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WO2025052273A1 - Méthodes pour traiter le cancer du poumon non à petites cellules - Google Patents

Méthodes pour traiter le cancer du poumon non à petites cellules Download PDF

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WO2025052273A1
WO2025052273A1 PCT/IB2024/058604 IB2024058604W WO2025052273A1 WO 2025052273 A1 WO2025052273 A1 WO 2025052273A1 IB 2024058604 W IB2024058604 W IB 2024058604W WO 2025052273 A1 WO2025052273 A1 WO 2025052273A1
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day
cycle
dose
bispecific anti
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PCT/IB2024/058604
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Roland Elmar KNOBLAUCH
Joshua BAUML
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Janssen Biotech, Inc.
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Publication of WO2025052273A1 publication Critical patent/WO2025052273A1/fr

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    • 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
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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
    • A61K2039/507—Comprising a combination of two or more separate 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • 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
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • 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 Epidermal Growth Factor Receptor (EGFR)-positive non-small cell lung cancer (NSCLC) in a subject that had disease progression on or after treatment with at least one prior tyrosine kinase inhibitor (TKI).
  • EGFR Epidermal Growth Factor Receptor
  • NSCLC non-small cell lung cancer
  • TKI tyrosine kinase inhibitor
  • NSCLC non-small cell lung cancer
  • EGFR-TKI EGFR tyrosine kinase inhibitors
  • c-Met Hepatocyte Growth Factor Receptor
  • 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. In some embodiments, the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is administered at a dose of about 240 mg orally, once daily.
  • 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 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 any of the above methods of this disclosure, the one or more EGFR mutations comprise one or more exon 19 deletions. In some embodiments of any of the above methods of this disclosure, the one or more EGFR mutations comprise exon 21 L858R substitution.
  • said at least one prior TKI comprises a 1st generation EGFR TKI. In some embodiments of any of the above methods of this disclosure, said at least one prior TKI comprises a 2nd generation EGFR TKI. In some embodiments of any of the above methods of this disclosure, said at least one prior TKI comprises a 3rd generation EGFR TKI. In some embodiments of any of the above methods of this disclosure, said at least one prior TKI comprises osimertinib.
  • administration of the combination therapy begins on Cycle 1 Day 1 of the first 21 -day cycle, and continues in subsequent 21 -day cycles.
  • the bispecific anti-EGFR/c-Met antibody is administered intravenously. In some embodiments of any of the above methods of this disclosure, the bispecific anti-EGFR/c-Met antibody is administered subcutaneously.
  • the method comprises administering the bispecific anti-EGFR/c-Met antibody in an amount of between about 140 mg and about 2240 mg.
  • 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg. In some embodiments of any of the above methods of this disclosure wherein the bispecific anti- EGFR/c-Met antibody dose of Cycle 1 Day 1 is administered as a split dose over Day 1 and 2. [0015] In some embodiments of any of the above methods of this disclosure, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1750 mg on Day 1 of each 21- day cycle, starting with Cycle 3 if the subject has a body weight of less than 80 kg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1750 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of greater than or equal to 80 kg. In some embodiments of any of the above methods of this disclosure wherein the bispecific anti-EGFR/c-Met antibody dose of Cycle 1 Day 1 is administered as a split dose over Day 1 and 2.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 2100 mg on Day 1 of each 21- day cycle, starting with Cycle 3 if the subject has a body weight of greater than or equal to 80 kg.
  • the method comprises administering the carboplatin at a dose of AUC 5 on Day 1 of each 21 -day cycle, for up to 4 cycles.
  • the method comprises administering the pemetrexed at a dose of about 500 mg/m 2 on Day 1 of each 21- day cycle, with the carboplatin for up to 4 cycles, and then as maintenance until disease progression.
  • the method comprises: a) (i) administering the bispecific anti-EGFR/c-Met antibody at a dose of about 1400 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg; or (ii) administering the bispecific anti-EGFR/c-Met antibody at a dose of about 1750 mg on Day 1 of each 21 -day cycle, starting with Cycle 3 if the subject has a body weight of less than 80 kg; or (iii) administering the bispecific anti-EGFR/c-Met antibody at a dose of about 1750 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of greater than or equal to 80 kg; or (iv) administering the bispecific anti-EGFR/c- Met antibody at a dose of about 2100 mg on Day 1 of each 21 -day cycle, starting with Cycle 3 if the subject has a body weight of greater than or equal to
  • the combination therapy achieves an improvement in the median PFS of at least two weeks. In some embodiments of any of the above methods of this disclosure, the combination therapy achieves an improvement in the median PFS of at least 1 month. In some embodiments of any of the above methods of this disclosure, the combination therapy achieves an improvement in the median PFS of at least 1.5 months. In some embodiments of any of the above methods of this disclosure, the combination therapy achieves an improvement in the median PFS of at least 2 months. In some embodiments of any of the above methods of this disclosure, the subject exhibits PFS for at least 4.5 months. In some embodiments of any of the above methods of this disclosure, the subject exhibits PFS for at least 5 months.
  • the subject exhibits progression-free survival for at least 5.5 months. In some embodiments of any of the above methods of this disclosure, the subject exhibits PFS for at least 6 months. In some embodiments of any of the above methods of this disclosure, the subject exhibits progression-free survival for at least 10 months. In some embodiments of any of the above methods of this disclosure, the subject exhibits PFS for at least 12 months. In some embodiments of any of the above methods of this disclosure, the subject exhibits PFSfor at least 14 months.
  • the combination therapy further achieves an improvement in objective response relative to said reference population. In some embodiments of any of the above methods of this disclosure, the combination therapy further achieves an improvement in overall survival (OS) relative to said reference population. In some embodiments of any of the above methods of this disclosure, the combination therapy further achieves an improvement in duration of response (DoR) relative to said reference population. In some embodiments of any of the above methods of this disclosure, the combination therapy further achieves an improvement in time to subsequent therapy relative to said reference population. In some embodiments of any of the above methods of this disclosure, the combination therapy further achieves an improvement in PFS after first subsequent therapy (PFS2) relative to said reference population. In some embodiments of any of the above methods of this disclosure, the combination therapy further achieves an improvement in intracranial median PFS relative to said reference population.
  • PFS2 first subsequent therapy
  • 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 one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitution, or any combination thereof.
  • 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.
  • said at least one prior TKI comprises a 1 st generation EGFR TKI. In some embodiments, said at least one prior TKI comprises a 2 nd generation EGFR TKI. In some embodiments, said at least one prior TKI comprises a 3 rd generation EGFR TKI. In some embodiments, said at least one prior TKI comprises osimertinib.
  • administration of the combination therapy begins on Cycle 1 Day 1 of the first 21 -day cycle, and continues in subsequent 21 -day cycles.
  • the bispecific anti-EGFR/c-Met antibody is administered intravenously. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered subcutaneously.
  • the method comprises administering the bispecific anti- EGFR/c-Met antibody in an amount of between about 140 mg and about 2240 mg.
  • 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg.
  • the bispecific anti-EGFR/c-Met antibody dose of Cycle 1 Day 1 is administered as a split dose over Day 1 and 2.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1750 mg on Day 1 of each 21 -day cycle, starting with Cycle 3 if the subject has a body weight of less than 80 kg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1750 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of greater than or equal to 80 kg.
  • the bispecific anti-EGFR/c-Met antibody dose of Cycle 1 Day 1 is administered as a split dose over Day 1 and 2.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 2100 mg on Day 1 of each 21 -day cycle, starting with Cycle 3 if the subject has a body weight of greater than or equal to 80 kg.
  • the method comprises administering the carboplatin at a dose of AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles.
  • the method comprises administering the pemetrexed at a dose of about 500 mg/m 2 on Day 1 of each 21-day cycle, with the carboplatin for up to 4 cycles, and then as maintenance until disease progression.
