib group. Tick marks indicate censoring of data.
  • the objective response rate was 86% (95% CI, 83 to 89) in the amivantamab-lazertinib group and 85% (95% CI, 81 to 88) in the osimertinib group, with median response duration among confirmed responders of 25.8 months (95% CI, 20.1 to not estimable) and 16.8 months (95% CI, 14.8 to 18.5), respectively.
  • FIG. 13 shows a Kaplan-Meier estimate of time to treatment discontinuation in the efficacy population.
  • the efficacy population included all patients who had undergone randomization. Tick marks indicate censoring of data.
  • FIG. 14 shows Kaplan-Meier estimates of time to subsequent therapy in the efficacy population.
  • the efficacy population included all patients who had undergone randomization. Tick marks indicate censoring of data.
  • FIG. 15 shows a Kaplan-Meier estimate of progression-free survival after first subsequent therapy, which was defined from the time from randomization until the date of objective disease progression (by investigator) or death after initiation of subsequent anticancer systemic therapy, whichever occurs first.
  • the efficacy population included all patients who had undergone randomization. Tick marks indicate censoring of data.
  • FIG. 16 shows MARIPOSA study design and methods for high risk subgroups. Detection of circulating tumor (ctDNA) and co-mutations were analyzed by next-generation sequencing (NGS) of blood at baseline. Detection and clearance of Exl9del and L858R ctDNA in blood were analyzed with droplet digital PCR (ddPCR) at baseline and C3D 1.
  • ddPCR droplet digital PCR
  • FIG. 17 shows progression-free survival by BICR. Amivantamab + Lazertinib reduced the risk of progression or death by 30% and improved median PFS by 7.1 months.
  • FIG. 18 shows progression-free survival in patients with brain metastases.
  • Osimertinib showed a median PFS of 13.0 months among patients with brain metastases at baseline, indicating a poor prognostic subgroup.
  • amivantamab + lazertinib reduced the risk of progression or death by 31% vs Osimertinib.
  • FIG. 19 shows progression-free survival in patients with liver metastases.
  • Osimertinib showed a median PFS of 11.0 months among patients with liver metastases at baseline, indicating a poor prognostic subgroup.
  • amivantamab + lazertinib reduced the risk of progression or death by 42% vs Osimertinib.
  • FIG. 20 shows next-generation sequencing circulating tumor DNA (ctDNA) pathogenic mutation patterns at baseline. 85% (540/636 samples) had pathogenic alterations detected in ctDNA at baseline by NGS. TP53 co-mutations were observed in 56% from the amivantamab + lazertinib arm and 53% from the osimertinib arm. MET amplification occurred in 1 patient in each arm (neither with high-level amplification). Only pathogenic mutations occurring in >2% of patients are shown. Pathogenic mutations were detected with the Guardant Health G360® panel.
  • FIG. 21 shows progression-free survival in patients with TP53 co-mutations.
  • Osimertinib showed a median PFS of 12.9 months among patients with TP53 co-mutations at baseline, indicating a poor prognostic subgroup.
  • amivantamab + lazertinib reduced the risk of progression or death by 35% vs Osimertinib.
  • FIG. 22 shows detectable EGFR mutant (EGFRm) ctDNA at baseline and on treatment. Detection and clearance of Exl9del and L858R ctDNA in the blood were analyzed by ddPCR.
  • EGFRm EGFR mutant
  • FIG. 23 shows progression-free survival in Patients With Detectable Baseline ctDNA (Exl9del or L858R by Biodesix ddPCR).
  • Osimertinib showed a median PFS of 14.8 months among patients with detectable ctDNA at baseline, indicating a poor prognostic subgroup.
  • amivantamab + lazertinib reduced the risk of progression or death by 32% vs Osimertinib.
  • FIG. 24 shows progression-free survival in patients without cleared ctDNA at C3D1 (Exl9del or L858R by Biodesix ddPCR. Cycles were 28 days).
  • Osimertinib showed a median PFS of 9.1 months among patients without cleared ctDNA at C3D1, indicating a poor prognostic subgroup.
  • amivantamab + lazertinib reduced the risk of progression or death by 51% vs Osimertinib.
  • FIG. 25 shows progression-free survival for patients with high-risk features.
  • MARIPOSA study, 89% of patients had at least 1 high-risk feature detected at baseline (Patients with analyzable ctDNA by NGS at baseline were included in this pooled analysis.
  • High-risk features included baseline detectable ctDNA by NGS or baseline metastases of the liver or brain. For patients with detectable ctDNA, it was assumed TP53 co-mutations would be identified if present).
  • transitional terms “comprising,” “consisting essentially of,” and “consisting of’ are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of’ excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention.
  • Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of’ and “consisting essentially of.”
  • “Co-administration,” “administration with,” “administration in combination with,” “in combination with” or the like, encompass administration of the selected therapeutics or drugs to a single patient, and are intended to include treatment regimens in which the therapeutics or drugs are administered by the same or different route of administration or at the same or different time.
  • isolated refers to a homogenous population of molecules (such as synthetic polynucleotides, polypeptides vectors or viruses) which have been substantially separated and/or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step.
  • molecules such as synthetic polynucleotides, polypeptides vectors or viruses
  • isolated refers to a molecule that is substantially free of other cellular material and/or chemicals and encompasses molecules that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.
  • Treat”, “treating” or “treatment” of a disease or disorder such as cancer refers to accomplishing one or more of the following: reducing the severity and/or duration of the disorder, inhibiting worsening of symptoms characteristic of the disorder being treated, limiting or preventing recurrence of the disorder in subjects that have previously had the disorder, or limiting or preventing recurrence of symptoms in subjects that were previously symptomatic for the disorder.
  • Prevent means preventing that a disorder occurs in subject.
  • Diagnosing refers to methods to determine if a subject is suffering from a given disease or condition or may develop a given disease or condition in the future or is likely to respond to treatment for a prior diagnosed disease or condition, i.e., stratifying a patient population on likelihood to respond to treatment. Diagnosis is typically performed by a physician based on the general guidelines for the disease to be diagnosed or other criteria that indicate a subject is likely to respond to a particular treatment.
  • “Responsive”, “responsiveness” or “likely to respond” refers to any kind of improvement or positive response, such as alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Newly diagnosed refers to a subject who has been diagnosed with cancer (e.g., EGFR or c-Met expressing cancer) but has not yet received treatment (e.g., treatment for lung cancer).
  • cancer e.g., EGFR or c-Met expressing cancer
  • treatment e.g., treatment for lung cancer
  • “Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient.
  • “Refractory” refers to a disease that does not respond to a treatment. A refractory disease can be resistant to a treatment before or at the beginning of the treatment, or a refractory disease can become resistant during a treatment.
  • Relapsed refers to the return of a disease or the signs and symptoms of a disease after a period of improvement after prior treatment with a therapeutic.
  • Subject includes any human or nonhuman animal.
  • Nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • the terms “subject” and “patient” are used interchangeably herein.
  • “Reference subject” or “reference population of subjects” refers to a subject or population of subjects having a locally advanced or metastatic EGFR-mutated NCSLC harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naive and who have been administered osimertinib or lazertinib without the bispecific anti-EGFR/c-Met antibody instead of a combination therapy comprising the disclosed bispecific anti-EGFR/c-Met antibody and lazertinib.
  • the reference subject or the reference population of subjects can have substantially the same disease progression as the subject or population of subjects that are treated with the combination therapy comprising the disclosed bispecific anti-EGFR/c-Met antibody and lazertinib.
