Treatment methods for non-small cell lung cancer

Abstract

This disclosure provides a method for treating EGFR-positive non-small cell lung cancer (NSCLC) in subjects who have experienced disease progression during or after treatment with at least one prior tyrosine kinase inhibitor (TKI).

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 536,575, filed on 5 September 2023, and U.S. Provisional Patent Application No. 63 / 564,664, filed on 13 March 2024, the disclosures of each of these applications being incorporated herein by reference in their entirety.

[0002] (Sequence Listing) This application includes a sequence listing submitted electronically in XML format, the entirety of which is incorporated herein by reference. The XML copy was created on 3 September 2024, named JBI6835_SeqListing.xml, and has a size of 20,480 bytes.

[0003] (Field of Invention) This disclosure provides a method for treating epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) in subjects who have experienced disease progression during or after treatment with at least one prior tyrosine kinase inhibitor (TKI). [Background technology]

[0004] Stratification of advanced non-small cell lung cancer (NSCLC) based on cancer driver gene mutations improved overall survival and quality of life, as well as solid tumor-targeted therapy, in patients with treatable driver gene mutations. In NSCLC, specific mutations in the EGFR gene are associated with a high response rate to EGFR tyrosine kinase inhibitors (EGFR TKIs). While the majority of NSCLC patients with EGFR mutations initially respond to EGFR TKI therapy, virtually all acquire resistance that prevents a sustained response. Nearly 60% of all tumors that become resistant to EGFR tyrosine kinase inhibitors show increased hepatocyte growth factor receptor (c-Met) expression, amplification of the c-Met gene, or increased levels of hepatocyte growth factor, its only known ligand (Turke et al., Cancer Cell, 17:77-88, 2010).

[0005] The progression of acquired resistance to EGFR-TKIs such as osimertinib in epidermal growth factor receptor variant (EGFRm) NSCLC is likely to arise from a complex and heterogeneous pattern of resistance, along with the simultaneous development of multiple resistance mechanisms, and therefore the details of such mechanisms remain unclear. Consequently, the duration and persistence of responses to targeted therapies present unique challenges, and a new therapeutic paradigm is still needed for patients with NSCLC whose disease has progressed during or after treatment with at least one previous tyrosine kinase inhibitor (TKI). [Overview of the project]

[0006] In one embodiment, the foregoing provides a method for improving the median progression-free survival (PFS) in a population of subjects having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations and whose NSCLC has progressed during or after prior treatment with at least one tyrosine kinase inhibitor (TKI), the method comprising administering to the subject population a combination therapy comprising (i) a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, wherein the improvement in median PFS is compared to the median PFS of a reference population of subjects having NSCLC with one or more EGFR mutations and whose NSCLC has progressed during or after prior treatment with at least one TKI, the reference population of subjects having been administered carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody.

[0007] In another embodiment, provided herein is a method for improving the median progression-free survival (PFS) in a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer having one or more epidermal growth factor receptor (EGFR) mutations and having progressed during or after treatment with at least one tyrosine kinase inhibitor (TKI), the method comprising: (i) a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody; (ii) a therapeutically effective dose of razertinib or a pharmaceutically acceptable salt or hydrate thereof; iii) administering a combination therapy comprising a therapeutically effective dose of carboplatin and (iv) a therapeutically effective dose of pemetrexed, wherein the improvement in median PFS is compared to the median PFS of a reference population of subjects having NSCLC with one or more EGFR mutations, where NSCLC progressed during or after treatment with at least one prior TKI, and the reference population was administered carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody, razertinib, or any pharmaceutically acceptable salt or hydrate thereof. In some embodiments, razertinib, or any pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate. In some embodiments, razertinib, or any pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate monohydrate. In some embodiments, razertinib, or a pharmaceutically acceptable salt or hydrate thereof, is administered orally once daily in a dose of approximately 240 mg.

[0008] In some embodiments of any of the methods described above in this disclosure, a bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0009] In some embodiments of any of the methods described above in this disclosure, one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. In some embodiments of any of the methods described above in this disclosure, one or more EGFR mutations include one or more exon 19 deletions. In some embodiments of any of the methods described above in this disclosure, one or more EGFR mutations include exon 21 L858R substitutions.

[0010] In some embodiments of any of the methods described above in this disclosure, the at least one prior TKI includes a first-generation EGFR TKI. In some embodiments of any of the methods described above in this disclosure, the at least one prior TKI includes a second-generation EGFR TKI. In some embodiments of any of the methods described above in this disclosure, the at least one prior TKI includes a third-generation EGFR TKI. In some embodiments of any of the methods described above in this disclosure, the at least one prior TKI includes osimertinib.

[0011] In some embodiments of any of the methods described above in this disclosure, administration of the combination therapy is initiated on day 1 of cycle 1 of a first 21-day cycle and continues in subsequent 21-day cycles.

[0012] In some embodiments of any of the methods described above in this disclosure, the bispecific anti-EGFR / c-Met antibody is administered intravenously. In some embodiments of any of the methods described above in this disclosure, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0013] In some embodiments of any of the above methods of the Disclosure, the method comprises administering a bispecific anti-EGFR / c-Met antibody in amounts ranging from about 140 mg to about 2240 mg. In some embodiments of any of the above methods of the Disclosure, the bispecific anti-EGFR / c-Met antibody is administered in doses 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.

[0014] In some embodiments of any of the above methods of this disclosure, a bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, if the subject has a body weight of less than 80 kg. In some embodiments of any of the above methods of this disclosure, the dose of bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

[0015] In some embodiments of any of the methods described above in this disclosure, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3, if the subject has a body weight of less than 80 kg.

[0016] In some embodiments of any of the above methods of this disclosure, a bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2, if the subject has a body weight of 80 kg or more. In some embodiments of any of the above methods of this disclosure, the dose of bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

[0017] In some embodiments of any of the methods described above in this disclosure, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3, if the subject has a body weight of 80 kg or more.

[0018] In some embodiments of any of the methods described above in this disclosure, the method includes administering carboplatin at a dose of AUC5 on day 1 of each 21-day cycle for up to 4 cycles.

[0019] In some embodiments of any of the above methods of this disclosure, the method involves administering pemetrexed at approximately 500 mg / m². 2 This includes administering the drug at the specified dose on day 1 of each 21-day cycle, together with carboplatin, for up to four cycles, followed by pemetrexed as maintenance therapy until disease progression.

[0020] In some embodiments of any of the above methods of the present disclosure, the method comprises: a) (i) if the subject has a body weight of less than 80 kg, administering the bispecific anti-EGFR / c-Met antibody at a dose of about 1400 mg on Day 1, Day 8, and Day 15 of Cycle 1, and Day 1 of Cycle 2; or (ii) if the subject has a body weight of less than 80 kg, administering the bispecific anti-EGFR / c-Met antibody at a dose of about 1750 mg starting from Cycle 3 on Day 1 of each 21-day cycle; or (iii) if the subject has a body weight of 80 kg or more, administering the bispecific anti-EGFR / c-Met antibody at a dose of about 1750 mg on Day 1, Day 8, and Day 15 of Cycle 1, and Day 1 of Cycle 2; or (iv) if the subject has a body weight of 80 kg or more, administering the bispecific anti-EGFR / c-Met antibody at a dose of about 2100 mg starting from Cycle 3 on Day 1 of each 21-day cycle; b) administering carboplatin at an AUC5 dose on Day 1 of each 21-day cycle for up to 4 cycles; and c) pemetrexed at about 500 mg / m 2 dose, administered on Day 1 of each 21-day cycle in combination with carboplatin for up to 4 cycles, followed by administration of pemetrexed as maintenance therapy until disease progression. In some embodiments of any of the above methods of the present disclosure, the Day 1 dose of Cycle 1 is administered as a divided dose over Day 1 and Day 2.

[0021] In some embodiments of any of the above methods of this disclosure, the combination therapy achieves an improvement of at least two weeks in median PFS. In some embodiments of any of the above methods of this disclosure, the combination therapy achieves an improvement of at least one month in median PFS. In some embodiments of any of the above methods of this disclosure, the combination therapy achieves an improvement of at least one.5 months in median PFS. In some embodiments of any of the above methods of this disclosure, the combination therapy achieves an improvement of at least two months in median PFS. In some embodiments of any of the above methods of this disclosure, the subjects show a PFS of at least four.5 months. In some embodiments of any of the above methods of this disclosure, the subjects show a PFS of at least five months. In some embodiments of any of the above methods of this disclosure, the subjects show a progression-free survival of at least five.5 months. In some embodiments of any of the above methods of this disclosure, the subjects show a PFS of at least six months. In some embodiments of any of the above methods of this disclosure, the subjects show a progression-free survival of at least ten months. In some embodiments of any of the methods described above in this disclosure, the subject matter shows a PFS over a period of at least 12 months. In some embodiments of any of the methods described above in this disclosure, the subject matter shows a PFS over a period of at least 14 months.

[0022] In some embodiments of any of the above methods of the present disclosure, the combination therapy further achieves an improvement in objective response as compared to the reference population. In some embodiments of any of the above methods of the present disclosure, the combination therapy further achieves an improvement in overall survival (OS) as compared to the reference population. In some embodiments of any of the above methods of the present disclosure, the combination therapy further achieves an improvement in duration of response (DoR) as compared to the reference population. In some embodiments of any of the above methods of the present disclosure, the combination therapy further achieves an improvement in time to subsequent therapy as compared to the reference population. In some embodiments of any of the above methods of the present disclosure, the combination therapy further achieves an improvement in post-progression survival after first subsequent therapy (PFS2) as compared to the reference population. In some embodiments of any of the above methods of the present disclosure, the combination therapy further achieves an improvement in median intracranial PFS as compared to the reference population.