  • the method comprises: a) (i) administering the bispecific anti -EGFR/c -Met antibody at a dose of about 1400 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg; or
  • the combination therapy achieves an improvement in the median OS of at least two months.
  • the combination therapy achieves an improvement in the median OS of at least 2.4 months.
  • the combination therapy achieves an improvement in the median OS of about 2.4 months.
  • the subject exhibits overall survival for at least 17 months.
  • the subject exhibits overall survival for at least about 17.7 months.
  • the subject exhibits overall survival for about 17.7 months.
  • the combination therapy further achieves an improvement in time to symptomatic progression (TTSP) relative to said reference population.
  • TTSP time to symptomatic progression
  • TTST time to subsequent therapy
  • the combination therapy further achieves an improvement in PFS after first subsequent therapy (PFS2) relative to said reference population.
  • the combination therapy further achieves an improvement in time to treatment discontinuation (TTD) relative to said reference population.
  • TTD time to treatment discontinuation
  • FIG. 1 shows an exemplary schematic overview of the study.
  • FIG. 2 shows MARIPOSA-2 Study Design, a - Analyses were further stratified based on osimertinib line of therapy, history of brain metastases, and race (Asian vs nonAsian).
  • ECOG PS Eastern Cooperative Oncology Group performance status
  • EGFR epidermal growth factor receptor
  • Exl9del exon 19 deletion
  • NSCLC non-small cell lung cancer
  • OS overall survival.
  • FIG. 3 shows Overall Survival. Ami, amivantamab; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; OS, overall survival.
  • FIG. 4 shows Time to Symptomatic Progression (TTSP).
  • Ami amivantamab; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; TTSP, time to symptomatic progression.
  • FIG. 5 shows Time to Treatment Discontinuation.
  • Ami amivantamab
  • chemo chemotherapy
  • CI confidence interval
  • HR hazard ratio
  • PD progressive disease
  • TTD time to treatment discontinuation.
  • FIG. 6 shows Time to Subsequent Therapy.
  • Ami amivantamab; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; TTST, time to subsequent therapy.
  • FIG. 7 shows PFS After First Subsequent Therapy. Ami, amivantamab; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; PFS2, progression-free survival after first subsequent therapy.
  • 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” 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.
  • “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.
  • 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.
  • “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 Maccicci 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.
  • 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.
  • 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.
  • 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.
  • 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. W01998/4400I, WOI988/01649, WOI994/13804 and WOI992/01047.
  • 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.
  • 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.
  • 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.
  • 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.
  • RECIST vl .1 criteria refer to publicly available guidelines for response evaluation criteria in solid tumors as described by Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247, which is incorporated by reference herein. Eisenhauer et al., provide the following definitions of criteria used to determine objective tumor response for target lesions:
  • CR Complete Response
  • PD Progressive Disease
  • SD Stable Disease
  • a partial response or better refers to a partial response (PR) or complete response (CR).
  • progression-free survival refers to the time from randomization in a clinical trial until the date of objective disease progression or death, whichever comes first, based on blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) vl .1 .
  • OR overall response
  • OS overall survival
  • DoR duration of response
  • TTST Time to Subsequent Therapy
  • PFS2 Progression-free Survival After the First Subsequent Therapy
  • TTSP Time to Symptomatic Progression
  • Intracranial Progression-Free Survival is defined as the time from randomization in a clinical trial until the date of objective intracranial disease progression or death, whichever comes first, based on BICR using RECIST vl . 1. Specifically, intracranial disease progression is defined as having progression of brain metastasis or occurrence of new brain lesion.
  • the present invention is directed to novel regimens for the treatment of patients with EGFR-mutated advanced NSCLC whose disease had progressed on or after a TKI therapy, such as osimertinib.
  • Embodiments of the present invention provide methods of significantly improving progression-free survival with amivantamab- chemotherapy and amivantamab- lazertinib-chemotherapy compared with chemotherapy in patients with EGFR-mutated advanced NSCLC whose disease had progressed on or after osimertinib monotherapy.
  • a method of improving median PFS in a population of subjects with locally advanced or metastatic (NSCLC harboring one or more (EGFR mutations whose NSCLC progressed on or after treatment with at least one prior TKI comprises administering to the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR/c-Met antibody, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed 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 whose NSCLC progressed on or after treatment with the prior TKI, said reference population having been administered carboplatin and pemetrexed but not said bispecific anti-EGFR/c-Met antibody.
  • a method of improving median PFS in a population of subjects with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations whose NSCLC progressed on or after treatment with a prior TKI comprises administering to the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR/c-Met antibody, (ii) a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, (iii) a therapeutically effective amount of carboplatin, and (iv) a therapeutically effective amount of pemetrexed, 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 whose NSCLC progressed on or after treatment with a third-generation TKI ,
  • a method of improving median intracranial PFS in a population of subjects with locally advanced or metastatic NSCLC harboring one or more EGFR mutations whose NSCLC progressed on or after treatment with at least one prior TKI comprises administering to the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR/c-Met antibody, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed 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 whose NSCLC progressed on or after treatment with the prior TKI, said reference population having been administered carboplatin and pemetrexed but not said bispecific anti-EGFR/c-Met antibody.
  • a method of improving median intracranial PFS in a population of subjects with locally advanced or metastatic NSCLC harboring one or more EGFR mutations whose NSCLC progressed on or after treatment with a prior TKI comprises administering to the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR/c-Met antibody, (ii) a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, (iii) a therapeutically effective amount of carboplatin, and (iv) a therapeutically effective amount of pemetrexed, 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 whose NSCLC progressed on or after treatment with a third-generation TKI , said reference population having been administered
  • a method of treating a subject with locally advanced or metastatic NSCLC harboring one or more EGFR mutations whose NSCLC progressed on or after treatment with a prior TKI comprises administering to the subject a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR/c-Met antibody, (ii) a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, (iii) a therapeutically effective amount of carboplatin, and (iv) a therapeutically effective amount of pemetrexed, wherein administration of the combination therapy begins on Cycle 1 Day 1 of a first 21 -day cycle, and continues in subsequent 21 -day cycles, and wherein the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, after administration of the carboplatin is completed (e.
  • 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 method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, at a dose of about 240 mg orally, once daily.
  • the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, at a dose of about 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if said carboplatin is discontinued earlier.
  • 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 at least one prior TKI comprises a 1st generation EGFR TKI. In some embodiments, the at least one prior TKI comprises a 2 nd generation EGFR TKI. In some embodiments, the at least one prior TKI comprises a 2 nd generation EGFR TKI. In some embodiments, the at least one prior TKI comprises osimertinib.
  • EGFR-TKIs are EGFR- targeted agents that interfere with EGFR signaling. To date, three different generations of EGFR-TKIs are available, though all remain subject to development of resistance mechanisms.
  • first-generation TKIs e.g., Erlotinib, Gefinitib, and Icotinib
  • Second- generation TKIs e.g., Afatinib and Dacominitib
  • Third generation TKIs e.g., Osimertinib, Rociletinib, Olmutinib, Lazertinib
  • 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. In some embodiments, the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, at a dose in an amount of about 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if said carboplatin is discontinued earlier.
  • administration of the combination therapy begins on Cycle 1 Day 1 of the first 21 -day cycle, and continues in subsequent 21 -day cycles.
  • the method elicits a clinical response in the subject according to RECIST vl. 1 criteria.
  • the method achieves a partial response or better in the subject according to RECIST vl. l criteria.
  • the combination therapy achieves an improvement in the median PFS of at least two weeks.
  • the combination therapy achieves an improvement in the median PFS of at least 1 month.
  • the combination therapy achieves an improvement in the median PFS of at least 1.5 months.