  • the population of subjects and reference population of subjects contain at least two subjects.
  • the population of subjects and reference population of subjects contain a number of subjects that allow for a statistically significant analysis of the improvement in safety and efficacy.
  • “About” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.
  • Cancer refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread) to other areas of a patient’s body.
  • EGFR or c-Met expressing cancer refers to cancer that has detectable expression of EGFR or c-Met or has EGFR or c-Met mutation or amplification.
  • EGFR or c- Met expression, amplification and mutation status can be detected using know methods, such as sequencing, fluorescent in situ hybridization, immunohistochemistry, flow cytometry or western blotting.
  • Epidermal growth factor receptor or “EGFR” refers to the human EGFR (also known as HER1 or ErbBl (Ullrich et al., Nature 309:418-425, 1984)) having the amino acid sequence shown in GenBank accession number NP_005219, as well as naturally-occurring variants thereof.
  • Hepatocyte growth factor receptor or “c-Met” as used herein refers to the human c-Met having the amino acid sequence shown in GenBank Accession No: NP_001120972 and natural variants thereof.
  • Bispecific anti-EGFR/c-Met antibody or “bispecific EGFR/c-Met antibody” refers to a bispecific antibody having a first domain that specifically binds EGFR and a second domain that specifically binds c-Met.
  • the domains specifically binding EGFR and c- Met are typically VH/VL pairs, and the bispecific anti-EGFR/c-Met antibody is monovalent in terms of binding to EGFR and c-Met.
  • “Specific binding” or “specifically binds” or “specifically binding” or “binds” refer to an antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens.
  • the antibody binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (KD) of about 5x1 O' 8 M or less, for example about IxlO' 9 M or less, about IxlO' 10 M or less, about IxlO' 11 M or less, or about 1x1 O' 12 M or less, typically with the KD that is at least one hundred-fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein).
  • KD equilibrium dissociation constant
  • the dissociation constant may be measured using known protocols.
  • Antibodies that bind to the antigen or the epitope within the antigen may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fasciculciris (cynomolgus, cyno) or Pan troglodytes (chimpanzee, chimp). While a monospecific antibody binds one antigen or one epitope, a bispecific antibody binds two distinct antigens or two distinct epitopes.
  • Antibodies is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific etc., dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity.
  • “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM).
  • Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3).
  • Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL).
  • the VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • CDR complementarity determining regions
  • CDR CDR
  • HCDR1 CDR1
  • HCDR2 CDR3
  • LCDR1 CDR2
  • LCDR3 CDR3
  • Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence.
  • IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4.
  • Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (K) and lambda (X), based on the amino acid sequences of their constant domains.
  • K kappa
  • X lambda
  • Antigen binding fragment refers to a portion of an immunoglobulin molecule that binds an antigen.
  • Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, the VH and the VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3- CDR3-FR4 portions, the HCDR1, the HCDR2 and/or the HCDR3 and the LCDR1, the LCDR2 and/or the LCDR3.
  • dAb domain antibodies
  • VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs where the VH/VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. W01998/44001, WO1988/01649, WO1994/13804 and W01992/01047.
  • scFv single chain Fv
  • “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C- terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation.
  • Monoclonal antibodies typically bind one antigenic epitope.
  • a bispecific monoclonal antibody binds two distinct antigenic epitopes.
  • Monoclonal antibodies may have heterogeneous glycosylation within the antibody population.
  • Monoclonal antibody may be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.
  • Recombinant refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.
  • Bispecific refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen.
  • the bispecific antibody may have crossreactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.
  • Biosimilar (of an approved reference product/biological drug, i.e., reference listed drug) refers to a biological drug that is highly similar to the reference drug with no clinically meaningful differences between the biosimilar and the reference drug in terms of safety, purity and potency, based upon data derived from (a) analytical studies that demonstrate that the biological product is highly similar to the reference drug; (b) animal studies (including the assessment of toxicity); and/or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biosimilar.
  • the biosimilar may be an interchangeable product that may be substituted for the reference product at the pharmacy without the intervention of the prescribing healthcare professional.
  • the biosimilar is to be expected to produce the same clinical result as the reference product in any given patient and, if the biosimilar is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch.
  • the biosimilar utilizes the same mechanisms of action for the proposed conditions of use to the extend the mechanisms are known for the reference product.
  • the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biosimilar have been previously approved for the reference product.
  • the route of administration, the dosage form, and/or the strength of the biosimilar are the same as those of the reference product and the biosimilar is manufactured, processed, packed or held in a facility that meets standards designed to assure that the biosimilar continues to be safe, pure and potent.
  • the biosimilar may include minor modifications in the amino acid sequence when compared to the reference product, such as N- or C-terminal truncations that are not expected to change the biosimilar performance.
  • Antagonist refers to a molecule that, when bound to a cellular protein, suppresses at least one reaction or activity that is induced by a natural ligand of the protein.
  • a molecule is an antagonist when the at least one reaction or activity is suppressed by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one reaction or activity suppressed in the absence of the antagonist (e.g., negative control), or when the suppression is statistically significant when compared to the suppression in the absence of the antagonist.
  • PD-(L)1 axis inhibitor refers to a molecule that inhibits PD-1 downstream signaling.
  • PD-(L)1 axis inhibitor may be a molecule that binds PD-1, PD-L1 or PD-L2.
  • Biological sample refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject.
  • Exemplary samples are biological fluids such as blood, serum and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, feces, sputum, mucosal secretions of the secretory tissues and organs, vaginal secretions, ascites fluids, fluids of the pleural, pericardial, peritoneal, abdominal and other body cavities, fluids collected by bronchial lavage, synovial fluid, liquid solutions contacted with a subject or biological source, for example, cell and organ culture medium including cell or organ conditioned medium, lavage fluids and the like, tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine needle aspirations, surgically resected tissue, organ cultures or cell cultures.
  • biological fluids such as blood, serum and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, feces, sputum, mucosal secretions of the secretory tissues and organs, vaginal secretions, ascites fluids
  • the biological sample is a blood sample.
  • the biological sample is a plasma sample.
  • the biological sample is a tumor sample.
  • the biological sample is circulating tumor DNA (ctDNA) that may be isolated from various other biological samples disclosed herein such as, but not limited to, a blood or plasma sample.
  • the biological sample is tumor DNA that may be isolated from, e.g., a tumor sample.
  • Low fucose or “low fucose content” as used in the application refers to antibodies with fucose content of about between 1 %- 15%.
  • Normal fucose or “normal fucose content” as used herein refers to antibodies with fucose content of about over 50%, typically about over 80% or over 85%.