[0023] In one aspect, disclosed herein is a method of improving median overall survival (OS) in a population of subjects having locally advanced or metastatic non-small cell lung cancer (NSCLC) with one or more epidermal growth factor receptor (EGFR) mutations, and having NSCLC that progressed during or after treatment with at least one prior tyrosine kinase inhibitor (TKI), the method comprising 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 OS is compared to the median OS of a reference population of subjects having NSCLC with one or more EGFR mutations, wherein the NSCLC progressed during or after treatment with at least one prior TKI, and the reference population is administered carboplatin and pemetrexed but not administered the bispecific anti-EGFR / c-Met antibody.

[0024] In some embodiments, a bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain includes the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, the light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met includes the HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0025] In some embodiments, one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

[0026] In some embodiments, one or more EGFR mutations include one or more exon 19 deletions. In some embodiments, one or more EGFR mutations include an exon 21 L858R substitution.

[0027] In some embodiments, the prior at least one TKI comprises a first-generation EGFR TKI. In some embodiments, the prior at least one TKI comprises a second-generation EGFR TKI. In some embodiments, the prior at least one TKI comprises a third-generation EGFR TKI. In some embodiments, the prior at least one TKI comprises osimertinib.

[0028] In some embodiments, administration of the combination therapy begins on day 1 of cycle 1 of the first 21-day cycle and continues in subsequent 21-day cycles.

[0029] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0030] In some embodiments, the method involves administering a bispecific anti-EGFR / c-Met antibody in an amount ranging from approximately 140 mg to approximately 2240 mg.

[0031] In some embodiments, bispecific anti-EGFR / c-Met antibodies are administered in doses of approximately 700 mg, 750 mg, 800 mg, 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.

[0032] In some embodiments, if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2.

[0033] In some embodiments, the bispecific anti-EGFR / c-Met antibody dose for day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

[0034] In some embodiments, if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle.

[0035] In some embodiments, if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2.

[0036] In some embodiments, the bispecific anti-EGFR / c-Met antibody dose for day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

[0037] In some embodiments, if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle.

[0038] In some embodiments, the method involves administering carboplatin at a dose of AUC5 on day 1 of each 21-day cycle for up to four cycles.

[0039] In some embodiments, this method involves administering pemetrexed at approximately 500 mg / m². 2 This involves administering the specified dose with carboplatin on day 1 of each 21-day cycle for up to four cycles, followed by pemetrexed as maintenance therapy until disease progression.

[0040] In some embodiments, this method a)(i) If the subject has a body weight of less than 80 kg, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, or (ii) If the subject has a body weight of less than 80 kg, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle, or (iii) If the subject has a body weight of 80 kg or more, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, or (iv) If the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody should be administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle. b) Administer carboplatin at a dose equal to AUC5 on day 1 of each 21-day cycle for a maximum of 4 cycles. c) Pemetrexed, approximately 500 mg / m² 2This includes administering the specified dose together with carboplatin on day 1 of each 21-day cycle for up to 4 cycles, followed by pemetrexed as maintenance therapy until disease progression.

[0041] In some embodiments, the bispecific anti-EGFR / c-Met antibody dose for day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

[0042] In some embodiments, the combination therapy achieves an improvement in median overall survival (OS) for at least two months.

[0043] In some embodiments, the combination therapy achieves an improvement in median overall survival (OS) for at least 2.4 months.

[0044] In some embodiments, combination therapy achieves an improvement in median overall survival (OS) over approximately 2.4 months.

[0045] In some embodiments, subjects demonstrate an overall survival period of at least approximately 17 months.

[0046] In some embodiments, subjects exhibit an overall survival period of at least approximately 17.7 months.

[0047] In some embodiments, subjects exhibit an overall survival period of approximately 17.7 months.

[0048] In some embodiments, combination therapy achieves further improvement in time to disease progression (TTSP) compared to the reference population.

[0049] In some embodiments, combination therapy achieves further improvement in time to subsequent therapy (TTST) compared to the reference population.

[0050] In some embodiments, the combination therapy achieves further improvement in PFS (PFS2) after the first subsequent therapy compared to the reference population.

[0051] In some embodiments, combination therapy achieves further improvement in time to discontinuation (TTD) compared to the reference population. [Brief explanation of the drawing]

[0052] [Figure 1] A schematic overview of the research is provided below. [Figure 2] The MARIPOSA-2 study design is shown. a-Analysis was further stratified based on treatment with osimertinibrine, history of brain metastases, and race (Asian vs. non-Asian). ECOG PS, US East Coast Cancer Clinical Trials Group Performance Status; EGFR, Epidermal Growth Factor Receptor; Ex19del, Exon 19 Deletion; NSCLC, Non-Small Cell Lung Cancer; OS, Overall Survival. [Figure 3] This indicates overall survival. Ami: amivantamab; Chemo: chemotherapy; CI: confidence interval; HR: hazard ratio; OS: overall survival rate. [Figure 4] This indicates the time to disease progression (TTSP). Ami: amivantamab; Chemo: chemotherapy; CI: confidence interval; HR: hazard ratio; TTSP: time to disease progression. [Figure 5] This indicates the time until treatment is discontinued. Ami: amibantamab; Chemo: chemotherapy; CI: confidence interval; HR: hazard ratio; PD: progressive disease; TTD: time until treatment is discontinued. [Figure 6] This indicates the time to follow-up therapy. Ami: amivantamab; Chemo: chemotherapy; CI: confidence interval; HR: hazard ratio; TTST: time to follow-up therapy. [Figure 7] This shows PFS after the first subsequent therapy. Ami, amivantamab; Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; PFS2, progression-free survival after the first subsequent therapy. [Modes for carrying out the invention]

[0053] definition All publications cited herein, including but not limited to patents and patent applications, are incorporated herein by reference as if they were fully described.

[0054] The terms used herein should be understood to be used solely to describe specific embodiments and not to limit them. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention pertains.

[0055] Any methods and materials similar to or equivalent to those described herein may be used to carry out the tests of the present invention, and exemplary materials and methods are described herein. The following terms are used in describing and claiming the present invention.

[0056] Where a list is presented, please understand that, unless otherwise stated, each individual element of that list and all combinations of that list are distinct embodiments. For example, a list of embodiments presented as "A, B, or C" should be interpreted as including embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0057] As used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple objects unless otherwise explicitly indicated. For example, a reference to "a cell" includes a combination of two or more cells.

[0058] The connecting term "and / or" between multiple enumerated elements is understood to encompass both individual and combined options. For example, when two elements are connected by "and / or," the first option refers to the applicability of the first element without the second element. The second option refers to the applicability of the second element without the first element. The third option refers to the applicability of the first and second elements together. It is understood that any one of these options, when included in the context, satisfies the requirements of the term "and / or." The simultaneous applicability of two or more of the options is also understood to be included in the meaning and therefore satisfies the requirements of the term "and / or."

[0059] The transitional phrases “comprising,” “consisting essentially of,” and “consisting of” are intended to imply meanings generally accepted in patent terminology, namely, (i) “comprising” is synonymous with “including,” “contains,” or “characterizes,” and is comprehensive or non-restrictive, not excluding additional unlisted elements or process steps; (ii) “consisting of” excludes any elements, processes, or components not specified in the claims; and (iii) “consisting essentially of” limits the scope of the claims to specified materials or processes and those that “do not substantially affect the basic and novel features” of the claimed invention. Embodiments described with the phrase “comprising” (or its synonyms) are also provided as embodiments described independently with “consisting of” and “consisting essentially of.”

[0060] Terms such as "co-administration," "administered together," "administered in combination," and "in combination" encompass the administration of the selected therapeutic agent or drug to a single patient and are intended to include treatment regimens in which the therapeutic agent or drug is administered by the same or different routes of administration or at the same or different times.

[0061] "Isolated" refers to a homogeneous population of molecules (e.g., synthetic polynucleotides, polypeptides, vectors, or viruses) that has been substantially separated and / or purified from other components of the system in which the molecule is produced, such as recombinant cells, in addition to proteins that have undergone at least one purification or isolation step. "Isolated" means a molecule that is substantially free of other cellular material and / or chemicals, and includes molecules isolated to a higher purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0062] "To treat," "to be treating," or "to treat" a disease or disability such as cancer means achieving one or more of the following: reducing the severity and / or duration of the disability; inhibiting the worsening of symptoms characteristic of the disability being treated; limiting or preventing recurrence of the disability in a person who previously had the disability; or limiting or preventing recurrence of symptoms in a person who previously had the disability.

[0063] To "prevent," "prevent," "prevention," or "prophylaxis" a disease or disability means to prevent the occurrence of the disability in the subject.

[0064] "To diagnose" or "diagnose" refers to determining whether a subject has a given disease or condition, or is likely to develop it in the future, or is likely to respond to treatment for a previously diagnosed disease or condition; in other words, it refers to a method of stratifying a patient population based on their likelihood of responding to treatment. Diagnosis is typically made by a physician based on general guidelines for the disease being diagnosed, or other criteria indicating that the subject is likely to respond to a particular treatment.

[0065] "Responsive," "responsive," or "likely responsive" means any kind of improvement or positive response, whether detectable or undetectable, such as reduction or recovery of one or more symptoms, a decrease in the severity of the disease, a stabilized (i.e., non-worsening) disease state, prevention of disease spread, delay or slowing of disease progression, recovery or mitigation of a disease state, and remission (whether partial or total).

[0066] The "therapeutic dose" refers to the amount effective in achieving the desired therapeutic outcome at the required dosage and duration. The therapeutic dose may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the drug or combination of drugs to induce the desired response in the individual. An example of an effective drug or combination of drugs is, for example, the patient's improved health status.

[0067] "Subject" includes any human or non-human animal. "Human animal" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, and reptiles. The terms "subject" and "patient" are used interchangeably in this specification.

[0068] "Approximately" means that a particular value is within the acceptable margin of error as determined by those skilled in the art, and this depends to some extent on the method by which the value is measured or determined, i.e., on the limitations of the measurement system. In the context of a particular assay, result, or embodiment, unless otherwise expressly stated in the example or elsewhere in this specification, "approximately" means within one standard deviation or up to 5%, whichever is greater, according to the practice of the art.