  • the combination therapy achieves an improvement in the median PFS of at least 2 months. In some embodiments, the subject exhibits PFSfor at least 4.5 months. In some embodiments, the subject exhibits PFSfor at least 5 months. In some embodiments, the subject exhibits PFS for at least 5.5 months. In some embodiments, the subject exhibits PFS for at least 6 months, or at least 10 months, or at least 12 months, or at least 14 months. In some embodiments, the combination therapy further achieves an improvement in objective response relative to said reference population. In some embodiments, the combination therapy further achieves an improvement in OS relative to said reference population. In some embodiments, the improvement in OS is at least two months relative to said reference population.
  • the improvement in OS is at least about 2.4 months relative to said reference population. In some embodiments, the improvement in OS is about 2.2 months relative to said reference population. In some embodiments, the improvement in OS is about 2.3 months relative to said reference population. In some embodiments, the improvement in OS is about 2.4 months relative to said reference population. In some embodiments, the improvement in OS is about 2.5 months relative to said reference population. In some embodiments, the improvement in OS is about 2.6 months relative to said reference population. In some embodiments, the combination therapy further achieves an improvement in duration of response (DoR) relative to said reference population. In some embodiments, the combination therapy further achieves an improvement in time to subsequent therapy relative to said reference population.
  • DoR duration of response
  • the combination therapy further achieves an improvement in PFS after first subsequent therapy (PFS2) relative to said reference population.
  • PFS2 first subsequent therapy
  • the combination therapy further achieves an improvement in intracranial median PFS relative to said reference population.
  • the improvement in PFS2 is at least two months relative to said reference population.
  • the improvement in PFS2 is at least about 4.4 months relative to said reference population.
  • the improvement in PFS2 is about 4.5 months relative to said reference population.
  • the improvement in PFS2 is about 5 months relative to said reference population.
  • the combination therapy further achieves an improvement in time to symptomatic progression (TTSP) relative to said reference population.
  • TTSP time to symptomatic progression
  • the subject is progression-free after at least 20 months. In some embodiments, the subject is progression-free after at least 30 months. In some embodiments, the method achieves a PFS rate of 85% at 12 months, 65% at 24 months, and/or 51% at 36 months in a population of the treatment naive subjects diagnosed with locally advanced or metastatic NSCLC harboring one or more EGFR mutations.
  • the subject’s overall survival (OS) is at least 17 months. In some embodiments, the subject’s overall survival (OS) is at least 17.7 months. In some embodiments, the subject’s overall survival (OS) is about 17 months. In some embodiments, the subject’s overall survival (OS) is at least 17.5 months. In some embodiments, the subject’s overall survival (OS) is at least 18 months.
  • the subject’s time to subsequent therapy is at least 12 months. In some embodiments, the subject’s time to subsequent therapy (TTST) is at least 12.2 months.
  • the subject’s time to symptomatic progression is at least 16 months. In some embodiments, the subject’s time to symptomatic progression (TTSP) is about 16 months.
  • the subject’s time to treatment discontinuation is at least 10 months. In some embodiments, the subject’s time to treatment discontinuation (TTD) is at least 10.4 months. In some embodiments, the subject’s time to treatment discontinuation (TTD) is about 10.4 months.
  • the subject’s progression-free survival after first subsequent therapy is at least 16 months. In some embodiments, the subject’s progression-free survival after first subsequent therapy (PFS2) is about 16 months.
  • 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 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.
  • the method comprises administering the dose weekly for 4 weeks, then administering the dose every 2 weeks starting at Week 5, wherein, for body weight at baseline that is less than 80 kg, the dose is 1050 mg; and for body weight at baseline that is greater than or equal to 80 kg, the dose is 1400 mg.
  • the initial dose is administered as a split infusion in Week 1 on Day 1 and Day 2. In some embodiments, the initial dose is administered in Week 1 on Day 1.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg.
  • the initial dose is administered as a split infusion in Week 1 on Day 1 and Day 2.
  • the bispecific anti-EGFR/c- Met antibody is administered at a dose of about 1750 mg on Day 1 of each 21 -day cycle, starting with Cycle 3 if the subject has a body weight of less than 80 kg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1750 mg on Cycle 1 Days 1, 8, and 15 , and Cycle 2 Day 1 if the subj ect has a body weight of greater than or equal to 80 kg.
  • the initial dose is administered as a split infusion in Week 1 on Day 1 and Day 2.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 2100 mg on Day 1 of each 21 -day cycle, starting with Cycle 3 if the subject has a body weight of greater than or equal to 80 kg.
  • 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 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 biantennary glycan structure with a fucose content of about between 2% to about 14%.
  • the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 3% to about 13%. In some embodiments, 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%.
  • the bispecific anti-EGFR/c- Met antibody comprises a biantennary glycan structure with a fucose content of about 2%. In some embodiments, 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%.
  • the bispecific anti-EGFR/c- Met antibody comprises a biantennary glycan structure with a fucose content of about 6%. In some embodiments, 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%.
  • the bispecific anti-EGFR/c- Met antibody comprises a biantennary glycan structure with a fucose content of about 10%. In some embodiments, 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%.
  • 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, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in development for the treatment of non-small cell lung cancer (NSCLC).
  • EGFR epidermal growth factor receptor
  • TKI tyrosine kinase inhibitor
  • Lazertinib is described in WO 2016/060443 as N-(5-(4-(4-((dimethylamino)methyl)- 3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-ylamino)-4-methoxy-2- morpholinophenyl)acrylamide, depicted below as a compound of Formula I.
  • Formula I N-(5-(4-(4-((dimethylamino)methyl)- 3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-ylamino)-4-methoxy-2- morpholinophenyl)acrylamide, depicted below as a compound of Formula I.
  • 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, 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 method comprises administering the carboplatin at a dose of AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles.
  • Carboplatin may be administered at a dose of AUC 5 in accordance with commercially available methods that are approved by health authorities.
  • the method comprises administering the pemetrexed at a dose of about 500 mg/m 2 on Day 1 of each 21-day cycle, with the carboplatin for up to 4 cycles, and then as maintenance until disease progression.
  • the bispecific anti-EGFR/c-Met antibody may be administered in a pharmaceutically acceptable carrier.
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the invention is administered.
  • vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • 0.4% saline and 0.3% glycine may be used to formulate the bispecific anti-EGFR/c-Met antibody.
  • These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration).
  • the carrier may comprise sterile water and other excipients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Troy, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, See especially pp. 958-989.
  • the mode of administration may be any suitable route that delivers the bispecific anti-EGFR-c-Met antibody to the host, such as parenteral administration, e.g., intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal), using a formulation in a tablet, capsule, solution, powder, gel, particle; and contained in a syringe, an implanted device, osmotic pump, cartridge, micropump; or other means appreciated by the skilled artisan, as well known in the art.
  • parenteral administration e.g., intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal), using a formulation in a tablet, capsule, solution, powder, gel, particle; and contained in a syringe, an implanted device, osmotic pump, cartridge
  • Site specific administration may be achieved by for example intratumoral, intra-articular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intracardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intravesical, intralesional, vaginal, rectal, buccal, sublingual, intranasal, or transdermal delivery.
  • the bispecific anti-EGFR/c-Met antibody is administered intravenously.
  • the bispecific anti-EGFR/c-Met antibody is administered subcutaneously or intradermally to the subject.
  • the bispecific anti-EGFR/c-Met antibody may be administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.
  • the method comprises administering the dose weekly for 4 weeks, then administering the dose every 2 weeks starting at Week 5, wherein, for body weight at baseline that is less than 80 kg, the dose is 1050 mg; and for body weight at baseline that is greater than or equal to 80 kg, the dose is 1400 mg.