  • treatment naive refers to a subject that has been diagnosed with locally advanced or metastatic NSCLC and has not yet received anti-cancer treatment for the NSCLC; the subject is therefore chemotherapy naive and TKI naive, e.g., has not received chemotherapy, or a tyrosine kinase inhibitor (including 1st generation TKI, 2nd generation TKI or 3rd generation TKI), or other anti-NSCLC treatment.
  • a method of treating a treatment naive subject may also be referred to as first-line or front line treatment.
  • CR Complete Response
  • PFS median
  • PFS median
  • OS overall survival
  • NSCLC locally advanced or metastatic non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of a bispecific anti-EGFR/c-Met antibody, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a reference subject or a reference population of subjects with NSCLC harboring one or more EGFR mutations who are treatment-naive, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR/c-Met antibody.
  • OS overall survival
  • NSCLC locally advanced or metastatic non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • OS overall
  • OS overall
  • the methods are performed on a subject and the methods provide an improvement in OS compared to a reference subject. In some embodiments, the methods are performed on a subject and the methods provide an improvement in OS compared to a reference population of subjects. In some embodiments, the methods are performed on a population of subjects and the methods provide an improvement in OS compared to a reference population of subjects.
  • the lazertinib, or pharmaceutically acceptable salt or hydrate thereof is lazertinib mesylate. In some embodiments of the disclosed methods, the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is lazertinib mesylate monohydrate.
  • the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitution, or any combination thereof. In some embodiments of the disclosed methods, the one or more EGFR mutations comprise one or more exon 19 deletions. In some embodiments of the disclosed methods, the one or more EGFR mutations comprise exon 21 L858R substitution.
  • the subject has newly diagnosed, locally advanced or metastatic NSCLC that is not amenable to curative therapy including surgical resection or chemoradiation.
  • the curative therapy includes surgical resection or chemoradiation.
  • the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, in an amount of about 80 mg to about 320 mg orally once daily. In some embodiments of the disclosed methods, the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, in an amount of about 240 mg orally once daily.
  • the method elicits a clinical response in the subject according to RECIST vl .1 criteria. In some embodiments of the disclosed methods, the method achieves a partial response or better in the subject according to RECIST vl . 1 criteria. In some embodiments of the disclosed methods, the clinical response comprises a median duration of response (DOR) of at least 1 year, at least 2 years, or at least 3 years. In some embodiments of the disclosed methods, the clinical response comprises a median duration of response (DOR) of at least 25 months. [00117] In some embodiments of the disclosed methods, the subject is progression-free after at least 20 months. In some embodiments of the disclosed methods, the subject is progression-free after at least 24 months.
  • DOR median duration of response
  • the subject is progression-free after at least 30 months. In some embodiments of the disclosed methods, the subject is progression-free after at least 11 months. In some embodiments of the disclosed methods, the subject is progression-free after at least 23 months. In some embodiments of the disclosed methods, the method achieves a PFS rate of 85% at 12 months, 65% at 24 months, and 51% at 36 months in a population of the treatment naive subjects diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations.
  • EGFR epidermal growth factor receptor
  • the method achieves a PFS rate of 87% at 6 months, 73% at 12 months, 60% at 18 months, 48% at 24 months, and 41% at 30 months in a population of the treatment naive subjects diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations In some embodiments of the disclosed methods, the method achieves a PFS rate of 86% in a population of the treatment naive subjects diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations.
  • EGFR epidermal growth factor receptor
  • the bispecific anti-EGFR/c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11 and the LCDR3 of SEQ ID NO: 12.
  • HCDR1 heavy chain complementarity determining region 1
  • LCDR2 of SEQ ID NO: 2
  • the first domain that specifically binds EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.
  • the bispecific anti-EGFR/c- Met antibody is an IgGl isotype.
  • the first domain that specifically binds EGFR comprises a heavy chain variable region (VH) comprising SEQ ID NO: 13 and a light chain variable region (VL) comprising SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises a VH comprising SEQ ID NO: 15 and a VL comprising SEQ ID NO: 16.
  • the bispecific anti-EGFR/c-Met antibody is an IgGl isotype.
  • the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19 and a second light chain (LC2) of SEQ ID NO: 20.
  • the bispecific anti-EGFR/c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 4, a LCDR2 comprising SEQ ID NO: 5 and a LCDR3 comprising SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises a HCDR1 comprising SEQ ID NO: 7, a HCDR2 comprising SEQ ID NO: 8, a HCDR3 comprising SEQ ID NO: 9, a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising SEQ ID NO
  • the first domain that specifically binds EGFR comprises a heavy chain variable region (VH) comprising SEQ ID NO: 13 and a light chain variable region (VL) comprising SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises a VH comprising SEQ ID NO: 15 and a VL comprising SEQ ID NO: 16.
  • the bispecific anti-EGFR/c-Met antibody is an IgGl isotype.
  • the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain (HC1) comprising SEQ ID NO: 17, a first light chain (LC1) comprising SEQ ID NO: 18, a second heavy chain (HC2) comprising SEQ ID NO: 19, and a second light chain (LC2) comprising SEQ ID NO: 20.
  • the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about between l% to about 15%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 2% to about 14%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 3% to about 13%.
  • the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 4% to about 12%. In some embodiments, the bispecific anti- EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 5% to about 11%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 1%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 2%.
  • the bispecific anti- EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 3%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 4%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 5%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 6%.
  • the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 7%. In some embodiments, the bispecific anti- EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 8%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 9%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 10%.
  • the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 11%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 12%. In some embodiments, the bispecific anti- EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 13%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 14%. In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about 15%.
  • the bispecific anti-EGFR/c-Met antibody disclosed herein may be administered in combination with a tyrosine kinase inhibitor (TKI) such as, but not limited to an epidermal growth factor receptor (EGFR TKI).
  • TKI tyrosine kinase inhibitor
  • EGFR TKI epidermal growth factor receptor
  • TKI is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.
  • the bispecific anti-EGFR/c-Met antibody disclosed herein may be administered in combination with lazertinib.
  • Lazertinib is an oral, third-generation, brain-penetrant EGFR TKI that targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR.
  • Lazertinib is described in WO 2016/060443 as N-(5-(4-(4-)
  • WO2018/194356 describes salts, hydrates and crystalline forms thereof; and WO2019/022485, WO2019/022486 and WO2019/022487 disclose processes for the production of lazertinib.