[0069] Cancer refers to the abnormal proliferation of cells that grow uncontrollably and, in some cases, tend to metastasize (spread) to other parts of the patient's body.

[0070] "EGFR or c-Met expressing cancer" refers to cancer that has detectable expression of EGFR or c-Met, or has mutations or amplifications of EGFR or c-Met. EGFR or c-Met expression, amplification, and mutation status can be detected using known methods such as sequencing, fluorescence in situ hybridization, immunohistochemical analysis, flow cytometry, or Western blotting.

[0071] "Epidermal growth factor receptor" or "EGFR" refers to human EGFR (also known as HER1 or ErbB1 (Ullrich et al., Nature 309:418-425, 1984)) having the amino acid sequence shown in GenBank accession number NP_005219, as well as its naturally occurring variants.

[0072] As used herein, “hepatocyte growth factor receptor” or “c-Met” refers to human c-Met and its native variants having the amino acid sequence shown in GenBank accession number NP_001120972.

[0073] The term "bispecific anti-EGFR / c-Met antibody" or "bispecific EGFR / c-Met antibody" refers to a bispecific antibody having a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met. The domains that specifically bind to EGFR and c-Met are typically VH / VL pairs, and the bispecific anti-EGFR / c-Met antibody is monovalent for binding to EGFR and c-Met.

[0074] "Specific binding", "specifically binds", or "specific binding", or "binds" refers to that an antibody binds to an antigen or an epitope within the antigen with higher affinity than to other antigens. Typically, the antibody has an equilibrium dissociation constant (K D ) that is at least 100-fold lower than the K D for binding to non-specific antigens (e.g., BSA, casein), about 5×10 -8 M or less, for example, about 1×10 -9 M or less, about 1×10 -10 M or less, about 1×10 -11 M or less, or about 1×10 -12 M or less K D to bind to the antigen or the epitope within the antigen. The dissociation constant can be measured using known protocols. However, an antibody that binds to an antigen or an epitope within the antigen may have cross-reactivity to other related antigens, for example, the same antigen (homolog) derived from other species such as human or monkey, for example, Macaca fascicularis (cynomolgus monkey, cyno) or Pan troglodytes (chimpanzee, chimp). A monospecific antibody binds to one antigen or one epitope, while a bispecific antibody binds to two different antigens or two different epitopes.

[0075] The term "antibody" has a broad meaning and includes monoclonal antibodies, including mouse, human, humanized, and chimeric monoclonal antibodies; antigen-binding fragments; multispecific antibodies such as bispecific, triplicate, and quadruplicate antibodies; dimers, tetramers, or multimers; single-chain antibodies; domain antibodies; and immunoglobulin molecules, including any other modified forms of immunoglobulin molecules containing antigen-binding sites of the required specificity. A "full-length antibody" consists of two heavy chains (HC) and two light chains (LC), interconnected by disulfide bonds, and a multimer thereof (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions are interspersed with framework regions (FRs) and can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs). Each VH and VL consists of three CDRs and four FR segments arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from the amino terminus to the carboxyl terminus.

[0076] A "biosimilar" (an approved reference product / biological drug, i.e., a biosimilar of a reference drug) refers to a biological drug that is very similar to a reference drug, with no clinically significant difference in safety, purity, and potency between the biosimilar and the reference drug, and this similarity is based on data derived from: (a) analytical studies demonstrating that the biological product is very similar to the reference drug; (b) animal studies (including toxicity assessments); and / or (c) clinical trials (including immunogenicity and pharmacokinetic or pharmacodynamic assessments) sufficient to demonstrate safety, purity, and potency under one or more appropriate conditions of use, such as the conditions of use under which the standard formulation is approved and the conditions under which the standard formulation is intended to be used, as well as the conditions for granting approval to the biosimilar. A biosimilar may be an interchangeable product that can be used as a substitute for the standard formulation in a pharmacy without intervention from a prescribing healthcare professional. To comply with further standards of "interoperability," biosimilars are required to produce the same clinical outcomes as the standard formulation in any given patient, and if the biosimilar is administered to an individual multiple times, the risk of reduced safety or efficacy from alternating or switching between the use of the biosimilar and the standard formulation shall not exceed the risk of using the standard formulation without such alternation or switching. To the extent that the mechanism of action of the standard formulation is known, the biosimilar shall utilize the same mechanism of action for the proposed conditions of use. The conditions of use specified, recommended, or presented in the proposed labeling for the biosimilar are already approved for the standard formulation. The route of administration, dosage form, and / or potency of the biosimilar shall be the same as that of the standard formulation, and the biosimilar shall be manufactured, processed, packaged, or stored in facilities that meet standards designed to ensure that the biosimilar maintains safety, purity, and potency. Biosimilars may include slight modifications to the amino acid sequence (e.g., N-terminal or C-terminal shortening) that are not expected to alter the performance of the biosimilar compared to the standard formulation.

[0077] The "complementarity-determining region (CDR)" is the region of an antibody that binds to an antigen. CDRs can be defined using various descriptions, such as those by Kabat (Wu et al. (1970) J Exp Med 132:211-50) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. (1987) J Mol Biol 196:901-17), IMGT (Lefranc et al. (2003) Dev Comp Immunol 27:55-77), and AbM (Martin and Thornton (1996) J Bmol Biol 263:800-15). Correspondence between various descriptions and variable region numbering is documented (e.g., Lefranc et al. (2003) Dev Comp Immunol 27:55-77, Honegger and Pluckthun, (2001) J Mol Biol 309:657-70, International ImMunoGeneTics (IMGT) database, web resource, http: / / imgt_org). CDRs can be described using available programs such as abYsis by UCL Business PLC. As used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2”, and “LCDR3” include CDRs defined by any of the Kabat, Chothia, IMGT, or AbM methods described above, unless otherwise expressly stated herein.

[0078] Immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of their heavy chain constant domain. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be assigned to one of two distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0079] An "antigen-binding fragment" refers to a portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments may be synthetic polypeptides, enzyme-available polypeptides, or genetically modified polypeptides, and include VH, VL, VH and 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, camelid VH domains, FR3-CDR3-FR4 moieties, and other smallest recognition units consisting of amino acid residues that reproduce the CDR of an antibody, such as HCDR1, HCDR2, and / or HCDR3, as well as LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can be linked to each other via synthetic linkers to form various types of single-chain antibody designs. When the VH and VL domains are expressed in separate single-chain antibody constructs, the VH / VL domains can form intramolecular or intermolecular pairs to form monovalent antigen-binding sites, such as single-chain Fv (scFv) or diabodies, which are described, for example, in International Publications 1998 / 44001, 1988 / 01649, 1994 / 13804, and 1992 / 01047.

[0080] A "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules that is identical except for possible known modifications such as removal of the C-terminal lysine from the antibody heavy chain, isomerization or deamidementation of amino acids, oxidation of methionine, or post-translational modifications such as deamidementation of asparagine or glutamine; i.e., an individual antibody constituting a population. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monospecific or multispecific, such as bispecific, and may be monovalent, bivalent, or polyvalent.

[0081] "Recombinant" refers to DNA, antibodies, and other proteins prepared, expressed, created, or isolated by recombinant means when segments from different sources join together to produce recombinant DNA, antibodies, or proteins.

[0082] "Bispecificity" refers to an antibody that specifically binds to two different antigens, or to two different epitopes within the same antigen. Bispecific antibodies may cross-react to other related antigens, such as human or monkey antigens, or to the same antigen (homolog) from other species, such as Macaca cynomolgus (e.g., cynomolgus, cyno) or Pan troglodytes, or they may bind to epitopes shared between two or more different antigens.

[0083] An "antagonist" or "inhibitor" is a molecule that, when bound to a cellular protein, inhibits at least one reaction or activity induced by that protein's native ligand. A molecule is an antagonist if at least one reaction or activity is inhibited by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than at least one reaction or activity inhibited in the absence of the antagonist (e.g., a negative control), or if the inhibition is statistically significant compared to the inhibition in the absence of the antagonist.

[0084] A “biological sample” refers to a collection of fluids, cells, or tissues present within a subject, in addition to similar fluids, cells, or tissues isolated from the subject. Exemplary samples include biological fluids such as blood, serum, and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tears, feces, sputum, mucosal secretions from secretory tissues and organs, vaginal secretions, ascites, fluids from the pleural cavity, pericardial cavity, peritoneal cavity, abdominal cavity, and other body cavities, fluids recovered by bronchial lavage, synovial fluid, the subject or biological origin, such as cell and organ culture media including conditioned media for cells or organs, liquid solutions in contact with lavage solutions, tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine-needle aspirations, surgically excised tissues, organ cultures, or cell cultures. In a non-limiting example, a biological sample is a blood sample. In another non-limiting example, a biological sample is a plasma sample. In yet another non-limiting example, a biological sample is a tumor sample. In some embodiments, the biological sample is circulating tumor DNA (ctDNA) that can be isolated from various other biological samples disclosed herein, such as but not limited to blood or plasma samples. In some embodiments, the biological sample is tumor DNA that can be isolated from, for example, a tumor sample.

[0085] As used in this application, "low fucose" or "low fucose content" refers to an antibody having a fucose content of approximately 1% to 15%.

[0086] As used herein, “normal fucose” or “normal fucose content” means that the antibody has a fucose content greater than approximately 50%, typically greater than approximately 80%, or greater than 85%.

[0087] As used herein, “treatment-naive” refers to subjects diagnosed with locally advanced NSCLC or metastatic NSCLC who have not yet received anti-cancer treatment for NSCLC, and therefore, subjects are chemotherapy-naive and TKI-naive, meaning they have not received, for example, chemotherapy or tyrosine kinase inhibitors (including first-generation, second-generation, or third-generation TKIs) or other anti-NSCLC treatments. Methods of treating treatment-naive subjects may also be referred to as first-line treatment or front-line treatment.