  • the initial dose is administered as a split infusion in Week 1 on Day 1 and Day 2.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 140 mg and about 2240 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 1400 mg to about 3360 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 1400 mg to about 1750 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg,
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 350 mg, about 700 mg, about 1050 mg, about 1400 mg, about 1750 mg or about 21 OOmg. 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.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 850 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 900 mg. In some embodiments, the bispecific anti-EGFR/c- Met antibody is administered at a dose of about 950 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1000 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1100 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1150 mg. In some embodiments, the bispecific anti-EGFR/c- Met antibody is administered at a dose of about 1200 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1250 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1300 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1350 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400 mg. In some embodiments, the bispecific anti-EGFR/c- Met antibody is administered at a dose of about 1750 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 2100 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered is administered at a dose of about 1400 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg. In some embodiments, the bispecific anti- EGFR/c-Met antibody is administered is administered at a dose of about 1400 mg on Cycle 1 Days 1/2 (split dosing), 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1750 mg on Day 1 of each 21-day cycle, starting with Cycle 3 if the subject has a body weight of less than 80 kg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1750 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of greater than or equal to 80 kg. In some embodiments, the bispecific anti- EGFR/c-Met antibody is administered at a dose of about 1750 mg on Cycle 1 Days 1/2 (split dosing), 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of greater than or equal to 80 kg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 2100 mg on Day 1 of each 21-day cycle, starting with Cycle 3 if the subject has a body weight of greater than or equal to 80 kg.
  • the bispecific anti-EGFR/c-Met antibody is administered twice a week.
  • the bispecific anti-EGFR/c-Met antibody is administered once a week.
  • the bispecific anti-EGFR/c-Met antibody is administered once in two weeks.
  • the bispecific anti-EGFR/c-Met antibody is administered once in three weeks.
  • the bispecific anti- EGFR/c-Met antibody is administered once in four weeks.
  • 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 mode of administration that may the suitable route that delivers lazertinib to the subject may be oral administration, such as oral administration of a tablet.
  • Lazertinib tablet formulations suitable for oral administration in accordance with the present invention are described, for example, in WO2021/209893 and W02020/079637, which are incorporated by reference herein.
  • lazertinib is administered at a dose of between about 10 mg to about 400 mg. In some embodiments, lazertinib is administered at a dose of between about 20 mg to about 320 mg. In some embodiments, lazertinibis administered at a dose of between about 50 mg to about 300 mg. In some embodiments, lazertinib is administered at a dose of between about 100 mg to about 300 mg. In some embodiments, lazertinib is administered at a dose of between about 150 mg to about 280 mg. In some embodiments, lazertinib is administered at a dose of between about 200 mg to about 250 mg. In some embodiments, lazertinib is administered at a dose of between about 220 mg to about 250 mg.
  • lazertinib is administered at a dose of about 20 mg, about 50 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, or about 400 mg. In some embodiments, lazertinib is administered at a dose of about 240 mg.
  • lazertinib is administered daily. In some embodiments, lazertinibis administered twice a week. In some embodiments, lazertinibis administered once a week. In some embodiments, lazertinib is administered once in two weeks. In some embodiments, lazertinib is administered once in three weeks. In some embodiments, lazertinibis administered once in four weeks.
  • the bispecific anti-EGFR/c-Met antibody disclosed herein may be administered in combination with lazertinib, which may be administered using any of the doses and dosages disclosed herein. In some embodiments, lazertinib is administered at a dose of between about 10 mg to about 400 mg.
  • lazertinib is administered at a dose of between about 20 mg to about 320 mg. In some embodiments, lazertinib is administered at a dose of about 20 mg, about 50 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, or about 400 mg. In some embodiments, lazertinib is administered at a dose of about 240 mg.
  • the bispecific anti-EGFR/c-Met antibody disclosed herein may be administered in any of these doses and dosages disclosed herein in combination with lazertinib, which may be administered in any of these doses and dosages disclosed herein.
  • 1400 mg amivantamab may be administered in combination with 240 mg lazertinib.
  • 1750 mg amivantamab may be administered in combination with 240 mg lazertinib.
  • 2100 mg amivantamab may be administered in combination with 240 mg lazertinib.
  • the bispecific anti-EGFR/c-Met antibody disclosed herein may be administered in combination with lazertinib, wherein lazertinib is administered daily, every other day, twice a week, or once a week. In some embodiments, the bispecific anti- EGFR/c-Met antibody disclosed herein may be administered in combination with lazertinib, wherein lazertinib is administered daily. In some embodiments, the bispecific anti-EGFR/c- Met antibody disclosed herein may be administered in combination with lazertinib, wherein lazertinib is administered orally.
  • the bispecific anti-EGFR/c-Met antibody disclosed herein may be administered in combination with carboplatin.
  • the bispecific anti-EGFR/c-Met antibody disclosed herein may be administered in combination with pemetrexed.
  • the bispecific anti-EGFR/c-Met antibody disclosed herein may be administered in combination with Lazertinib, carboplatin and pemetrexed.
  • the combination therapy comprising a bispecific anti- EGFR/c-Met bispecific antibody and an EGFR TKI may further include one or more additional anti -cancer therapies.
  • the methods of the present disclosure comprise administering to a subject a cancer therapy which does not include the combination therapy comprising a bispecific anti- EGFR/c-Met bispecific antibody and an EGFR TKI disclosed herein.
  • the cancer therapy may include any one of those described herein.
  • the cancer therapy that may be administered in the methods of the disclosure may comprise any number of various platinum-based chemotherapies or combinations thereof.
  • the platinum-based chemotherapy comprises carboplatin, cisplatin, or a combination thereof.
  • Additional anti -cancer therapies may include any one or more of the chemotherapeutic drugs or other anti-cancer therapeutics known to those of skill in the art.
  • Chemotherapeutic agents are chemical compounds useful in the treatment of cancer and include growth inhibitory agents or other cytotoxic agents and include alkylating agents, anti-metabolites, anti-microtubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors and the like.
  • chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine,
  • anti-hormonal agents that act to regulate or inhibit hormone action on tumors
  • anti -estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (FARESTON®); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • An exemplary bispecific anti-EGFR/c-Met antibody that can be used in the methods of the disclosures is amivantamab.
  • Amivantamab is an IgGl anti-EGFR/c-Met bispecific antibody described in U.S. Pat. No. 9,593,164, which is incorporated herein by reference in its entirety.
  • Amivantamab is characterized by following amino acid sequences: EGFR binding arm
  • 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, aHCDR2 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 the second domain 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 a HCDR3 of SEQ ID
  • 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 is amivantamab.
  • the bispecific anti-EGFR/c-Met antibody is a biosimilar of amivantamab.
  • a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: btt.ps://us.proteogenrx science/producVamivantamab-biosimilar-anti-egfr-me-rccp -mab-research ⁇ rade/.
  • a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: https://www_thermofisher_com/antibody/product/Amivantamab-Antibody-Recombinant- Monoclonal/MA5 -42260.
  • a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: https://www_gcncmcdi.nct/i/biologics- biosimilar-GMP-Bios-ab-021.
  • a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: https://www_prosci- inc_com/product/amivantamab-egfr-me-rccp2-research-grade-biosimilar-10-966/.
  • a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: https://www_antibodysystem_com/product/6201.html.
  • a non-limiting example of a biosimilar of amivantamab can be found in publicly available Web resource: https://www_biorbyt_com/amivantamab- biosimilar-antibody-orb 1140752.html .
  • the bispecific anti-EGFR/c-Met antibody comprises one or more Fc silencing mutations.
  • the one or more Fc silencing mutations decrease affinity to Fey receptors.
  • the one or more Fc silencing mutations comprise V234A/G237A/P238 S/H268 A/V309L/A330S/P331 S .
  • the bispecific anti-EGFR/c-Met antibody comprises a biantennary glycan structure with a fucose content between about 1% to about 15%.
  • Antibodies with reduced fucose content can be made using different methods reported to lead to the successful expression of relatively high defucosylated antibodies bearing the biantennary complex-type of Fc oligosaccharides such as control of culture osmolality (Konno et al., Cytotechnology 64(:249-65, 2012), application of a variant CHO line Lecl3 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), application of a variant CHO line EB66 as the host cell line (Olivier et al., MAbs ;2(4), 2010; Epub ahead of print; PMID:20562582), application of a rat hybridoma cell line YB2/0 as the host cell line (Shinkawa
  • bispecific anti-EGFR/c-Met antibodies publicly available may also be used in the methods of the disclosure as long as they demonstrate similar characteristics when compared to amivantamab as described in U.S. Pat. No. 9,593,164.