  • Lazertinib mesylate monohydrate is depicted below as a compound of Formula la, which may be referred to as JV-[5-[[4-[4-[(dimethylamino)methyl]-3-phenyl-lH-pyrazol-l- yl]pyrimidin-2-yl]amino]-4-methoxy-2-(morpholin-4-yl)phenyl]acrylamide methanesulfonate hydrate.
  • the methods of the present disclosure useful for treating a cancer in a subject in need thereof may comprise administering to a subject an effective amount of a combination therapy comprising a bispecific anti -epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) bispecific antibody and an EGFR tyrosine kinase inhibitor (TKI).
  • EGFR bispecific anti -epidermal growth factor receptor
  • c-Met hepatocyte growth factor receptor
  • TKI EGFR tyrosine kinase inhibitor
  • the methods of the present disclosure useful for improving median progression free survival (PFS) in a population of subjects with a cancer may comprise administering to a subject an effective amount of a combination therapy comprising a bispecific anti-epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) bispecific antibody and an EGFR tyrosine kinase inhibitor (TKI).
  • EGFR bispecific anti-epidermal growth factor receptor
  • c-Met hepatocyte growth factor receptor
  • TKI EGFR tyrosine kinase inhibitor
  • the methods of the present disclosure useful for improving overall survival (OS) in a subject or a population of subjects with a cancer may comprise administering to a subject an effective amount of a combination therapy comprising a bispecific anti -epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) bispecific antibody and an EGFR tyrosine kinase inhibitor (TKI).
  • a combination therapy comprising a bispecific anti -epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) bispecific antibody and an EGFR tyrosine kinase inhibitor (TKI).
  • the bispecific anti-EGFR/c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11 and the LCDR3 of SEQ ID NO: 12.
  • HCDR1 heavy chain complementarity determining region 1
  • LCDR2 of SEQ ID NO: 2
  • the first domain that specifically binds EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.
  • the bispecific anti-EGFR/c- Met antibody is an IgGl isotype.
  • the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19 and a second light chain (LC2) of SEQ ID NO: 20.
  • the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 1% to about 15%.
  • the bispecific anti-EGFR/c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 4, a LCDR2 comprising SEQ ID NO: 5, and a LCDR3 comprising SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises a HCDR1 comprising SEQ ID NO: 7, a HCDR2 comprising SEQ ID NO: 8, a HCDR3 comprising SEQ ID NO: 9, a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising SEQ ID NO
  • the first domain that specifically binds EGFR comprises a heavy chain variable region (VH) comprising SEQ ID NO: 13 and a light chain variable region (VL) comprising SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises a VH comprising SEQ ID NO: 15 and a VL comprising SEQ ID NO: 16.
  • the bispecific anti-EGFR/c-Met antibody is an IgGl isotype.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 350 mg, about 700 mg, about 1050 mg, or about 1400 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 350 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 750 mg. In some embodiments, the bispecific anti-EGFR/c- Met antibody is administered at a dose of about 800 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 850 mg.
  • the bispecific anti- EGFR/c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met
  • the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 4, a LCDR2 comprising SEQ ID NO: 5, and a LCDR3 comprising SEQ ID NO: 6,
  • the second domain that binds c-Met comprises a HCDR1 comprising SEQ ID NO: 7, a HCDR2 comprising SEQ ID NO: 8, a HCDR3 comprising SEQ ID NO: 9, a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising HCDR1 comprising SEQ ID NO:
  • the bispecific anti- EGFR/c-Met antibody comprises a first heavy chain (HC1) comprising SEQ ID NO: 17, a first light chain (LC1) comprising SEQ ID NO: 18, a second heavy chain (HC2) comprising SEQ ID NO: 19, and a second light chain (LC2) comprising SEQ ID NO: 20.
  • NSCLC non-small cell lung cancer
  • the bispecific anti- EGFR/c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11 and the LCDR3 of SEQ ID NO: 12.
  • HCDR1 heavy chain complementarity determining region 1
  • bispecific anti-EGFR/c- Met antibody is an IgGl isotype.
  • 20b The method of any one of embodiments lb-19b, wherein the bispecific anti- EGFR/c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19 and a second light chain (LC2) of SEQ ID NO: 20.
  • bispecific anti- EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 1% to about 15%.
  • CHRYSALIS (NCT02609776) is a Phase 1, first-in-human, open-label dose escalation and expansion study of amivantamab in combination with lazertinib (Study 61186372EDI1001, known as EDI1001).
  • enrolled subjects must have been diagnosed with EGFR Exon 19del or exon 21 L858R activating mutation and be treatment-naive for metastatic disease, without access to third generation TKI in the front-line setting or have progressed after front-line treatment with first or second generation or have been treated with a third generation TKI in either the front-line or second line setting.
  • the initial dose cohort combined amivantamab 700/1050 mg (i.e., 700 mg in subjects weighing ⁇ 80 kg and 1050 mg in subjects weighing >80 kg) and lazertinib 240 mg.
  • the subsequent dose cohort combined each agent at its RP2D from monotherapy studies, namely amivantamab 1050/1400 mg and lazertinib 240 mg. Both dose cohorts were cleared without identification of a dose-limiting toxicity and additional subjects were enrolled.
  • Pharmacokinetic (PK) data demonstrated a lack of drug-drug interaction, as the PK profile of each drug when administered in combination was consistent with the PK profile of each drug when administered as a monotherapy.
  • RP2D was the recommended monotherapy of each molecule: amivantamab, 1050 mg ( ⁇ 80 kg)/1400 mg (>80 kg), intravenous dosing, Cl once weekly, then every 2 weeks and 240 mg lazertinib oral daily dosing.
  • the purpose of the study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of amivantamab as a monotherapy and in combination with lazertinib, and to determine the recommended Phase 2 dose (RP2D) (monotherapy), recommended Phase 2 combination dose (RP2CD) (combination therapy), and to determine recommended Phase 2 Dose (RP2Q3W) with combination chemotherapy (amivantamab in combination with standard of care carboplatin and pemetrexed) in 21 day treatment cycle for participants with advanced non-small cell lung cancer (NSCLC).
  • R2D Phase 2 dose
  • RP2CD recommended Phase 2 combination dose
  • RP2Q3W recommended Phase 2 Dose
  • Part 1 is a Amivantamab Monotherapy and Combination Dose Escalations and Part 2 Amivantamab Monotherapy and Combination Dose Expansions.
  • participants with evaluable NSCLC will be enrolled into cohorts at increasing dose levels of Amivantamab monotherapy, the RP2CD of the Amivantamab and lazertinib combination which will be administered in 28 day treatment cycles, and RP2Q3W of Amivantamab in combination with standard of care carboplatin and pemetrexed (chemotherapy combination) which will be administered in 21 day treatment cycles.
  • the dose will be escalated until the maximum tolerated dose (MTD, or maximum administered dose (MAD), if no MTD is found) is reached.
  • MTD maximum tolerated dose
  • MAD maximum administered dose
  • Part 1 will follow a traditional 3+3 design. At each dose level, 3 participants will complete Cycle 1. If no dose limiting toxicity (DLT) occurs in these 3 participants, then escalation will continue in a new cohort of 3 participants. Data from Part 1 will be used to determine one or more RP2D regimen(s).
  • AUCtau Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Amivantamab [Time Frame: Up to EOT (30 days after last dose)].
  • the AUCtau is the area under the serum concentration-time curve during a dose interval time period (tau).
  • AUCtau Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Amivantamab [Time Frame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)].
  • the AUCtau is the area under the serum concentration-time curve during a dose interval time period (tau).
  • Tmax Time to Reach Maximum Observed Serum Concentration (Tmax) of Lazertinib [Time Frame: Cycle 1 Day 1: predose through EOT (30 [+7] days after last dose [Cycle 4 Day 15]) (each cycle is of 28 days)]. Tmax is defined as time to reach maximum observed serum concentration of lazertinib.
  • PFS Progression-Free Survival
  • TTF Time to Treatment Failure
  • OS Overall Survival
  • NSCLC non-small cell lung cancer