[0088] As used herein, RECIST v1.1 criteria refer to the publicly available guidelines for response evaluation criteria in solid tumors described in Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247 (incorporated herein by reference). Eisenhauer et al. provide definitions of the following criteria used to determine the objective tumor response to a target lesion: - Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must be reduced to less than 10 mm in their short axis. - Partial response (PR): A reduction of at least 30% in the sum of the diameters of target lesions, relative to the sum of the diameters at baseline. - Progressive disease (PD): An increase of at least 20% in the sum of the diameters of target lesions, based on the minimum sum in the trial (including the baseline sum if it is the minimum in the trial). In addition to a 20% relative increase, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression). -Stable disease (SD): Based on the minimum sum of diameters during the trial, there is neither sufficient contraction to qualify for partial reduction (PR) nor sufficient increase to qualify for progressive reduction (PD).

[0089] As used herein, partial response or better means partial response (PR) or complete response (CR).

[0090] As used herein, progression-free survival (PFS) refers to the time from randomization in a clinical trial to the earlier of objective disease progression or death, based on a blinded, independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

[0091] As used herein, overall response (OR) is defined as the number of participants in a clinical trial who achieve either a partial response (PR) or a complete response (CR) as the best response, as defined by BICR using RECIST v1.1.

[0092] As used herein, overall survival (OS) is defined as the time from randomization in a clinical trial to the date of death from any cause.

[0093] As used herein, duration of response (DoR) is defined as the time from the date of the first documented response (PR or CR) in the clinical trial to the date of documented progression or death (whichever comes first) for a participant who has a partial response (PR) or complete response (CR).

[0094] As used herein, time to follow-up therapy (TTST) is defined as the time from the date of randomization in a clinical trial to the start of follow-up anticancer therapy after discontinuation of the study treatment or death, whichever comes first.

[0095] As used herein, progression-free survival (PFS2) after the first subsequent therapy is defined as the time from randomization in a clinical trial to the earlier of the second objective disease progression day or death after the initiation of subsequent anticancer therapy, based on the investigator's assessment (assessment after use for PFS).

[0096] As used herein, time to disease progression (TTSP) is defined as the time from randomization to the documentation of either a new symptom or a worsening of a symptom (whichever comes first) that the investigator considers to be related to lung cancer and requires either a change in anticancer treatment and / or a clinical intervention to manage the symptom.

[0097] As used herein, intracranial progression-free survival (intracranial PFS) is defined, based on BICR using RECIST v1.1, as the time from randomization in a clinical trial to the earlier of objective progression of intracranial disease or death. Specifically, progression of disease within the brain is defined as the progression of brain metastases or the development of new brain lesions.

[0098] Method of Disclosure Resistance to osimertinib is diverse, polyclonal, and difficult to treat. Currently, there are no approved targeted therapies for the post-osimertinib situation. Two recent studies of immunotherapy-chemotherapy regimens have failed to demonstrate efficacy in the TKI-resistant situation. There are currently six other phase 3 trials (NCT05261399, NCT04765059, NCT05089734, NCT05338970, NCT04656652, NCT05184712) investigating targeted therapy combinations with chemotherapy as a second-line (or later) treatment in EGFR-mutated progressive NSCLC, highlighting an unmet need in this patient population.

[0099] The present invention relates to a novel regimen for the treatment of patients with EGFR-mutated progressive NSCLC whose disease has progressed during or after TKI therapy, such as osimertinib. Embodiments of the present invention provide a method for significantly improving progression-free survival compared to chemotherapy alone in patients with EGFR-mutated progressive NSCLC whose disease has progressed during or after osimertinib monotherapy, using amivantamab chemotherapy and amivantamab-razertinib chemotherapy.

[0100] According to one embodiment of the present invention, a method for improving the median PFS in a population of subjects having locally advanced or metastatic NSCLC (NSCLC having one or more EGFR mutations, where the NSCLC has progressed during or after treatment with at least one prior TKI) (i.e., subjects are not untreated but have previously received TKI therapy) comprises administering to the population of subjects a combination therapy comprising (i) a therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, wherein the improvement in median PFS is compared to the median PFS of a reference population of subjects having NSCLC with one or more EGFR mutations where the NSCLC has progressed during or after treatment with a prior TKI, and the reference population has been administered carboplatin and pemetrexed but not bispecific anti-EGFR / c-Met antibody.

[0101] According to another embodiment of the present invention, a method is provided for improving the median progression-free survival (PFS) in a population of subjects having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer having one or more epidermal growth factor receptor (EGFR) mutations, and whose NSCLC has progressed during or after prior treatment with at least one tyrosine kinase inhibitor (TKI) (i.e., a population of subjects who are not treatment-naive but have previously received TKI therapy), the method comprising: (i) a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody; (ii) a therapeutically effective dose of razertinib or the same The treatment includes administering a combination therapy comprising (iii) a therapeutically effective dose of carboplatin and (iv) a therapeutically effective dose of pemetrexed, wherein the improvement in median PFS is compared to the median PFS of a reference population of subjects with NSCLC having one or more EGFR mutations who experienced progression of NSCLC during or after treatment with a third-generation TKI, and who received carboplatin and pemetrexed but not bispecific anti-EGFR / c-Met antibody, lasertinib, or any pharmaceutically acceptable salts or hydrates thereof.

[0102] According to embodiments of the present invention, a method for improving the median intracranial PFS in a population of subjects having locally advanced or metastatic NSCLC with one or more EGFR mutations that has progressed during or after prior treatment with at least one TKI (i.e., a population of subjects who have previously received TKI therapy, rather than being treatment-naive) comprises administering to the population of subjects a combination therapy comprising (i) a therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective dose of carboplatin, and (iii) a therapeutically effective dose of pemetrexed, wherein the improvement in median PFS is compared to the median PFS of a reference population of subjects having NSCLC with one or more EGFR mutations that has progressed during or after prior treatment with TKI, the reference population which has been administered carboplatin and pemetrexed but not bispecific anti-EGFR / c-Met antibody.

[0103] According to another embodiment of the present invention, a method for improving the median intracranial PFS in a population of subjects having locally advanced or metastatic NSCLC with one or more EGFR mutations, where the NSCLC has progressed during or after prior treatment with a TKI (i.e., the subjects are not treatment-naive but have previously received TKI therapy), is to administer to the population of subjects: (i) a therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective dose of razertinib or a pharmaceutically acceptable salt or hydrate thereof, and (iii) a therapeutically effective dose of kale The treatment includes administering a combination therapy comprising (iv) a therapeutically effective dose of pemetrexed, wherein the improvement in median PFS is compared to the median PFS of a reference population of subjects with NSCLC having one or more EGFR mutations who experienced progression of NSCLC during or after treatment with a third-generation TKI, and who were administered carboplatin and pemetrexed but not bispecific anti-EGFR / c-Met antibodies, lasertinib, or any pharmaceutically acceptable salts or hydrates thereof.

[0104] According to another embodiment of the present invention, a method for treating a subject having locally advanced or metastatic NSCLC having one or more EGFR mutations, wherein the NSCLC has progressed during or after treatment with a prior TKI (i.e., a subject who has previously received TKI therapy, but is not untreated), comprises administering a combination therapy to the subject comprising: (i) a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody; (ii) a therapeutically effective dose of razertinib or a pharmaceutically acceptable salt or hydrate thereof; (iii) a therapeutically effective dose of carboplatin; and (iv) a therapeutically effective dose of pemetrexed, wherein the administration of the combination therapy is performed in the first two steps. The method involves starting on day 1 of cycle 1 of a 1-day cycle and continuing for the following 21-day cycles, and includes administering razertinib or a pharmaceutically acceptable salt or hydrate thereof after completion of carboplatin administration (for example, the method includes (a) administering carboplatin at a dose of AUC5 on day 1 of each 21-day cycle for up to 4 cycles, and (b) if carboplatin is discontinued early, administering razertinib or a pharmaceutically acceptable salt or hydrate thereof orally once daily at a dose of approximately 240 mg, starting on day 1 of cycle 5, or earlier).

[0105] In some embodiments, lasertinib, or a pharmaceutically acceptable salt or hydrate thereof, is lasertinib mesylate. In some embodiments, lasertinib, or a pharmaceutically acceptable salt or hydrate thereof, is lasertinib mesylate monohydrate.

[0106] In some embodiments, the method involves orally administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, once daily at a dose of about 240 mg.

[0107] In some embodiments, the method includes administering razertinib or a pharmaceutically acceptable salt or hydrate thereof orally once daily at a dose of about 240 mg, starting on day 1 of cycle 5 or earlier, if carboplatin is discontinued early.

[0108] In some embodiments, one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. In some embodiments, one or more EGFR mutations include one or more exon 19 deletions. In some embodiments, one or more EGFR mutations include exon 21 L858R substitutions.

[0109] In some embodiments, at least one prior TKI comprises a first-generation EGFR TKI. In some embodiments, at least one prior TKI comprises a second-generation EGFR TKI. In some embodiments, at least one prior TKI comprises a second-generation EGFR TKI. In some embodiments, at least one prior TKI comprises osimertinib. EGFR-TKIs are EGFR targeting agents that interfere with EGFR signaling. To date, three different generations of EGFR-TKIs are available, but all remain susceptible to the development of resistance mechanisms. The mechanism of action of first-generation TKIs (e.g., erlotinib, gefitinib, and icotinib) causes reversible ATP binding site blockade, halting downstream signaling. Second-generation TKIs (e.g., afatinib and dacominib) provide alternatives for patients who have developed resistance to first-generation TKIs. Third-generation TKIs (e.g., osimertinib, rosiletinib, olmutinib, razertinib) provide treatment for patients who have developed resistance to first- and second-generation TKIs. See, for example, Caponnetto et al., J.Mol.Pathol.2021,2(1),1-10.