  • Bispecific anti-EGFR/c- Met antibodies that may be used in the methods of the disclosure may also be generated by combining EGFR binding VH/VL domains and c-Met binding VH/VL domains that are publicly available and testing the resulting bispecific antibodies for their characteristics as described in U.S. Pat. No. 9,593,164.
  • the anti-EGFR/c-Met antibodies are biosimilar of anti-EGFR/c-Met antibodies as described in U.S. Pat. No. 9,593,164.
  • Bispecific anti-EGFR/c-Met antibodies used in the methods of the disclosure may be generated for example using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodies by introducing substitutions at the heavy chain CH3 interface in each half molecule to favor heterodimer formation of two antibody half molecules having distinct specificity either in vitro in cell-free environment or using coexpression.
  • the Fab arm exchange reaction is the result of a disulfide -bond isomerization reaction and dissociation-association of CH3 domains. The heavy chain disulfide bonds in the hinge regions of the parental monospecific antibodies are reduced.
  • the resulting free cysteines of one of the parental monospecific antibodies form an inter heavy-chain disulfide bond with cysteine residues of a second parental monospecific antibody molecule and simultaneously CH3 domains of the parental antibodies release and reform by dissociationassociation.
  • the CH3 domains of the Fab arms may be engineered to favor heterodimerization over homodimerization.
  • the resulting product is a bispecific antibody having two Fab arms or half molecules which each bind a distinct epitope, i.e., an epitope on EGFR and an epitope on c-Met.
  • the bispecific antibodies of the invention may be generated using the technology described in Int.Pat. Publ. No. WO2011/131746.
  • Mutations F405L in one heavy chain and K409R in the other heavy chain may be used in case of IgGl antibodies.
  • IgG2 antibodies a wild -type IgG2 and a IgG2 antibody with F405L and R409K substitutions may be used.
  • IgG4 antibodies a wild-type IgG4 and a IgG4 antibody with F405L and R409K substitutions may be used.
  • first monospecific bivalent antibody and the second monospecific bivalent antibody are engineered to have the aforementioned mutation in the Fc region, the antibodies are incubated together under reducing conditions sufficient to allow the cysteines in the hinge region to undergo disulfide bond isomerization; thereby generating the bispecific antibody by Fab arm exchange.
  • the incubation conditions may optimally be restored to non-reducing.
  • Exemplary reducing agents that may be used are 2- mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine and beta- mercaptoethanol.
  • incubation for at least 90 min at a temperature of at least 20°C in the presence of at least 25 mM 2-MEA or in the presence of at least 0.5 mM dithiothreitol at a pH of from 5-8, for example at pH of 7.0 or at pH of 7.4 may be used.
  • Bispecific anti-EGFR/c-Met antibodies used in the methods of the disclosure may also be generated using designs such as the Knob-in-Hole (Genentech), CrossMAbs (Roche) and the electrostatically-matched (Chugai, Amgen, NovoNordisk, Oncomed), the LUZ-Y (Genentech), the Strand Exchange Engineered Domain body (SEEDbody)(EMD Serono), and the Biclonic (Merus).
  • Knob-in-Hole Genentech
  • CrossMAbs Roche
  • electrostatically-matched Chougai, Amgen, NovoNordisk, Oncomed
  • the LUZ-Y Genentech
  • SEEDbody Strand Exchange Engineered Domain body
  • EMD Serono EMD Serono
  • Biclonic Biclonic
  • WO 2006/028936 select amino acids forming the interface of the CH3 domains in human IgG can be mutated at positions affecting CH3 domain interactions to promote heterodimer formation.
  • An amino acid with a small side chain (hole) is introduced into a heavy chain of an antibody specifically binding a first antigen and an amino acid with a large side chain (knob) is introduced into a heavy chain of an antibody specifically binding a second antigen.
  • a heterodimer is formed as a result of the preferential interaction of the heavy chain with a “hole” with the heavy chain with a “knob”.
  • Exemplary CH3 substitution pairs forming a knob and a hole are (expressed as modified position in the first CH3 domain of the first heavy chain/ modified position in the second CH3 domain of the second heavy chain): T366Y/F405A, T366W/F405W, F405W/Y407A, T394W/Y407T, T394S/Y407A, T366W/T394S, F405W/T394S and T366W/T366S_L368A_Y407V.
  • CrossMAb technology in addition to utilizing the “knob-in-hole” strategy to promoter Fab arm exchange utilizes CH1/CL domain swaps in one half arm to ensure correct light chain pairing of the resulting bispecific antibody (see e.g., U.S. Patent No. 8,242,247).
  • Other cross-over strategies may be used to generate full length bispecific antibodies of the invention by exchanging variable or constant, or both domains between the heavy chain and the light chain or within the heavy chain in the bispecific antibodies, either in one or both arms. These exchanges include for example VH-CH1 with VL-CL, VH with VL, CH3 with CL and CH3 with CHI as described in Int. Patent Publ. Nos. W02009/080254, W02009/080251, W02009/018386 and W02009/080252.
  • heterodimerization may be promoted by following substitutions (expressed as modified positions in the first CH3 domain of the first heavy chain/ modified position in the second CH3 domain of the second heavy chain): L351Y_F4O5A_Y4O7V7T394W, T366I_K392M_T394W/F405A_Y407V, T366L_K392M_T394W/F405A_Y407V, L351Y_Y407A/T366A_K409F, L351Y_Y407A/T366V_K409F, Y407A/T366A_K409F, or T350V_L35IY_F405A_Y407V/T350V_T366L_K392L_T394W as described in U.S.
  • SEEDbody technology may be utilized to generate bispecific antibodies of the invention.
  • SEEDbodies have, in their constant domains, select IgG residues substituted with IgA residues to promote heterodimerization as described in U.S. Patent No. US20070287170.
  • Mutations are typically made at the DNA level to a molecule such as the constant domain of the antibody using standard methods.
  • 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) 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,
  • 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.
  • administration of the combination therapy begins on Cycle 1 Day 1 of the first 21 -day cycle, and continues in subsequent 21 -day cycles.
  • the method of any one of embodiments 1-10, wherein the bispecific anti-EGFR/c- Met antibody is administered intravenously.
  • the method of any one of embodiments 1-10, wherein the bispecific anti-EGFR/c- Met antibody is administered subcutaneously.
  • the method of any one of embodiments 1-20 wherein the method comprises administering the carboplatin at a dose of AUC 5 on Day 1 of each 21 -day cycle, for up to 4 cycles.
  • the method of any one of embodiments 1-21 wherein the method comprises administering the pemetrexed at a dose of about 500 mg/m 2 on Day 1 of each 21 -day cycle, with the carboplatin for up to 4 cycles, and then as maintenance until disease progression.
  • the method of embodiment 32 wherein at least one subject within the population of subjects exhibits progression-free survival for at least 10 months.
  • the method of embodiment 34 wherein at least one subject within the population of subjects exhibits progression-free survival for at least 14 months.
  • the method of any one of embodiments 1-35, wherein the combination therapy further achieves an improvement in objective response relative to said reference population e.g., wherein the combination therapy achieves an ORR of at least about 60%, or at least about 61%, or at least about 62%).
  • any one of embodiments 1-36 wherein the combination therapy further achieves an improvement in overall survival (OS) relative to said reference population.
  • OS overall survival
  • DoR duration of response
  • any one of embodiments 1-38 wherein the combination therapy further achieves an improvement in time to subsequent therapy (TTST) relative to said reference population (e.g., wherein the combination therapy achieves a median TTST of at least about 7 months, or at least about 8 months, or at least about 9 months, or at least about 10 months, or at least about 11 months, or at least about 12 months).