  • Participants must have either progressed after prior standard of care therapy (Cohorts C and hepatocyte growth factor receptor gene [MET]-1: epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKI]; Cohort D: platinum-based chemotherapy; MET-2: per regional standard of care; Cohorts wild-type adenocarcinoma (WT-Ad) and wild-type squamous cell carcinoma (WT-Sq): platinum-containing chemotherapy and programmed death- 1/ ligand-1 (PD-1/L1) therapy, either as a combined regimen or as separate lines of therapy) for metastatic disease, or be ineligible for, or have refused all other currently available therapeutic options.
  • MET hepatocyte growth factor receptor gene
  • EGFR epidermal growth factor receptor
  • TKI tyrosine kinase inhibitor
  • WT-Ad wild-type adenocarcinoma
  • WT-Sq platinum-containing
  • EGFR epidermal growth factor receptor
  • Cohort C Participants with primary EGFR mutated disease, with a documented EGFR alteration (example, C797S) mediating resistance to previous treatment with a third generation EGFR TKI (for example, osimertinib), in participants with primary Exon 20ins disease, the documented EGFR alteration may arise following treatment with a TKI with known activity against Exon 20ins disease (for example, poziotinib).
  • Cohort D participants must have been previously diagnosed with an EGFR Exon 20 insertion and have not been previously treated with a TKI with known activity against Exon 20ins disease (example, poziotinib).
  • Cohort MET-1 Participants with documented primary EGFR mutated disease and documented MET amplification or MET mutation after progression on any EGFR TKI. Participants with disease characterized by both MET amplification and EGFR resistance mutations to prior third generation EGFR TKI will be preferentially enrolled into Cohort C. Participants may have received or have been intolerant to prior platinum-based chemotherapy.
  • Cohort MET-2 Participants with documented primary MET Exon 14 skipping mutation non-small cell lung cancer (NSCLC).
  • Cohort E (combination Amivantamab and lazertinib): Participants must have been diagnosed with EGFR exon 19del or exon 21 L858R activating mutation and have progressed after first or second-line treatment with a third generation TKI (e.g., osimertinib).
  • Cohort WT-Ad Participant must have been diagnosed with NSCLC of adenocarcinoma histology, with positive EGFR and/or MET expression as detected on a validated immunohistochemistry (IHC) assay performed by the central laboratory and have progressed on prior platinum containing chemotherapy and PD- 1/L1 therapy, either as a combined regimen or as a separate line of therapy.
  • IHC immunohistochemistry
  • Eligibility may be determined through IHC analysis of either archival (pre-screening) or mandatory fresh tumor tissue collected during the Screening period.
  • Cohort WT-Sq Participant must have been diagnosed with NSCLC of squamous cell carcinoma histology, with positive EGFR and/or MET expression as detected on a validated IHC assay performed by the central laboratory and have progressed on prior platinum- containing chemotherapy and PD-1/L1 therapy, either as a combined regimen or as a separate line of therapy.
  • Eligibility may be determined through IHC analysis of either archival (pre-screening) or mandatory fresh tumor tissue collected during the Screening.
  • Exclusion Criteria • Participant has uncontrolled inter-current illness, including but not limited to poorly controlled hypertension, or diabetes, ongoing or active infection, (that is, has discontinued all antibiotics for at least one week prior to first dose of study drug), or psychiatric illness/social situation that would limit compliance with study requirements. Participants with medical conditions requiring chronic continuous oxygen therapy are excluded. For Part 1 Chemotherapy Combination Cohort only: additionally, participants with active bleeding diathesis.
  • Chemotherapy Combination Cohort only Any previous treatment with systemic anti -cancer immunotherapy in the past 3 months or localized radiotherapy to lung within the past 6 months.
  • Cohorts A and B Prior treatment with chemotherapy for metastatic disease is not allowed unless the tumor mutation carries de-novo resistance to EGFR TKI (example, Exon 20 insertions).
  • Cohort C and MET-1 Prior treatment with more than 2 lines of cytotoxic chemotherapy for metastatic disease (maintenance therapy is not included).
  • Cohort D Previous treatment with an EGFR TKI with activity against EGFR Exon 20 insertions (such as poziotinib).
  • Cohort E (combination Amivantamab and lazertinib): Any previous treatment in the metastatic setting with other than a first, second, or third generation EGFR TKI.
  • Cohorts WT-Ad and WT-Sq more than three lines of prior systemic therapy in the metastatic setting.
  • Participant has a history of malignancy other than the disease under study within 3 years before Screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with or minimal risk of recurrence within a year from Screening).
  • CHRYSALIS (NCT02609776) evaluated the combination of amivantamab (ami) and lazertinib (laz) in treatment-naive patients (pts) with epidermal growth factor receptor (EGFR)-mutated NSCLC. As previously reported, 20 pts achieved a partial response (overall response rate of 100%) but interpretation of long-term outcomes was limited by the length of follow up (Cho Ann Oncol 2020;31:suppl_4, 12580; Cho J Thorac Oncol 2022;17:S126, Pl. 16-01). Herein, long-term results are presented from this treatment-naive cohort.
  • the treatment-naive cohort enrolled pts with EGFR exon 19 deletion (exl9del) or exon 21 L858R mutated advanced NSCLC. All pts received 1050 mg IV ami (1400 mg if >80 kg) and 240 mg oral laz. Response was assessed by the investigator per RECIST vl.l. Circulating tumor DNA (ctDNA) was analyzed from plasma samples prior to initiation of treatment, at Cycle 3 Day 1, and at end of treatment (EOT).
  • ctDNA Circulating tumor DNA
  • MARIPOSA is an international Phase 3 randomized study of amivantamab and lazertinib combination therapy versus osimertinib versus lazertinib as first- line treatment in approximately 1000 subjects with EGFR-mutated locally advanced or metastatic NSCLC (Study 73841937NSC3003, also known as NSC3003, and Mariposa). [00247] The study includes a screening phase, a Treatment Phase, and a Follow-up Phase. Participants must complete screening procedures within 28 days before randomization. To be randomized, all participants must have been previously diagnosed with NSCLC, characterized by exon 19del or exon 21 L858R substitution EGFR mutations.
  • the Treatment Phase for a participant will begin on Cycle 1 Day 1 and continue as 28-day cycles until the End of Treatment visit, approximately 30 days after discontinuation of study treatment. Participants who discontinue study treatment for any reason will be followed for survival and symptomatic progression in the Follow-up Phase.
  • the Follow-up Phase starts after the End of Treatment visit and continues until the end of study, death, lost to follow-up, or withdrawal of consent, whichever comes first.
  • the purpose of this study is to assess the efficacy of the amivantamab and lazertinib combination, compared with osimertinib, in participants with epidermal growth factor receptor (EGFR) mutation (exon 19 deletions [Exon 19del] or exon 21 L858R substitution) positive, locally advanced or metastatic non-small cell lung cancer (NSCLC).
  • EGFR epidermal growth factor receptor
  • NSCLC metastatic non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • Osimertinib and Lazertinib are EGFR tyrosine kinase inhibitors (TKIs).
  • Amivantamab is a novel bispecific antibody that targets the extracellular domain of both EGFR and MET and can inhibit tumor growth driven by EGFR and mesenchymal-epithelial transition (MET) receptors.
  • Lazertinib inhibits primary activating exon 19del and exon 21 L858R substitution EGFR mutations, and the EGFR T790M+ resistance mutation.
  • Intervention Model Parallel Assignment.
  • Masking Triple (Participant, Investigator, Outcomes Assessor).
  • PFS Independent Central Review
  • ORR Objective Response Rate
  • DOR Duration of Response
  • PFS2 Progression-Free Survival After First Subsequent Therapy
  • TTSP Time to Symptomatic Progression
  • eCRF electronic case report form
  • Intracranial PFS [Time Frame: Up to approximately 42 months]. Intracranial PFS is defined as the time from randomization until the date of objective intracranial disease progression or death, whichever comes first, based on BICR using RECIST vl.l.