[0110] In some embodiments, the method includes orally administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, once daily in an amount of about 80 mg to about 320 mg. In some embodiments, the method includes orally administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, once daily in an amount of about 240 mg. In some embodiments, if carboplatin is discontinued early, the method includes orally administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, at a dose of about 240 mg, once daily, starting on day 1 of cycle 5, or earlier.

[0111] In some embodiments, administration of the combination therapy begins on day 1 of cycle 1 of the first 21-day cycle and continues in subsequent 21-day cycles.

[0112] In some embodiments, the method induces a clinical response in subjects according to RECIST v1.1 criteria. In some embodiments, the method achieves a partial response or better response in subjects according to RECIST v1.1 criteria. In some embodiments, the combination therapy achieves an improvement in median PFS of at least two weeks. In some embodiments, the combination therapy achieves an improvement in median PFS of at least one month. In some embodiments, the combination therapy achieves an improvement in median PFS of at least one.5 months. In some embodiments, the combination therapy achieves an improvement in median PFS of at least two months. In some embodiments, subjects exhibit PFS for at least four.5 months. In some embodiments, subjects exhibit PFS for at least five months. In some embodiments, subjects exhibit PFS for at least five.5 months. In some embodiments, subjects exhibit PFS for at least six months, or at least ten months, or at least twelve months, or at least fourteen months. In some embodiments, the combination therapy achieves a further improvement in objective response compared to the reference population. In some embodiments, the combination therapy achieves further improvement in overall survival (OS) compared to the reference population. In some embodiments, the OS improvement is at least 2 months compared to the reference population. In some embodiments, the OS improvement is at least about 2.4 months compared to the reference population. In some embodiments, the OS improvement is about 2.2 months compared to the reference population. In some embodiments, the OS improvement is about 2.3 months compared to the reference population. In some embodiments, the OS improvement is about 2.4 months compared to the reference population. In some embodiments, the OS improvement is about 2.5 months compared to the reference population. In some embodiments, the OS improvement is about 2.6 months compared to the reference population. In some embodiments, the combination therapy achieves further improvement in duration of response (DoR) compared to the reference population. In some embodiments, the combination therapy achieves further improvement in time to subsequent therapy compared to the reference population.In some embodiments, the combination therapy achieves further improvement in PFS after the first subsequent therapy (PFS2) compared to the reference population. In some embodiments, the combination therapy achieves further improvement in the median intracranial PFS compared to the reference population. In some embodiments, the improvement in PFS2 is at least 2 months compared to the reference population. In some embodiments, the improvement in PFS2 is at least about 4.4 months compared to the reference population. In some embodiments, the improvement in PFS2 is at least about 4.5 months compared to the reference population. In some embodiments, the improvement in PFS2 is at least about 5 months compared to the reference population. In some embodiments, the combination therapy achieves further improvement in time to disease progression (TTSP) compared to the reference population. In some embodiments, the improvement in TTSP is at least about 4 months compared to the reference population. In some embodiments, the improvement in TTSP is at least about 4.2 months compared to the reference population. In some embodiments, the improvement in TTSP is at least about 4.5 months compared to the reference population. In some embodiments, the combination therapy achieves further improvement in time to discontinuation (TTD) compared to the reference population. In some embodiments, the improvement in TTD is at least about 5.5 months compared to the reference population. In some embodiments, the improvement in TTD is at least about 5.9 months compared to the reference population. In some embodiments, the improvement in TTD is at least about 6 months compared to the reference population. In some embodiments, the combination therapy achieves further improvement in time to follow-up therapy (TTST) compared to the reference population. In some embodiments, the improvement in TTST is at least about 5 months compared to the reference population. In some embodiments, the improvement in TTST is at least about 5.5 months compared to the reference population. In some embodiments, the improvement in TTST is at least about 5.6 months compared to the reference population. In some embodiments, the improvement in TTST is at least about 6 months compared to the reference population.

[0113] In some embodiments, subjects are progression-free after at least 20 months. In some embodiments, subjects are 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 treatment-naive population of subjects diagnosed with locally advanced or metastatic NSCLC with one or more EGFR mutations.

[0114] In some embodiments, the overall survival (OS) of the subject is at least 17 months. In some embodiments, the overall survival (OS) of the subject is at least 17.7 months. In some embodiments, the overall survival (OS) of the subject is approximately 17 months. In some embodiments, the overall survival (OS) of the subject is at least 17.5 months. In some embodiments, the overall survival (OS) of the subject is at least 18 months.

[0115] In some embodiments, the time to subsequent therapy (TTST) is at least 12 months. In some embodiments, the time to subsequent therapy (TTST) is at least 12.2 months.

[0116] In some embodiments, the time to progression (TTSP) is at least 16 months. In some embodiments, the time to progression (TTSP) is approximately 16 months.

[0117] In some embodiments, the time to discontinue the treatment (TTD) is at least 10 months. In some embodiments, the time to discontinue the treatment (TTD) is at least 10.4 months. In some embodiments, the time to discontinue the treatment (TTD) is approximately 10.4 months.

[0118] In some embodiments, the progression-free survival (PFS2) after the first subsequent therapy is at least 16 months. In some embodiments, the progression-free survival (PFS2) after the first subsequent therapy is approximately 16 months.

[0119] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain includes the heavy chain complementarity determination region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, the light chain complementarity determination region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met includes the HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12. In some embodiments, the first domain that specifically binds to EGFR includes the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met includes the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16. In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. In some embodiments, 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. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 1% to about 15%.

[0120] In some embodiments, 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 in doses ranging from approximately 140 mg to approximately 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses ranging from approximately 700 mg, 750 mg, 800 mg, 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. According to certain embodiments, the method involves administering a dose weekly for four weeks, and then every two weeks from the fifth week onward, with a dose of 1050 mg for a baseline weight of less than 80 kg and a dose of 1400 mg for a baseline weight of 80 kg or more. In some embodiments, the initial dose is administered as a divided infusion on days 1 and 2 of week 1. In some embodiments, the initial dose is administered on day 1 of week 1.

[0121] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, if the subject weighs less than 80 kg. In some embodiments, the initial dose is administered as a divided infusion on days 1 and 2 of week 1. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3, if the subject weighs less than 80 kg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, if the subject weighs 80 kg or more. In some embodiments, the initial dose is administered as a divided infusion on days 1 and 2 of week 1. In some embodiments, if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle.

[0122] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks.

[0123] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain includes the heavy chain complementarity determination region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, the light chain complementarity determination region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met includes the HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12. In some embodiments, the first domain that specifically binds to EGFR includes the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met includes the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0124] In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0125] In some embodiments, 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.

[0126] In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 1% to about 15%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 2% to about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 3% to about 13%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 4% to about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 5% to about 11%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 1%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 2%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 3%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 4%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 5%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 6%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 7%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 8%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 9%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 10%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 11%.In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 13%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 15%.

[0127] In some embodiments, 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). Non-limited examples of TKIs include kinase inhibitors such as erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, razertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib. In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib.

[0128] Lazertinib is an oral third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) currently under development for the treatment of non-small cell lung cancer (NSCLC).

[0129] Lazertinib is described in International Publication No. 2016 / 060443 as N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazole-1-yl)pyrimidine-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide, shown below as the compound of formula I.

[0130] [ka]

[0131] Furthermore, International Publication No. 2018 / 194356 describes its salt, hydrate and crystalline forms; International Publication Nos. 2019 / 022485, 2019 / 022486, and 2019 / 022487 disclose methods for producing razertinib.

[0132] Lazertinib mesylate monohydrate is shown below as the compound of formula Ia,

[0133] [ka] This may be referred to as N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazole-1-yl]pyrimidine-2-yl]amino]-4-methoxy-2-(morpholine-4-yl)phenyl]acrylamide methanesulfonate hydrate.

[0134] In some embodiments, the method involves administering carboplatin at a dose of AUC5 on day 1 of each 21-day cycle for up to four cycles. Carboplatin may be administered at a dose of AUC5 according to commercially available methods approved by health authorities.

[0135] In some embodiments, this method involves administering pemetrexed at approximately 500 mg / m². 2 This involves administering the specified dose with carboplatin on day 1 of each 21-day cycle for up to four cycles, followed by pemetrexed as maintenance therapy until disease progression.

[0136] Administration Bispecific anti-EGFR / c-Met antibodies can be administered in a pharmaceutically acceptable carrier. “Carrier” refers to a diluent, adjuvant, excipient, or vehicle in which the antibody of the present invention is administered together. Such a vehicle may be water and a liquid oil, including oils derived from petroleum, animal, plant, or synthetic sources, such as peanut oil, soybean oil, mineral oil, or sesame oil. For example, a bispecific anti-EGFR / c-Met antibody may be formulated using 0.4% physiological saline and 0.3% glycine. These solutions are sterile and generally free of particulate matter. They can be sterilized by conventional, well-known sterilization techniques (e.g., filtration). For parenteral administration, the carrier may contain sterile water, and other excipients may be added for increased solubility or preservation. Suspensions or solutions for injection may also be prepared using an aqueous carrier with appropriate additives. Suitable vehicles and formulations (including other human proteins, such as human serum albumin) are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing, pp. 691-1092, and in particular, see pp. 958-989.

[0137] The mode of administration may be any preferred route for delivering the bispecific anti-EGFR-c-Met antibody to the host using formulations of tablets, capsules, liquids, powders, gels, or particles, for example, parenteral administration such as intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous, or pulmonary, or transmucosal (oral, intranasal, intravaginal, or intrarectal), and the formulations may be contained in syringes, implantable devices, osmotic pumps, cartridges, micropumps, or other means well known in the art and recognized by those skilled in the art. Site-specific administration can be achieved, for example, by intratumor, intraarticular, intrabronchial, intraabdominal, intraarticular capsule, intracartilage, intrasinus, intracavitary, intracerebellar, intraventricular, intracolon, intracervical, intrastomical, intrahepatic, intramyocardium, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostate, intrapulmonary, intrarectum, intranephrium, intraretinal, intraspinal cord, synovial sac, intrathoracic, intrauterine, intravascular, intrabladder, intrafocal, intravaginal, rectal, oral cavity, sublingual, intranasal, or percutaneous delivery.