  • TTST time to subsequent therapy
  • PFS2 PFS after first subsequent therapy
  • any one of embodiments 1-40 wherein the combination therapy further achieves an improvement in intracranial median PFS relative to said reference population (e.g., wherein the combination therapy achieves a median intracranial PFS of at least about 9 months, or at least about 10 months, or at least about 11 months, or at least about 12 months).
  • a therapeutically effective amount of pemetrexed 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 whose NSCLC progressed on or after treatment with the at least one prior TKI, said reference population having been administered carboplatin and pemetrexed but not said bispecific anti-EGFR/c- Met antibody nor said lazertinib or pharmaceutically acceptable salt or hydrate thereof.
  • 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) 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,
  • 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.
  • the method of any one of embodiments 42-46, wherein said at least one prior TKI comprises a 1st generation EGFR TKI.
  • the method of any one of embodiments 42-46, wherein said at least one prior TKI comprises a 3rd generation EGFR TKI.
  • the method of any one of embodiments 42-46, wherein said at least one prior TKI comprises osimertinib.
  • the method of any one of embodiments 42-50, wherein administration of the combination therapy begins on Cycle 1 Day 1 of the first 21 -day cycle, and continues in subsequent 21 -day cycles.
  • the method of any one of embodiments 42-51 wherein the bispecific anti-EGFR/c- Met antibody is administered intravenously.
  • the method of any one of embodiments 42-51, wherein the bispecific anti-EGFR/c- Met antibody is administered subcutaneously.
  • any one of embodiments 42-53 wherein the method comprises administering the bispecific anti-EGFR/c-Met antibody in an amount of between about 140 mg and about 2240 mg.
  • the method of embodiment 54 wherein 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.
  • the method of embodiment 55 wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg.
  • the method of embodiment 56, wherein the bispecific anti-EGFR/c-Met antibody dose of Cycle 1 Day 1 is administered as a split dose over Day 1 and 2.
  • the method of embodiment 55 wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1750 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of greater than or equal to 80 kg.
  • the method of embodiment 59, wherein the bispecific anti-EGFR/c-Met antibody dose of Cycle 1 Day 1 is administered as a split dose over Day 1 and 2.
  • the method of any one of embodiments 42-61, wherein the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is lazertinib mesylate.
  • the method of any one of embodiments 42-61, wherein the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is lazertinib mesylate monohydrate.
  • the method of any one of embodiments 42-63, wherein the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, at a dose of about 240 mg orally, once daily.
  • the method of embodiment 64 wherein the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, at a dose of about 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if said carboplatin is discontinued earlier.
  • the method of any one of embodiments 42-65 wherein the method comprises administering the carboplatin at a dose of AUC 5 on Day 1 of each 21 -day cycle, for up to 4 cycles.
  • the method of any one of embodiments 42-66 wherein the method comprises administering the pemetrexed at a dose of about 500 mg/m 2 on Day 1 of each 21 -day cycle, with carboplatin for up to 4 cycles, and then as maintenance until disease progression.
  • the method of embodiment 75 wherein at least one subject within the population of subjects exhibits progression-free survival for at least 5.5 months.
  • the method of embodiment 76 wherein at least one subject within the population of subjects exhibits progression-free survival for at least 6 months.
  • the method of embodiment 77 wherein at least one subject within the population of subjects exhibits progression-free survival for at least 10 months.
  • the method of embodiment 78 wherein at least one subject within the population of subjects exhibits progression-free survival for at least 12 months.
  • the method of embodiment 79 wherein at least one subject within the population of subjects exhibits progression-free survival for at least 14 months.
  • any one of embodiments 42-80 wherein the combination therapy further achieves an improvement in objective response relative to of said reference population (e.g., wherein the combination therapy achieves an ORR of at least about 60%, or at least about 61%, or at least about 62%).
  • DoR duration of response
  • any one of embodiments 42-83 wherein the combination therapy further achieves an improvement in time to subsequent therapy (TTST) relative to of said reference population (e.g., wherein the combination therapy achieves a median TTST of at least about 7 months, or at least about 8 months, or at least about 9 months, or at least about 10 months, or at least about 11 months, or at least about 12 months).
  • TTST time to subsequent therapy
  • PFS2 PFS after first subsequent therapy
  • the method of any one of embodiments 1-86, wherein the bispecific anti-EGFR/c- Met antibody is a biosimilar of amivantamab.
  • the combination therapy further achieves an improvement in TTD, TTST, and PFS2 relative to said reference population (e.g., wherein the combination therapy achieves a median TTD of greater than 4.5 months, or at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or at least about 11 months; and wherein the combination therapy achieves a median TTST of greater than 6.6 months, or at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months; and wherein the combination therapy achieves a median PFS2 of greater than 11.3 months, or at least about 12 months, or at least about 13 months).
  • TTSP time to symptomatic progression
  • 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 method of any one of embodiments 91-95, wherein said at least one prior TKI comprises a 1 st generation EGFR TKI.
  • the method of any one of embodiments 91-95, wherein said at least one prior TKI comprises a 2 nd generation EGFR TKI.
  • the method of embodiment 104 wherein 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg. .
  • the method of embodiment 106 wherein the bispecific anti-EGFR/c-Met antibody dose of Cycle 1 Day 1 is administered as a split dose over Day 1 and 2..
  • the method of embodiment 105 wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1750 mg on Day 1 of each 21 -day cycle, starting with Cycle 3 if the subject has a body weight of less than 80 kg. .
  • the method of embodiment 105, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1750 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of greater than or equal to 80 kg..
  • the method of embodiment 109 wherein the bispecific anti-EGFR/c-Met antibody dose of Cycle 1 Day 1 is administered as a split dose over Day 1 and 2.
  • the method of embodiment 105 wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 2100 mg on Day 1 of each 21 -day cycle, starting with Cycle 3 if the subject has a body weight of greater than or equal to 80 kg.
  • the method of any one of embodiments 91-111, wherein the method comprises administering the carboplatin at a dose of AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles. .
  • any one of embodiments 91-112, wherein the method comprises administering the pemetrexed at a dose of about 500 mg/m 2 on Day 1 of each 21-day cycle, with the carboplatin for up to 4 cycles, and then as maintenance until disease progression. .
  • the method of embodiment 113 wherein the method comprises: a) (i) administering the bispecific anti-EGFR/c-Met antibody at a dose of about 1400 mg on Cycle 1 Days 1, 8, and 15, and Cycle 2 Day 1 if the subject has a body weight of less than 80 kg; or (ii) administering the bispecific anti-EGFR/c-Met antibody at a dose of about 1750 mg on Day 1 of each 21 -day cycle, starting with Cycle 3 if the subject has a body weight of less than 80 kg; or
  • any one of embodiments 91-115 wherein the population of subjects administered the combination therapy achieves an improvement in the median OS of at least two months, relative to said reference population. .
  • the method of embodiment 116 wherein the population of subjects administered the combination therapy achieves an improvement in the median OS of at least about 2.2 months, 2.3 months, 2.4 months, 2.5 months, or 2.6 months, relative to said reference population. .
  • the method of embodiment 116 wherein the population of subjects administered the combination therapy achieves an improvement in the median OS of about 2.4 months, relative to said reference population.
  • the method of embodiment 116, wherein the population of subjects administered the combination therapy exhibits overall survival for at least 17 months. .
  • the method of embodiment 119 wherein the subject exhibits overall survival for at least about 17.2 months, about 17.4 months, about 17.6 months, about 17.7 months, about 17.8 months, or about 18 months. .
  • the method of any one of embodiments 91-121, wherein the population of subjects administered the combination therapy further achieves an improvement in time to subsequent therapy (TTST) relative to said reference population.