  • Serum Concentration of Amivantamab [Time Frame: Up to approximately 42 months]. Serum samples will be analyzed to determine concentrations of amivantamab. [00277] 12. Plasma Concentration of Eazertinib [Time Frame: Up to approximately 42 months]. Plasma samples will be analyzed to determine concentrations of lazertinib.
  • NSCLC-SAQ Non-Small Cell Eung Cancer - Symptom Assessment Questionnaire
  • EORTC-QLQ-C30 Change from Baseline in European Organization of Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) [Time Frame: Baseline Up to approximately 42 months].
  • EORTC-QLQ-C30 is a core 30-item questionnaire for evaluating the health-related quality of life (HRQoL) of participants participating in cancer clinical studies.
  • Time to Subsequent Therapy is defined as the time from the date of randomization in a clinical trial to the start date of the subsequent anticancer therapy following study treatment discontinuation or death, whichever comes first.
  • Inclusion Criteria • Participant must have newly diagnosed histologically or cytologically confirmed, locally advanced or metastatic non-small cell lung cancer (NSCLC) that is treatment naive and not amenable to curative therapy including surgical resection or chemoradiation.
  • NSCLC metastatic non-small cell lung cancer
  • FDA food and drug administration
  • CLIA clinical laboratory improvement amendments
  • Participant must have at least 1 measurable lesion, according to response evaluation criteria in solid tumors (RECIST) vl .1 that has not been previously irradiated. Measurable lesions should not have been biopsied during screening, but if only 1 nonirradiated measurable lesion exists, it may undergo a diagnostic biopsy and be acceptable as a target lesion, provided the baseline tumor assessment scans are performed at least 14 days after the biopsy.
  • RECIST solid tumors
  • Participant has an active or past medical history of leptomeningeal disease .
  • Participant has an active or past medical history of interstitial lung disease (ILD)/pneumonitis, including drug-induced or radiation ILD/pneumonitis.
  • ILD interstitial lung disease
  • Participant has known allergy, hypersensitivity, or intolerance to the excipients used in formulation of amivantamab, lazertinib, or osimertinib, or any contraindication to the use of Osimertinib.
  • Participant has symptomatic brain metastases.
  • a participant with asymptomatic or previously treated and stable brain metastases may participate in this study.
  • MARIPOSA which enrolled 1,074 patients, is a randomized, open-label Phase 3 study evaluating RYBREVANT® in combination with lazertinib versus osimertinib and versus lazertinib alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions (exl9del) or substitution mutations such as exon 21 L858R.
  • the primary endpoint of the study is PFS (using RECIST vl. l guidelines) as assessed by blinded independent central review (BICR).
  • Secondary endpoints include OS, objective response rate (ORR), duration of response (DoR), intracranial PFS, PFS after first subsequent therapy (PFS2), time to subsequent therapy (TTST), time to symptomatic progression (TTSP) and safety.
  • Results In total, 1074 patients were randomized (amivantamab+lazertinib, 429; osimertinib, 429; lazertinib, 216). Baseline characteristics were well balanced; median age was 63 years, 62% were female, 59% Asian, and 41% with history of brain metastases. [00293] At a median follow-up of 22.0 months, the median PFS was 23.7 months (95% CI, 19.1-27.7) for amivantamab+lazertinib and 16.6 months (95% CI, 14.8-18.5) for osimertinib (HR, 0.70; 95% CI, 0.58-0.85; ⁇ 0.001).
  • FIG. 1 An exemplary schematic overview of the MARIPOSA clinical study is shown in FIG. 1.
  • PFS results are shown in FIGs. 2-4.
  • OS results are shown in FIG. 5.
  • Table 8 Summary of Time to Symptomatic Progression (TTSP) results
  • Table 10 Summary of intracranial PFS results in participants with baseline brain metastasis
  • ECOG denotes Eastern Cooperative Oncology Group and EGFR epidermal growth factor receptor.
  • ⁇ Other histologic types included: adenocarcinoma & squamous cell carcinoma, lepidus adenocarcinoma, non-small-cell carcinoma, pleomorphic carcinoma, and unknown.
  • HOne patient in the amivantamab-lazertinib group had both EGFR mutation types (Exon 19 deletion and Exon 21 L858R).
  • EGFR epidermal growth factor receptor
  • Exl9del exon 19 deletion
  • NSCLC non-small cell lung cancer.
  • the median treatment duration was 18.5 months (range, 0.2 to 31.4) with amivantamab-lazertinib and 18.0 months (range, 0.2 to 32.7) with osimertinib.
  • the assigned treatment was still being administered in 230 patients (55%) in the amivantamab-lazertinib group and 213 (50%) in the osimertinib group.
  • the efficacy population included all the patients who had undergone randomization. NE denotes not estimable. f The objective response (complete or partial response) and response duration was assessed by blinded independent central review. Included in the analysis were 421 patients with measurable disease at baseline in the amivantamab-lazertinib group and 414 in the osimertinib group.
  • Table 17 Treatment-emergent Serious Adverse Events Occurring in At Least 1% of Patients*
  • rash dermatitis acneiform, folliculitis, rash maculopapular, skin lesion, acne, erythema, rash pustular, dermatitis, rash pruritic, rash papular, rash erythematous, rash macular, dermatitis infected, erythema multiforme, papule, drug eruption, rash follicular, rash vesicular, skin exfoliation, epidermolysis.
  • pulmonary embolism deep vein thrombosis, venous thrombosis limb, thrombosis, venous thrombosis, superficial vein thrombosis, thrombophlebitis, embolism, embolism venous, jugular vein thrombosis, pulmonary infarction, axillary vein thrombosis, portal vein thrombosis, post thrombotic syndrome, sigmoid sinus thrombosis, superior sagittal sinus thrombosis, vena cava thrombosis, pelvic venous thrombosis, pulmonary thrombosis.
  • VTE Venous thromboembolic
  • MARIPOSA (NCT04487080) is an international Phase 3 randomized study of amivantamab and lazertinib combination therapy versus osimertinib versus lazertinib as first- line treatment in approximately 1000 subjects with EGFR-mutated locally advanced or metastatic NSCLC (Study 73841937NSC3003, also known as NSC3003, and Mariposa).
  • Amivantamab + lazertinib meaningfully improved PFS, PFS2, and DoR versus osimertinib in MARIPOSA.
  • Detection of ctDNA and co-mutations were analyzed by next-generation sequencing (NGS) of blood at baseline. Detection and clearance of Exl 9del and L858R ctDNA in blood were analyzed with ddPCR at baseline and C3D 1.
  • NGS next-generation sequencing
  • Osimertinib showed a median PFS of 13.0 months among patients with brain metastases at baseline, indicating a poor prognostic subgroup.
  • amivantamab + lazertinib reduced the risk of progression or death by 31% vs Osimertinib.
  • Osimertinib showed a median PFS of 11.0 months among patients with liver metastases at baseline, indicating a poor prognostic subgroup.
  • amivantamab + lazertinib reduced the risk of progression or death by 42% vs Osimertinib.
  • NGS Next-Generation Sequencing
  • ctDNA Circulating Tumor DNA
  • TP53 co-mutations were observed in 56% from the amivantamab + lazertinib arm and 53% from the osimertinib arm.
  • MET amplification occurred in 1 patient in each arm (neither with high-level amplification).
  • PFS for Patients With High-risk Features In the MARIPOSA study, 89% of patients had at least 1 high-risk feature detected at baseline (Patients with analyzable ctDNA by NGS at baseline were included in this pooled analysis. High-risk features included baseline detectable ctDNA by NGS or baseline metastases of the liver or brain. For patients with detectable ctDNA, it was assumed TP53 co-mutations would be identified if present).
  • amivantamab + lazertinib showed a consistent PFS benefit over Osimertinib.
  • Amivantamab + Lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard-of-care for patients with EGFR-mutant advanced NSCLC.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente divulgation concerne des procédés pour améliorer la survie sans progression (PFS, « progression free survival ») médiane et améliorer la survie globale de patients n'ayant jamais reçu de traitement ou d'une population de patients n'ayant jamais reçu de traitement avec un cancer du poumon non à petites cellules (CPNPC) positif à EGFR.
PCT/IB2024/055039 2023-05-23 2024-05-23 Méthodes de traitement du cancer du poumon non à petites cellules (cpnpc) WO2024241273A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363468375P 2023-05-23 2023-05-23
US63/468,375 2023-05-23
US202363540742P 2023-09-27 2023-09-27
US63/540,742 2023-09-27