[0138] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously.

[0139] In some embodiments, 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 in a dose sufficient to achieve a therapeutic effect in the subject.

[0140] In some embodiments, the bispecific anti-EGFR / c-Met antibody is formulated as a subcutaneous formulation, as disclosed in PCT International Publication No. 2022 / 224187(A1).

[0141] In some embodiments, the method involves administering a dose weekly for four weeks, followed by administering a dose every two weeks starting in week five, with the dose being 1050 mg for a baseline weight of less than 80 kg and 1400 mg for a baseline weight of 80 kg or more. In some embodiments, the initial dose is administered as divided infusions on days 1 and 2 of week 1.

[0142] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 140 mg to approximately 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 1400 mg to approximately 3360 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 1400 mg to approximately 1750 mg.

[0143] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at 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, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg,Approximately 1510mg, approximately 1520mg, approximately 1530mg, approximately 1540mg, approximately 1550mg, approximately 1560mg, approximately 1570mg, 1575mg, approximately 1580mg, approximately 1590mg, approximately 1600mg, about 1610mg, 1620mg, about 1630mg, about 1640mg, about 1650mg, about 1660mg, about 1670mg, about 1680mg, about 1690mg, about 1 700mg, about 1710mg, about 1720mg, about 1730mg, about 1740mg, about 1750mg, about 1760mg, about 1770mg, about 1780mg, about 1790mg, about 1 800mg, about 1810mg, about 1820mg, about 1830mg, about 1840mg, about 1850mg, about 1860mg, about 1870mg, about 1880mg, 1890mg, about 19 00mg, about 1910mg, about 1920mg, about 1930mg, about 1940mg, about 1950mg, about 1960mg, about 1970mg, about 1980mg, about 1990mg, about 20 00mg, 2100mg, 2110mg, 2120mg, 2130mg, 2140mg, 2150mg, 2160mg, 2170mg, 2180mg, 2190mg, 2200m It is administered in doses of g, 2210 mg, 2220 mg, 2230 mg, 2240 mg, 2250 mg, 2260 mg, 2270 mg, 2280 mg, 2290 mg, 2300 mg, 2310 mg, 2320 mg, 2330 mg, 2340 mg, 2350 mg, 2360 mg, 2370 mg, 2380 mg, 2390 mg, 2400 mg, or 2410 mg.

[0144] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 350 mg, 700 mg, 1050 mg, 1400 mg, 1750 mg, or 2100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 700 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 800 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 850 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 900 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 950 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1000 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1050 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1150 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1200 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1250 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1300 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 2100 mg.

[0145] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, if the subject weighs less than 80 kg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1 / 2 (divided dose), 8, and 15 of cycle 1, and on day 1 of cycle 2, if the subject weighs less than 80 kg.

[0146] In some embodiments, if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle.

[0147] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, if the subject weighs 80 kg or more. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1 / 2 (divided dose), 8, and 15 of cycle 1, and on day 1 of cycle 2, if the subject weighs 80 kg or more.

[0148] In some embodiments, if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle.

[0149] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every three weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every four weeks.

[0150] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks.

[0151] In some embodiments, a suitable mode of administration for delivering razertinib to a target may be oral administration, for example, oral administration of tablets. Lazertinib tablet formulations suitable for oral administration according to the present invention are described, for example, in International Publication No. 2021 / 209893 and International Publication No. 2020 / 079637, which are incorporated herein by reference.

[0152] In some embodiments, lasertinib is administered in doses of approximately 10 mg to approximately 400 mg. In some embodiments, lasertinib is administered in doses of approximately 20 mg to approximately 320 mg. In some embodiments, lasertinib is administered in doses of approximately 50 mg to approximately 300 mg. In some embodiments, lasertinib is administered in doses of approximately 100 mg to approximately 300 mg. In some embodiments, lasertinib is administered in doses of approximately 150 mg to approximately 280 mg. In some embodiments, lasertinib is administered in doses of approximately 200 mg to approximately 250 mg. In some embodiments, lasertinib is administered in doses of approximately 220 mg to approximately 250 mg.

[0153] In some embodiments, lasertinib is administered in doses of approximately 20 mg, 50 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, or 400 mg. In some embodiments, lasertinib is administered in doses of approximately 240 mg.

[0154] In some embodiments, lasertinib is administered daily. In some embodiments, lasertinib is administered twice a week. In some embodiments, lasertinib is administered once a week. In some embodiments, lasertinib is administered once every two weeks. In some embodiments, lasertinib is administered once every three weeks. In some embodiments, lasertinib is administered once every four weeks.

[0155] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib, which may be administered using any of the doses and dosages disclosed herein. In some embodiments, razertinib is administered in doses ranging from about 10 mg to about 400 mg. In some embodiments, razertinib is administered in doses ranging from about 20 mg to about 320 mg. In some embodiments, lasertinib is administered in doses of approximately 20 mg, 50 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, or 400 mg. In some embodiments, lasertinib is administered in doses of approximately 240 mg.

[0156] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib, which may be administered in any of the doses and dosages disclosed herein. As an example, 1400 mg of amivantamab may be administered in combination with 240 mg of razertinib. As an example, 1750 mg of amivantamab may be administered in combination with 240 mg of razertinib. As an example, 2100 mg of amivantamab may be administered in combination with 240 mg of razertinib.

[0157] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib, which 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 razertinib, which is administered daily. In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib, which is administered orally.

[0158] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with carboplatin.

[0159] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with pemetrexed.

[0160] In some embodiments, the bispecific anti-EGFR / c-Met antibodies disclosed herein may be administered in combination with razertinib, carboplatin, and pemetrexed.

[0161] In some embodiments, the combination therapy comprising a bispecific anti-EGFR / c-Met bispecific antibody and an EGFR TKI may further comprise one or more additional anticancer therapies.

[0162] In some embodiments, the methods of the present disclosure involve administering a cancer therapy that does not include a combination therapy comprising a bispecific anti-EGFR / c-Met bispecific antibody and an EGFR TKI as disclosed herein. In some embodiments, the cancer therapy may include any one of those described herein. As a non-limiting example, the cancer therapy that may be administered in the methods of the present disclosure may include any number of different platinum-based chemotherapy regimens or combinations thereof. As a non-limiting example, the platinum-based chemotherapy regimens may include carboplatin, cisplatin, or combinations thereof.

[0163] The anticancer therapies that can be administered in the method of this disclosure include any one or more chemotherapeutic agents or other anticancer therapeutic agents known to those skilled in the art. Chemotherapy agents are chemical compounds useful for treating cancer and include growth inhibitors or other cytotoxic agents, such as alkylating agents, antimetabolites, antimicrotubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, and angiogenesis inhibitors. Examples of chemotherapeutic agents include alkylating agents, e.g., thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, e.g., busulfan, improsulfan, and piposulfan; aziridines, e.g., benzodopa, carbocon, metsuredopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards, e.g., chlorambucil, chlornafadin, chlorophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembitin, fenesterine, prednimustine, trophosphamide, uracil mustard; nitrosoureas, e.g., carmustine, chlorozotosine, fotemustine, lomustine, nimustine Ranimustine; antibiotics such as aclasinomysin, actinomycin, autramycin, azaserin, bleomycin, kactinomycin, calicheamicin, carabicin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zolubicin;Antimetabolites, e.g., methotrexate and 5-FU; folate analogs, e.g., denopterin, methotrexate, pteropterin, trimethrexate; purine analogs, e.g., fludarabine, 6-mercaptopurine, thiamipurine, thioguanine; pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, phloxuridine, etc.; androgens, e.g., carsterone, dromostanolone propionate, Epiciostanol, mepitiostane, testolactone; anti-adrenal agents, e.g., aminoglutethimide, mitotane, trilostane; folic acid supplements, e.g., folic acid; acegraton; aldofamide glycoside; aminolevulinic acid; amsacrin; bestrabusil; bisantren; edatraxate; defofamine; demecolsin; diazicone; elfornithine; elliptinium acetate acetate; etogluside; gallium nitrate; hydroxyurea; lentinan; ronidamin; mitogluazone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK(registered trademark); razoxane; schizophyllan; spirogermanium; tenuazonic acid; triaziquone; 2,2',2″-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitractol; pipobromane; gacytosine ine); Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Members of the taxoid or taxane family, e.g., paclitaxel (TAXOL®, docetaxel (TAXOTERE®)) and their analogues; Chlorambucil; Gemcitabine; 6-Thiogunine; Mercaptopurine; Methotrexate; Platinum analogues, e.g., cisplatin and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitomycin C; Mitoxantrone; Vincristine; Vinorelbine; Navelbine; Novantrone; Teniposide; Daunomycin;Aminopterin; Xeloda; Ibandronate; CPT-11; Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DMFO); Retinoic acid; Esperamicin; Capecitabine; Sorafenib (NEXAVAR®), Sunitinib (SUTENT®), Pazopanib (VOTRIENT®), Toceranib (PALLADIA®), Vandetanib (ZACTIMA®), Cediranib (RECENTIN®), Regorafenib (BAY73-4506), Axitinib (AG013736), Restaurtinib (CEP-701), Erlotinib (TARCEVA®), Gefitinib (IRESSA®), Afatinib (BIBW Examples include receptor tyrosine kinase and / or angiogenesis inhibitors, such as lapatinib (TYKERB®), neratinib (HKI-272), and any pharmaceutically acceptable salts, acids, or derivatives of any of the above. Antihormone agents that act to control or inhibit the hormonal effects on tumors, such as anti-estrogen agents including tamoxifen, raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifen, LY 117018, onapristone, and toremifene (FARESTON®); and anti-androgen agents, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and any pharmaceutically acceptable salts, acids, or derivatives of any of the above. Other conventional cytotoxic compounds disclosed in Wiemann et al., 1985, Medical Oncology (Calabresi et al., eds.), Chapter 10, McMillan Publishing, are also applicable to the method of the present invention.