  • TTST time to subsequent therapy
  • TTSP time to symptomatic progression
  • TTD time to treatment discontinuation
  • the method of embodiment 122 wherein the population of subjects administered the combination therapy exhibits TTST of about 12 months, about 12.2 months, or about 12.5 months. .
  • the method of embodiment 122 wherein the population of subjects administered the combination therapy exhibits TTST of about 12.2 months.
  • the method of embodiment 122, wherein the population of subjects administered the combination therapy exhibits TTST of about 2-fold longer at 18 months than the reference population.
  • the method of embodiment 123 wherein the population of subjects administered the combination therapy achieves an improvement of at least about 4 months TTSP relative to said reference population. .
  • the method of embodiment 123, wherein the population of subjects administered the combination therapy achieves an improvement of about 4 months, about 4.2 months, or about 4.5 months in TTSP relative to said reference population..
  • the method of embodiment 123 wherein the population of subjects administered the combination therapy achieves an improvement of about 4 months, in TTSP relative to said reference population. .
  • the method of embodiment 123 wherein the population of subjects administered the combination therapy achieves an improvement of about 4.2 months in TTSP relative to said reference population.
  • the method of embodiment 123 wherein the population of subjects administered the combination therapy exhibits TTSP of at least about 16 months.
  • the method of embodiment 123 wherein the population of subjects administered the combination therapy achieves a reduction of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% in TTSP relative to said reference population. .
  • the method of embodiment 123 wherein the population of subjects administered the combination therapy achieves a reduction of about 27% in TTSP at 18 months relative to said reference population.
  • the method of embodiment 124 wherein the population of subjects administered the combination therapy achieves an improvement in PFS2 of at least about 4 months, about 4.2 months, about 4.4 months, about 4.5 months, about 4.6 months, about 4.8 months, or about 5 months relative to said reference population..
  • the method of embodiment 124 wherein the population of subjects administered the combination therapy achieves an improvement in PFS2 of about 4 months, about 4.2 months, about 4.4 months, about 4.5 months, about 4.6 months, about 4.8 months, or about 5 months relative to said reference population. .
  • the method of embodiment 125 wherein the population of subjects administered the combination therapy achieves an improvement in TTD of at least about 5 months, about 5.3 months, about 5.5 months, about 5.7, about 5.9 months, or about 6 months, relative to said reference population. .
  • the method of embodiment 125 wherein the population of subjects administered the combination therapy achieves an improvement in TTD of about 5 months, about 5.3 months, about 5.5 months, about 5.7, about 5.9 months, or about 6 months, relative to said reference population.
  • CHRYSALIS-2 (NCT04077463) is an open-label Phase 1/lb study to evaluate the safety and pharmacokinetics of Lazertinib as monotherapy or in combinations with amivantamab in participants with advanced non-small cell lung cancer. The study includes multiple cohorts. Provided below are results for the LACP (lazertinib, amivantamab, carboplatin, pemetrexed) cohort of 20 patients.
  • MARIPOSA-2 is a randomized, open-label, active-controlled, parallel, multicenter, Phase 3 study to compare the efficacy and safety of Arm A (lazertinib, amivantamab, carboplatin, and pemetrexed “LACP/ACP-L”) versus Arm B (carboplatin and pemetrexed, “CP”) and Arm C (amivantamab, carboplatin, and pemetrexed, “ACP”) versus Arm B (CP) in participants with EGFR-mutated locally advanced or metastatic nonsquamous NSCLC who have progressed on or after treatment with osimertinib.
  • Study ID numbers include: NCT04988295, CR109061, 2021-001825-33 (EudraCT) and 61186372NSC3002.
  • the purpose of this study is to assess the efficacy of adding lazertinib to amivantamab, carboplatin, and pemetrexed (LACP/ACP-L dosing strategies) and amivantamab, carboplatin and pemetrexed (ACP) compared with carboplatin and pemetrexed (CP) in participants with locally advanced or metastatic epidermal growth factor receptor (EGFR) Exon 19del or Exon 21 L858R substitution non-small cell lung cancer (NSCLC) after osimertinib failure.
  • the purpose of the extension cohort is to further describe the safety and efficacy for the ACP-L dosing schedule versus ACP with additional data.
  • Arm A was eventually modified to withhold lazertinib during administration of carboplatin.
  • the modified dosing schedule whereby lazertinib was started after treatment with carboplatin was completed is referred to as ACP-L; the prior dosing schedule before modification (i.e., participants started lazertinib from the beginning of treatment) is referred to as LACP.
  • LACP prior dosing schedule before modification
  • the primary statistical analyses compared all participants randomized between Arm A and Arm B, regardless of dosing schedule, and between Arm C and Arm B on an intent to treat basis.
  • extension cohort was added to the study. Enrollment of participants into the extension cohort began after enrollment into the main study was complete. The extension cohort had the same eligibility criteria and study procedures, and operated within the same investigational sites as the main study. Participants were planned to be randomly assigned to study treatment arms in 2: 1 ratio (Arms A2 and C2 respectively) in the extension cohort.
  • Eligible patients were 18 years of age or older, had locally advanced or metastatic NSCLC with disease progression on or after osimertinib monotherapy (as the most recent line of treatment), and had EGFR Exl9del or L858R mutations. Patients with brain metastases were eligible provided intracranial disease was stable, asymptomatic, and on unchanged doses of steroids. Additional information about the criteria is provided below.
  • Participant must have at least 1 measurable lesion, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, that has not been previously irradiated;
  • NSCLC non-squamous non-small cell lung cancer
  • a participant with a history of brain metastases must have had all lesions treated as clinically indicated (that is, no current indication for further definitive local therapy). Any definitive local therapy to brain metastases must have been completed at least 14 days prior to randomization and the participant can be receiving no greater than 10 milligrams (mg) prednisone or equivalent daily for the treatment of intracranial disease; • Participant must have Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 ;
  • a woman of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study;
  • Participant must have progressed on or after osimertinib monotherapy as the most recent line of treatment.
  • Osimertinib must have been administered as either the first- line treatment for locally advanced or metastatic disease or in the second- line setting after prior treatment with first- or second-generation EGFR tyrosine kinase inhibitor (TKI) as a monotherapy.
  • Participants who received either neoadjuvant and/or adjuvant treatment of any type are eligible if progression to locally advanced or metastatic disease occurred at least 12 months after the last dose of such therapy and then the participant progressed on or after osimertinib in the locally advanced or metastatic setting.
  • Treatment with osimertinib must be discontinued at least 8 days (4 half-lives) prior to randomization (that is last dose no later than Day -8).
  • Participant has history of or current evidence of leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation;
  • ILD interstitial lung disease
  • Participant has a history of clinically significant cardiovascular disease including, but not limited to diagnosis of deep vein thrombosis or pulmonary embolism within 4 weeks prior to randomization; myocardial infarction; unstable angina; stroke; transient ischemic attack; coronary/peripheral artery bypass graft; or acute coronary syndrome. Participant has a significant genetic predisposition to venous thromboembolic events. Participant has a prior history of venous thromboembolic events and is not on appropriate therapeutic anticoagulation as per National Comprehensive Cancer Network or local guidelines.
  • Treatment duration/Trial duration Treatment duration/Trial duration
  • the study included a Screening Phase, a Treatment Phase, and a Follow-up Phase.
  • the Treatment Phase began on Cycle 1 Day 1 and continued in 21 -day cycles until the End of Treatment visit, that was to occur within 30 days after discontinuation of study treatment or prior to starting subsequent systemic therapy, whichever occurred first. Participants who discontinued study treatment for any reason were to 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 death, lost to follow-up, or withdrawal of consent, whichever comes first.
  • LACP Dosing Schedule 1
  • MARIPOSA-2 (NCT04988295) is a randomized, open-label Phase 3 study evaluating the efficacy and safety of two dosing regimens of RYBREVANT® (amivantamab) and chemotherapy.