Publications (1)

Publication Number Publication Date
WO2024241273A1 true WO2024241273A1 (fr) 2024-11-28

Family

ID=91581775

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/055039 WO2024241273A1 (fr) 2023-05-23 2024-05-23 Méthodes de traitement du cancer du poumon non à petites cellules (cpnpc)

Country Status (1)

Country Link
WO (1) WO2024241273A1 (fr)

Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001649A1 (fr) 1986-09-02 1988-03-10 Genex Corporation Molecules de liaison de chaines de polypeptide simples
WO1992001047A1 (fr) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Procede de production de chainon de paires a liaison specifique
WO1994013804A1 (fr) 1992-12-04 1994-06-23 Medical Research Council Proteines de liaison multivalentes et multispecifiques, leur fabrication et leur utilisation
WO1998044001A1 (fr) 1997-03-27 1998-10-08 Commonwealth Scientific And Industrial Research Organisation Reactifs polyvalents presentant une avidite elevee et une specificite multiple
WO2006028936A2 (fr) 2004-09-02 2006-03-16 Genentech, Inc. Molecules heteromultimeriques
US20070287170A1 (en) 2006-03-24 2007-12-13 Merck Patent Gmbh Engineered heterodimeric protein domains
WO2009018386A1 (fr) 2007-07-31 2009-02-05 Medimmune, Llc Protéines de liaison à épitope multispécifiques et leurs utilisations
WO2009080252A1 (fr) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Anticorps bivalents bispécifiques
WO2009080251A1 (fr) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Anticorps bivalents bispécifiques
WO2009080254A1 (fr) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Anticorps bivalents bispécifiques
US20090182127A1 (en) 2006-06-22 2009-07-16 Novo Nordisk A/S Production of Bispecific Antibodies
US20100015133A1 (en) 2005-03-31 2010-01-21 Chugai Seiyaku Kabushiki Kaisha Methods for Producing Polypeptides by Regulating Polypeptide Association
US20100028637A1 (en) 2005-06-22 2010-02-04 Sunjuet Deutschland Gmbh Multi-Layer Film Comprising a Barrier Layer and an Antistatic Layer
US20110123532A1 (en) 2009-04-27 2011-05-26 Oncomed Pharmaceuticals, Inc. Method for Making Heteromultimeric Molecules
WO2011131746A2 (fr) 2010-04-20 2011-10-27 Genmab A/S Protéines contenant des anticorps fc hétérodimères et leurs procédés de production
US20120149876A1 (en) 2010-11-05 2012-06-14 Zymeworks Inc. Stable Heterodimeric Antibody Design with Mutations in the Fc Domain
US8242247B2 (en) 2007-12-21 2012-08-14 Hoffmann-La Roche Inc. Bivalent, bispecific antibodies
US20130195849A1 (en) 2011-11-04 2013-08-01 Zymeworks Inc. Stable Heterodimeric Antibody Design with Mutations in the Fc Domain
WO2016060443A2 (fr) 2014-10-13 2016-04-21 Yuhan Corporation Composés et compositions destinés à moduler les activités kinase de l'egfr mutant
US9593164B2 (en) 2012-11-21 2017-03-14 Janssen Biotech, Inc. Bispecific EGFR/c-Met antibodies
WO2018194356A1 (fr) 2017-04-21 2018-10-25 Yuhan Corporation Sel d'un composé dérivé d'aminopyridine, forme cristalline de celui-ci, et son procédé de préparation
WO2019022487A1 (fr) 2017-07-28 2019-01-31 Yuhan Corporation Intermédiaires utiles pour la synthèse d'un inhibiteur sélectif vis-à-vis de la protéine kinase et leurs procédés de préparation
WO2019022485A1 (fr) 2017-07-28 2019-01-31 Yuhan Corporation Procédé amélioré pour la préparation de dérivés d'aminopyrimidine
WO2019022486A1 (fr) 2017-07-28 2019-01-31 Yuhan Corporation Nouveaux intermédiaires utiles pour la synthèse de dérivés d'aminopyrimidine, leur procédé de préparation et procédé de préparation de dérivés d'aminopyrimidine à l'aide de ceux-ci
WO2020079637A1 (fr) 2018-10-18 2020-04-23 Yuhan Corporation Composition pharmaceutique pour une administration par voie orale comprenant un dérivé d'aminopyrimidine ou son sel
WO2020230091A1 (fr) * 2019-05-14 2020-11-19 Janssen Biotech, Inc. Polythérapies avec des anticorps anti-egfr/c-met bispécifiques et des inhibiteurs de tyrosine kinase egfr de troisième génération
WO2021209893A1 (fr) 2020-04-14 2021-10-21 Janssen Biotech, Inc. Composition pharmaceutique pour administration orale comprenant un dérivé d'aminopyrimidine ou un sel, un hydrate ou un solvate pharmaceutiquement acceptable de celui-ci
WO2022224187A1 (fr) 2021-04-21 2022-10-27 Janssen Biotech, Inc. Formulations d'anticorps bispécifiques à haute concentration