[0164] Generation of bispecific anti-EGFR / c-Met antibodies used in the methods disclosed herein An exemplary bispecific anti-EGFR / c-Met antibody that can be used in the methods of this disclosure is amivantamab. Amivantamab is an IgG1 anti-EGFR / c-Met bispecific antibody described in U.S. Patent No. 9,593,164, which is incorporated herein by reference in its entirety. Amivantamab is characterized by the following amino acid sequence:

[0165] EGFR binding group >Sequence ID 1 (HCDR1, EGFR binding group) TYGMH >Sequence ID 2 (HCDR2, EGFR binding group) VIWDDGSYKYYGDSVKG >Sequence ID 3 (HCDR3, EGFR binding group) DGITMVRGVMKDYFDY >Sequence ID 4 (LCDR1, EGFR binding group) RASQDISSALV >Sequence ID 5 (LCDR2, EGFR binding group) DASSLES >Sequence ID 6 (LCDR3, EGFR binding group) QQFNSYPLT >Sequence ID 7 (HCDR1, c-Met binding group) SYGIS >Sequence ID 8 (HCDR2, c-Met binding group) WISAYNGYTNYAQKLQG >Sequence ID 9 (HCDR3, c-Met binding group) DLRGTNYFDY >Sequence ID 10 (LCDR1, c-Met binding group) RASQGISNWLA >Sequence ID 11 (LCDR2, c-Met binding group) AASSLLS >Sequence ID 12 (LCDR3, c-Met binding group) QQANSFPIT >SEQ ID NO: 13 (VH, EGFR binding group) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS >Sequence ID 14 (VL, EGFR binding group) AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK >Sequence ID 15 (VH, c-Met binding group) QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS >Sequence ID 16 (VL, c-Met binding group) DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK >Sequence ID 17 HC1 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >Sequence ID 18 LC1 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >Sequence ID 19 HC2 QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >Sequence ID 20 LC2 DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0166] In some embodiments, a bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain includes the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, the light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain includes the HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0167] In some embodiments, the first domain that specifically binds to EGFR includes the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met includes the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0168] In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0169] In some embodiments, 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.

[0170] In some embodiments, the bispecific anti-EGFR / c-Met antibody is amivantamab.

[0171] In some embodiments, bispecific anti-EGFR / c-Met antibodies are biosimilars to amivantamab.

[0172] In some embodiments, non-limiting examples of biosimilars of amivantamab can be found in the publicly available web resource: https: / / us.proteogenix_science / product / amivantamab-biosimilar-anti-egfr-me-rccp2-mab-research-grade / .

[0173] In some embodiments, non-limiting examples of biosimilars of amivantamab can be found in the publicly available web resource: https: / / www_thermofisher_com / antibody / product / Amivantamab-Antibody-Recombinant-Monoclonal / MA5-42260.

[0174] In some embodiments, non-limiting examples of biosimilars of amibantamab can be found in the publicly available web resource: https: / / www_genemedi.net / i / biologics-biosimilar-GMP-Bios-ab-021.

[0175] In some embodiments, non-limiting examples of biosimilars of amivantamab can be found in the publicly available web resource: https: / / www_prosci-inc_com / product / amivantamab-egfr-me-rccp2-research-grade-biosimilar-10-966 / .

[0176] In some embodiments, non-limiting examples of biosimilars of amivantamab can be found in the publicly available web resource: https: / / www_antibodysystem_com / product / 6201.html.

[0177] In some embodiments, non-limiting examples of biosimilars of amivantamab can be found in the publicly available web resource: https: / / www_biorbyt_com / amivantamab-biosimilar-antibody-orb1140752.html.

[0178] In one embodiment, the bispecific anti-EGFR / c-Met antibody contains one or more Fc silencing mutations.

[0179] In one embodiment, one or more Fc silencing mutations reduce affinity for the Fcγ receptor.

[0180] In one embodiment, one or more Fc silencing mutations include V234A / G237A / P238S / H268A / V309L / A330S / P331S.

[0181] In one embodiment, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content between approximately 1% and 15%. Antibodies with low fucose content can be produced using various methods that have been reported to successfully express relatively highly defucosylated antibodies containing branched complex-type Fc oligosaccharides, such as: control of culture osmotic pressure (Konno et al., Cytotechnology 64(:249-65, 2012), application of variant CHO strain Lec13 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), application of variant CHO strain EB66 as the host cell line (Olivier et al., MAbs;2(4), 2010; electronically published before print; PMID:20562582), and application of rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., J Biol Chem (278:3466-3473, 2003), introduction of specific small interfering RNA to the α1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expression of β-1,4-N-acetylglucosaminyltransferase III and kifunensin, a potent inhibitor of Golgi α-mannosidase II or α-mannosidase I (Ferrara et al., J Biol Chem 281:5032-5036, 2006, Ferrara et al., Biotechnol Bioeng 93:851-861, 2006, Xhou et al., Biotechnol Bioeng 99:652-65, 2008). Generally, antibody-mediated cytotoxicity is achieved by reducing the fucose content in the antibody glycan. Cellular cytotoxicity (ADCC) is enhanced.

[0182] Other publicly available bispecific anti-EGFR / c-Met antibodies may be used in the methods of this disclosure, provided they exhibit similar characteristics to amivantamab, as described in U.S. Patent No. 9,593,164. Bispecific anti-EGFR / c-Met antibodies that can be used in the methods of this disclosure may also be generated by combining a publicly available EGFR-binding VH / VL domain with a c-Met-binding VH / VL domain and testing the resulting bispecific antibody for its characteristics as described in U.S. Patent No. 9,593,164. In some embodiments, the anti-EGFR / c-Met antibody is a biosimilar to an anti-EGFR / c-Met antibody as described in U.S. Patent No. 9,593,164.

[0183] The bispecific anti-EGFR / c-Met antibodies used in the methods of this disclosure can be generated by Fab arm exchange (or half-arm exchange) between two monospecific bivalent antibodies, for example, by introducing substitutions at the heavy chain CH3 interface in each half to facilitate the formation of heterodimers of two antibody halves with different specificities, either in vitro or using co-expression in a cell-free environment. The Fab arm exchange reaction is the result of a disulfide bond isomerization reaction and dissociation-association of the CH3 domain. The heavy chain disulfide bond in the hinge region of the parent monospecific antibody is reduced. The resulting free cysteine ​​from one of the parent monospecific antibodies forms an intra-heavy chain disulfide bond with a cysteine ​​residue of the second parent monospecific antibody molecule, while simultaneously, the CH3 domain of the parent antibody is released and reformed by dissociation-association. The CH3 domain of the Fab arm may be modified to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody having two Fab groups or halves, each binding to a different epitope, namely, the epitope at EGFR and the epitope at c-Met. For example, the bispecific antibody of the present invention can be produced using the technique described in International Publication No. 2011 / 131746. In the case of an IgG1 antibody, the mutation F405L in one heavy chain and K409R in the other heavy chain can be used. For an IgG2 antibody, wild-type IgG2 and IgG2 antibodies with F405L and R409K substitutions may be used. For an IgG4 antibody, wild-type IgG4 and IgG4 antibodies with F405L and R409K substitutions may be used. To produce a bispecific antibody, a first monospecific bivalent antibody and a second monospecific bivalent antibody are manipulated to have the aforementioned mutations in the Fc region, and the antibodies are incubated together under sufficiently reducing conditions that allow cysteine ​​to undergo disulfide bond isomerization in the hinge region, thereby producing a bispecific antibody by Fab group exchange. The incubation conditions can, ideally, be returned to non-reducing conditions.Exemplary reducing agents that can be used include 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol. For example, incubation can be performed at a temperature of at least 20°C in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol at a pH of 5 to 8, for example, pH 7.0 or pH 7.4, for at least 90 minutes.

[0184] The bispecific anti-EGFR / c-Met antibodies used in the methods of this disclosure can also be generated using designs such as knob-in-hole (Genentech), CrossMAb (Roche), electrostatically-matched (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), and Biclonic (Merus).

[0185] In the "knob-in-hole" technique (see, for example, International Publication No. 2006 / 028936), the select amino acid forming the interface of the human IgG CH3 domain can be mutated at a position that affects CH3 domain interaction to promote heterodimer formation. An amino acid with a small side chain (the hole) is introduced into the heavy chain of an antibody that specifically binds to a first antigen, and an amino acid with a large side chain (the knob) is introduced into the heavy chain of an antibody that specifically binds to a second antigen. After co-expression of the two antibodies, a heterodimer is formed as a result of preferential interaction between the heavy chain containing the "hole" and the heavy chain containing the "knob". Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V (represented as the modification position in the first CH3 domain of the first heavy chain / the modification position in the second CH3 domain of the second heavy chain).

[0186] In addition to using a "knob-in-hole" technique for promoting Fab group exchange, CrossMAb technology utilizes CH1 / CL domain exchange in one of the semigroups to ensure correct light chain pairing of the resulting bispecific antibody (see, for example, U.S. Patents 8,242,247).

[0187] The full-length bispecific antibodies of the present invention may be generated by using other cross-referencing techniques to exchange variable, constant, or both domains between or within the heavy chain of the bispecific antibody, in one or both groups. Examples of such exchanges include VH-CH1 and VL-CL, VH and VL, CH3 and CL, and CH3 and CH1 as described in International Publications 2009 / 080254, 2009 / 080251, 2009 / 018386, and 2009 / 080252.

[0188] Other methods, such as promoting heavy chain heterodimerization by using electrostatic interactions through the substitution of a positively charged residue on one CH3 surface with a negatively charged residue on a second CH3 surface, may be used as described in U.S. Patent Application Publication 2010 / 0015133, U.S. Patent Application Publication 2009 / 0182127, U.S. Patent Application Publication 2010 / 028637, or U.S. Patent Application Publication 2011 / 0123532. In other methods, heterodimerization is performed by the following substitutions, as described in U.S. Patent Application Publication 2012 / 0149876 or U.S. Patent Application Publication 2013 / 0195849: L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / This can be enhanced by T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W (represented as the modification position in the first CH3 domain of the first heavy chain / the modification position in the second CH3 domain of the second heavy chain).