  • Patients with locally advanced or metastatic EGFR exl9del or L858R substitution NSCLC who had disease progression on or after osimertinib were randomized to treatment with RYBREVANT® plus chemotherapy, RYBREVANT® plus chemotherapy with lazertinib or chemotherapy alone.
  • Dual primary endpoints were used to compare the PFS (using RECIST vl.l guidelines) as assessed by blinded independent central review (BICR) for each experimental arm to chemotherapy alone.
  • SCSLC non-small cell lung cancer
  • the median progression-free survival by blinded independent central review was 6.3 months (95% CI, 5.55 to 8.4) with amivantamab-chemotherapy, 8.3 months (95% CI, 6.8 to 9.1) with amivantamab-lazertinib-chemotherapy, and 4.2 months (95% CI, 4.0 to 4.4) with chemotherapy.
  • the hazard ratio for disease progression or death was 0.48 (95% CI, 0.36 to 0.64; P ⁇ 0.001) for amivantamab-chemotherapy versus chemotherapy and similar in magnitude to amivantamab-lazertinib-chemotherapy versus chemotherapy (0.44; 95% CI, 0.35 to 0.56; P0.001).
  • the median investigator-assessed progression-free survival was 8.2 months (95% CI, 6.8 to 10.9) for amivantamab-chemotherapy and 8.3 months (95% CI, 7.1 to 9.9) for amivantamab-lazertinib-chemotherapy versus 4.2 months (95% CI, 4.0 to 4.5) for chemotherapy, corresponding to similar hazard ratios for disease progression or death of 0.41 and 0.38, respectively (P ⁇ 0.001 for both versus chemotherapy).
  • the progression-free survival benefit was consistent across predefined subgroups for amivantamab-chemotherapy and similar in magnitude to amivantamab-lazertinib- chemotherapy, including subgroups based on history of brain metastases, osimertinib line of therapy, and EGFR mutation type.
  • the objective response rate was 64% (95% CI, 55 to 72) for amivantamab- chemotherapy, 63% (95% CI, 57 to 69) for amivantamab-lazertinib-chemotherapy, and 36% (95% CI, 30 to 42) for chemotherapy, with similar significant improvements versus chemotherapy for amivantamab-chemotherapy (odds ratio, 3.10; 95% CI, 2.00 to 4.80;
  • Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy significantly prolonged progression-free survival versus chemotherapy, with a 52% and 56% reduction in the risk of disease progression or death, respectively.
  • Early separation of curves was observed between both amivantamab-chemotherapy and amivantamab-lazertinib- chemotherapy versus chemotherapy.
  • the progression-free survival benefit was consistent across predefined subgroups.
  • the magnitude of improvement over chemotherapy was similar for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy.
  • Amivantamab is a large molecule and was not expected to readily cross the bloodbrain barrier. This was one of the key drivers for including lazertinib, a known CNS-active TKI, in the amivantamab-lazertinib-chemotherapy arm. It is thus notable that amivantamab- chemotherapy demonstrated similar intracranial progression-free survival advantages over chemotherapy as amivantamab-lazertinib-chemotherapy. These findings suggest that amivantamab exerts an antitumor effect intracranially, whether this occurs through direct engagement with intracranial metastases or indirectly through an immune-based mechanism is unclear. Despite the frequent utilization of TKI continuation out of concern for CNS progression, no prior prospective trial has shown improved clinical outcomes with this approach.
  • progression-free survival was significantly longer with amivantamab- chemotherapy and amivantamab-lazertinib-chemotherapy compared with chemotherapy in patients with EGFR-mutated advanced NSCLC whose disease had progressed on or after osimertinib monotherapy.
  • pts with PD 75% (41/55) in the ami-chemo arm discontinued treatment after progression vs 93% (161/173) for chemo.
  • TTSP time to symptomatic progression
  • PROs patient-reported outcomes
  • TTSP tent-to-treat population
  • amivantamab-chemotherapy substantially prolonged time to sustained deterioration in lung cancer symptoms vs chemotherapy (11.6 vs 8.5 mo).
  • MARIPOSA-2 enrolled pts with FGFR-mutant (Exl9del/L858R) advanced NSCLC post-osi.
  • the primary endpoint was PFS.
  • IA2 of OS was prespecified to occur when -75% of total OS events were observed.
  • OS was to be evaluated at a 2-sided alpha of 0.0142 (O’Brien-Fleming alpha spending approach as implemented by the Lan- DeMets method).
  • Other endpoints were time to treatment discontinuation (TTD), time to subsequent therapy (TTST), and PFS after first subsequent therapy (PFS2).
  • FIG. 2 shows the MARIPOSA-2 Study Design. Secondary/Exploratory efficacy endpoints reported: overall survival (OS); time to symptomatic progression (TTSP); time to treatment discontinuation (TTD); time to subsequent therapy (TTST); and PFS after first subsequent therapy (PFS2).
  • OS overall survival
  • TTSP time to symptomatic progression
  • TTD time to treatment discontinuation
  • TTST time to subsequent therapy
  • PFS PFS after first subsequent therapy
  • the second interim analysis of OS was prespecified for when -75% of the planned OS events were observed. The significance level at the second interim analysis for OS was determined based on the O’Brien-Fleming alpha spending approach (2- sided alpha: 0.0142) as implemented by the Lan-DeMets method.
  • FIG. 3 shows overall survival. Amivantamab-chemotherapy demonstrated a clear and improving OS trend vs chemotherapy. P-value was calculated using a log-rank test stratified by osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes or no), and Asian race (yes vs no). OS was evaluated at a 2-sided alpha of 0.0142.
  • FIG. 4 shows Time to Symptomatic Progression (TTSP, time from randomization to onset of new symptoms or symptom worsening that was considered by the investigator to be related to lung cancer and required either a change in anticancer treatment and/or clinical intervention to manage symptoms).
  • TTSP was significantly improved with amivantamab- chemotherapy vs chemotherapy, b -
  • P-value was calculated using a logrank test stratified by osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes or no), and Asian race (yes vs no).
  • FIG. 5 shows Time to Treatment Discontinuation (TTD, time from randomization to discontinuation of all study treatments for any reason, including disease progression, treatment toxicity, or death), b -
  • TTD Time to Treatment Discontinuation
  • ami-chemo significantly prolonged TTD vs chemo (HR, 0.37; 95% CI, 0.28-0.50; P ⁇ 0.0001).
  • l cP-value is from a logrank test stratified by osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes or no), and Asian race (yes vs no).
  • FIG. 6 shows Time to Subsequent Therapy (Time from the date of randomization to the start date of the subsequent anticancer therapy following study treatment discontinuation, or death, whichever occurred first).
  • TTST was significantly prolonged with amivantamab-chemotherapy vs chemotherapy, b -
  • ami-chemo significantly prolonged TTST vs chemo (HR, 0.42; 95% CI, 0.30-0.59; P ⁇ 0.0001).
  • l P-value was determined using a log-rank test stratified by osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes or no), and Asian race (yes vs no).
  • FIG. 7 shows PFS After First Subsequent Therapy (PFS2, time from randomization until the date of second objective disease progression, after initiation of subsequent anticancer therapy, based on investigator assessment (after that used for PFS) or death, whichever occurred first).
  • PFS2 was significantly prolonged with amivantamab- chemotherapy vs chemotherapy, b -
  • P-value was calculated using a logrank test stratified by osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes or no), and Asian race (yes vs no). No single therapy class was identified as the most prominent subsequent therapy, highlighting the limited options in the third-line setting.
  • Amivantamab’s multi -targeted MoA and immune cell-directing activity combined with chemotherapy’s antitumor effects is likely contributing to the observed durability.

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Abstract

La présente divulgation concerne des méthodes pour traiter le cancer du poumon non à petites cellules (CPNPC) positif à l'EGFR chez un sujet chez qui la maladie a progressé pendant ou à la suite d'un traitement avec au moins un inhibiteur de tyrosine kinase (TKI) antérieur.
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