Patent Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001649A1 (fr) 1986-09-02 1988-03-10 Genex Corporation Molecules de liaison de chaines de polypeptide simples
WO1992001047A1 (fr) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Procede de production de chainon de paires a liaison specifique
WO1994013804A1 (fr) 1992-12-04 1994-06-23 Medical Research Council Proteines de liaison multivalentes et multispecifiques, leur fabrication et leur utilisation
WO1998044001A1 (fr) 1997-03-27 1998-10-08 Commonwealth Scientific And Industrial Research Organisation Reactifs polyvalents presentant une avidite elevee et une specificite multiple
WO2006028936A2 (fr) 2004-09-02 2006-03-16 Genentech, Inc. Molecules heteromultimeriques
US20100015133A1 (en) 2005-03-31 2010-01-21 Chugai Seiyaku Kabushiki Kaisha Methods for Producing Polypeptides by Regulating Polypeptide Association
US20100028637A1 (en) 2005-06-22 2010-02-04 Sunjuet Deutschland Gmbh Multi-Layer Film Comprising a Barrier Layer and an Antistatic Layer
US20070287170A1 (en) 2006-03-24 2007-12-13 Merck Patent Gmbh Engineered heterodimeric protein domains
US20090182127A1 (en) 2006-06-22 2009-07-16 Novo Nordisk A/S Production of Bispecific Antibodies
WO2009018386A1 (fr) 2007-07-31 2009-02-05 Medimmune, Llc Protéines de liaison à épitope multispécifiques et leurs utilisations
WO2009080254A1 (fr) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Anticorps bivalents bispécifiques
WO2009080251A1 (fr) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Anticorps bivalents bispécifiques
WO2009080252A1 (fr) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Anticorps bivalents bispécifiques
US8242247B2 (en) 2007-12-21 2012-08-14 Hoffmann-La Roche Inc. Bivalent, bispecific antibodies
US20110123532A1 (en) 2009-04-27 2011-05-26 Oncomed Pharmaceuticals, Inc. Method for Making Heteromultimeric Molecules
WO2011131746A2 (fr) 2010-04-20 2011-10-27 Genmab A/S Protéines contenant des anticorps fc hétérodimères et leurs procédés de production
US20120149876A1 (en) 2010-11-05 2012-06-14 Zymeworks Inc. Stable Heterodimeric Antibody Design with Mutations in the Fc Domain
US20130195849A1 (en) 2011-11-04 2013-08-01 Zymeworks Inc. Stable Heterodimeric Antibody Design with Mutations in the Fc Domain
US9593164B2 (en) 2012-11-21 2017-03-14 Janssen Biotech, Inc. Bispecific EGFR/c-Met antibodies
WO2016060443A2 (fr) 2014-10-13 2016-04-21 Yuhan Corporation Composés et compositions destinés à moduler les activités kinase de l'egfr mutant
WO2018194356A1 (fr) 2017-04-21 2018-10-25 Yuhan Corporation Sel d'un composé dérivé d'aminopyridine, forme cristalline de celui-ci, et son procédé de préparation
WO2019022487A1 (fr) 2017-07-28 2019-01-31 Yuhan Corporation Intermédiaires utiles pour la synthèse d'un inhibiteur sélectif vis-à-vis de la protéine kinase et leurs procédés de préparation
WO2019022485A1 (fr) 2017-07-28 2019-01-31 Yuhan Corporation Procédé amélioré pour la préparation de dérivés d'aminopyrimidine
WO2019022486A1 (fr) 2017-07-28 2019-01-31 Yuhan Corporation Nouveaux intermédiaires utiles pour la synthèse de dérivés d'aminopyrimidine, leur procédé de préparation et procédé de préparation de dérivés d'aminopyrimidine à l'aide de ceux-ci
WO2020079637A1 (fr) 2018-10-18 2020-04-23 Yuhan Corporation Composition pharmaceutique pour une administration par voie orale comprenant un dérivé d'aminopyrimidine ou son sel
WO2020230091A1 (fr) * 2019-05-14 2020-11-19 Janssen Biotech, Inc. Polythérapies avec des anticorps anti-egfr/c-met bispécifiques et des inhibiteurs de tyrosine kinase egfr de troisième génération
WO2021209893A1 (fr) 2020-04-14 2021-10-21 Janssen Biotech, Inc. Composition pharmaceutique pour administration orale comprenant un dérivé d'aminopyrimidine ou un sel, un hydrate ou un solvate pharmaceutiquement acceptable de celui-ci
WO2022224187A1 (fr) 2021-04-21 2022-10-27 Janssen Biotech, Inc. Formulations d'anticorps bispécifiques à haute concentration

Non-Patent Citations (25)

* Cited by examiner, † Cited by third party
Title
"GenBank", Database accession no. NP_005219
"Remington: The Science and Practice of Pharmacy", 2006, LIPINCOTT WILLIAMS AND WILKINS, article "Pharmaceutical Manufacturing", pages: 691 - 1092
ANONYMOUS: "Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response. | Journal of Clinical Oncology", 28 May 2021 (2021-05-28), pages 1 - 4, XP055949505, Retrieved from the Internet <URL:https://ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.9006> [retrieved on 20220805] *
CHO B.C. ET AL: "1258O Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation tyrosine kinase inhibitor (TKI), in advanced EGFR NSCLC", ANNALS OF ONCOLOGY, vol. 31, 1 September 2020 (2020-09-01), pages S813, XP055949501, DOI: 10.1016/j.annonc.2020.08.1572 *
CHOTHIA ET AL., J MOL BIOL, vol. 196, 1987, pages 901 - 17
EISENHAUER EATHERASSE PBOGAERTS J ET AL.: "New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1", EUR J CANCER., vol. 45, no. 2, 2009, pages 228 - 247, XP025841550, DOI: 10.1016/j.ejca.2008.10.026
FERRARA ET AL., BIOTECHNOL BIOENG, vol. 93, 2006, pages 851 - 861
FERRARA ET AL., J BIOL CHEM, vol. 281, 2006, pages 5032 - 5036
GOV CLINICALTRIALS ET AL: "A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA)", 6 May 2023 (2023-05-06), XP093201724, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT04487080> *
HONEGGERPLUCKTHUN, J MOL BIOL, vol. 309, 2001, pages 657 - 70
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, PUBLIC HEALTH SERVICE
KONNO ET AL., CYTOTECHNOLOGY, vol. 64, 2012, pages 249 - 65
LEFRANC ET AL., DEV COMP IMMUNOL, vol. 27, 2003, pages 55 - 77
MARTINTHORNTON, J BMOL BIOL, vol. 263, 1996, pages 800 - 15
MORI ET AL., BIOTECHNOL BIOENG, vol. 88, 2004, pages 901 - 908
OLIVIER ET AL., MABS, vol. 2, no. 4, 2010
SHIELDS ET AL., J BIOL CHEM, vol. 277, 2002, pages 26733 - 26740
SHINKAWA ET AL., J BIOL CHEM, vol. 278, 2003, pages 3466 - 3473
SHU C.A. ET AL: "1193MO Amivantamab plus lazertinib in post-osimertinib, post-platinum chemotherapy EGFR-mutant non-small cell lung cancer (NSCLC): Preliminary results from CHRYSALIS-2", ANNALS OF ONCOLOGY, vol. 32, no. S5, 1 September 2021 (2021-09-01), pages S952 - S953, XP055971982, DOI: 10.1016/j.annonc.2021.08.1797 *
SORIA ET AL., ENGL J MED, vol. 378, 2018, pages 113 - 125
TURKE ET AL., CANCER CELL, vol. 17, 2010, pages 77 - 88
ULLRICH ET AL., NATURE, vol. 309, 1984, pages 418 - 425
WIEMANN ET AL.: "Medical Oncology", 1985, MCMILLAN PUBLISHING
WU ET AL., J EXP MED, vol. 132, 1970, pages 211 - 50
XHOU ET AL., BIOTECHNOL BIOENG, vol. 99, 2008, pages 652 - 65

Similar Documents

Publication Publication Date Title
US11850248B2 (en) Therapies with 3rd generation EGFR tyrosine kinase inhibitors
US12215160B2 (en) Treatment of patients having c-met exon 14 skipping mutations
US20220064306A1 (en) Treatment of Non-Small Cell Lung Cancer with EGFR Mutations
US20220372581A1 (en) Methods for Identifying Cancer Patients for Combination Treatment
WO2024241273A1 (fr) Méthodes de traitement du cancer du poumon non à petites cellules (cpnpc)
WO2025052273A1 (fr) Méthodes pour traiter le cancer du poumon non à petites cellules
US20220298248A1 (en) Treatment of Cancers Lacking EGFR- Activating Mutations
US20230183360A1 (en) Use of Amivantamab to Treat Colorectal Cancer
US20240228634A1 (en) Treatment of Cancers Lacking EGFR- Activating Mutations
WO2024189544A1 (fr) Polythérapies avec des anticorps anti-egfr/c-met bispécifiques et des anticorps anti-pd-1
AU2023215753A1 (en) Methods for reducing infusion-related reactions in patients treated with egfr/met bispecific antibodies
KR20220010731A (ko) 이중특이성 항-EGFR/c-Met 항체와 제3 세대 EGFR 티로신 키나제 억제제에 의한 병용 요법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24733722

Country of ref document: EP

Kind code of ref document: A1