[0189] The bispecific antibodies of the present invention may be generated using SEEDbody technology. SEEDbody has a selective IgG residue in its constant domain that is substituted with an IgA residue to promote heterodimerization, as described in U.S. Patent Application Publication No. 2007 / 0287170.

[0190] Mutations are typically performed at the DNA level on molecules such as the constant domain of an antibody, using standard methods.

[0191] Exemplary Embodiments 1. A method to improve the median progression-free survival (PFS) in a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, and having NSCLC that has progressed during or after prior treatment with at least one tyrosine kinase inhibitor (TKI), wherein the target population... (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, (ii) A therapeutically effective dose of carboplatin, (iii) A therapeutically effective dose of pemetrexed, This includes administering combination therapy, Improvement in median PFS was compared to the median PFS of a reference population of subjects with NSCLC having one or more EGFR mutations that progressed during or after treatment with at least one previous TKI, and this reference population was administered carboplatin and pemetrexed but not bispecific anti-EGFR / c-Met antibodies. 2. The method according to Embodiment 1, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, the first domain comprising the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12. 3. The method according to Embodiment 1 or 2, wherein one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. 4. The method according to Embodiment 3, wherein one or more EGFR mutations include one or more exon 19 deletions. 5. The method according to Embodiment 3, wherein one or more EGFR mutations include an exon 21 L858R substitution. 6. The method according to any one of Embodiments 1 to 5, wherein the prior TKI comprises a first-generation EGFR TKI. 7. The method according to any one of Embodiments 1 to 5, wherein at least one prior TKI comprises a second-generation EGFR TKI. 8. The method according to any one of Embodiments 1 to 5, wherein at least one prior TKI comprises a third-generation EGFR TKI. 9. The method according to any one of Embodiments 1 to 5, wherein the prior TKI comprises osimertinib. 10. The method according to any one of Embodiments 1 to 9, wherein the administration of the combination therapy is initiated on day 1 of cycle 1 of the first 21-day cycle and continued in the subsequent 21-day cycles. 11. The method according to any one of Embodiments 1 to 10, wherein a bispecific anti-EGFR / c-Met antibody is administered intravenously. 12. The method according to any one of Embodiments 1 to 10, wherein a bispecific anti-EGFR / c-Met antibody is administered subcutaneously. 13. The method according to any one of Embodiments 1 to 12, wherein the method comprises administering a bispecific anti-EGFR / c-Met antibody in an amount of approximately 140 mg to approximately 2240 mg. 14. The method according to Embodiment 13, wherein a bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 700 mg, 750 mg, 800 mg, 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. 15. The method according to Embodiment 14, wherein, if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2. 16. The method according to Embodiment 15, wherein the dose of bispecific anti-EGFR / c-Met antibody for day 1 of cycle 1 is administered as a divided dose over days 1 and 2. 17. The method according to Embodiment 14, wherein, if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle. 18. The method according to Embodiment 14, wherein if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2. 19. The method according to Embodiment 18, wherein the dose of bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2. 20. The method according to Embodiment 14, wherein if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle. 21. The method according to any one of Embodiments 1 to 20, wherein the method comprises administering carboplatin at a dose of AUC5 on day 1 of each 21-day cycle for up to 4 cycles. 22. The method involves administering pemetrexed at approximately 500 mg / m². 2 The method according to any one of Embodiments 1 to 21, comprising administering pemetrexed in a dose on day 1 of each 21-day cycle for up to 4 cycles together with carboplatin, and then administering pemetrexed as maintenance therapy until disease progression. 23. The method is, a)(i) If the subject has a body weight of less than 80 kg, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, or (ii) If the subject has a body weight of less than 80 kg, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle, or (iii) If the subject has a body weight of 80 kg or more, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, or (iv) If the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody should be administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle. b) Administer carboplatin at a dose equal to AUC5 on day 1 of each 21-day cycle for a maximum of 4 cycles. c) Pemetrexed, approximately 500 mg / m² 2 The drug is administered at this dose on day 1 of each 21-day cycle, along with carboplatin, for up to 4 cycles, followed by pemetrexed as maintenance therapy until disease progression. The method according to Embodiment 22, including the method described in Embodiment 22. 24. The method according to Embodiment 23, wherein the dose of bispecific anti-EGFR / c-Met antibody for day 1 of cycle 1 is administered as a divided dose over days 1 and 2. 25. The method according to any one of Embodiments 1 to 24, wherein the combination therapy achieves an improvement in median PFS of at least two weeks. 26. The method according to Embodiment 25, wherein the combination therapy achieves an improvement in median PFS for at least one month. 27. The method according to Embodiment 26, wherein the combination therapy achieves an improvement in median PFS for at least 1.5 months. 28. The method according to Embodiment 27, wherein the combination therapy achieves an improvement in median PFS for at least two months. 29. The method according to Embodiment 28, wherein at least one subject in the target population exhibits a progression-free survival period of at least 4.5 months. 30. The method according to Embodiment 29, wherein at least one subject in the target population exhibits progression-free survival for at least 5 months. 31. The method according to Embodiment 30, wherein at least one subject in the target population exhibits progression-free survival for at least 5.5 months. 32. The method according to Embodiment 31, wherein at least one subject in the target population exhibits progression-free survival for at least six months. 33. The method according to Embodiment 32, wherein at least one subject in the target population exhibits progression-free survival for at least 10 months. 34. The method according to Embodiment 33, wherein at least one subject in the target population exhibits progression-free survival for at least 12 months. 35. The method according to Embodiment 34, wherein at least one subject in the target population exhibits progression-free survival for at least 14 months. 36. The method according to any one of Embodiments 1 to 35, wherein the combination therapy achieves further improvement in objective response compared to the reference population (for example, the combination therapy achieves an ORR of at least about 60%, or at least about 61%, or at least about 62%). 37. The method according to any one of Embodiments 1 to 36, wherein the combination therapy achieves further improvement in overall survival (OS) compared to the reference population. 38. The method according to any one of Embodiments 1 to 37, wherein the combination therapy achieves further improvement in duration of response (DoR) compared to the reference population (for example, the combination therapy achieves a median DoR of at least about 6 months, or at least about 7 months, or at least about 8 months, or at least about 9 months). 39. The method according to any one of Embodiments 1 to 38, wherein the combination therapy achieves further improvement in time to subsequent therapy (TTST) compared to the reference population (for example, 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). 40. The method according to any one of Embodiments 1 to 39, wherein the combination therapy achieves further improvement in PFS (PFS2) after the first subsequent therapy compared to the reference population (for example, the combination therapy achieves a median PFS2 of at least about 12 months, at least about 13 months, or at least about 14 months). 41. The method according to any one of Embodiments 1 to 40, wherein the combination therapy achieves further improvement in median intracranial PFS compared to the reference population (for example, 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). 42. A method for improving the median progression-free survival (PFS) in a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, and having NSCLC that has progressed during or after prior treatment with at least one tyrosine kinase inhibitor (TKI), wherein the target population... (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, (ii) A therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof (iii) A therapeutically effective dose of carboplatin, and (iv) A therapeutically effective dose of pemetrexed, This includes administering combination therapy that includes, The method involves comparing the median PFS improvement with the median PFS of a reference population of subjects with NSCLC having one or more EGFR mutations that progressed during or after treatment with at least one previous TKI, the reference population being treated with carboplatin and pemetrexed but not with bispecific anti-EGFR / c-Met antibodies, razertinib, or any pharmaceutically acceptable salts or hydrates thereof. 43. The method according to claim 42, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, the first domain comprising the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12. 44. The method according to Embodiment 42 or 43, wherein one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. 45. The method according to Embodiment 44, wherein one or more EGFR mutations include one or more exon 19 deletions. 46. ​​The method according to Embodiment 44, wherein one or more EGFR mutations include an exon 21 L858R substitution. 47. The method according to any one of embodiments 42 to 46, wherein at least one prior TKI comprises a first-generation EGFR TKI. 48. The method according to any one of embodiments 42 to 46, wherein at least one prior TKI comprises a second-generation EGFR TKI. 49. The method according to any one of embodiments 42 to 46, wherein at least one prior TKI comprises a third-generation EGFR TKI. 50. The method according to any one of embodiments 42 to 46, wherein the prior TKI comprises osimertinib. 51. The method according to any one of embodiments 42 to 50, wherein the administration of the combination therapy is initiated on day 1 of cycle 1 of the first 21-day cycle and continued in the subsequent 21-day cycles. 52. The method according to any one of embodiments 42 to 51, wherein a bispecific anti-EGFR / c-Met antibody is administered intravenously. 53. The method according to any one of Embodiments 42 to 51, wherein a bispecific anti-EGFR / c-Met antibody is administered subcutaneously. 54. The method according to any one of Embodiments 42 to 53, wherein the method comprises administering a bispecific anti-EGFR / c-Met antibody in an amount of approximately 140 mg to approximately 2240 mg. 55. The method according to Embodiment 54, wherein a bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 700 mg, 750 mg, 800 mg, 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. 56. The method according to Embodiment 55, wherein, if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2. 57. The method according to Embodiment 56, wherein the dose of bispecific anti-EGFR / c-Met antibody for day 1 of cycle 1 is administered as a divided dose over days 1 and 2. 58. The method according to Embodiment 55, wherein, if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle. 59. The method according to Embodiment 55, wherein if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2. 60. The method according to Embodiment 59, wherein the dose of bispecific anti-EGFR / c-Met antibody for day 1 of cycle 1 is administered as a divided dose over days 1 and 2. 61. The method according to Embodiment 55, wherein if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle. 62. The method according to any one of Embodiments 42 to 61, wherein razertinib, or a pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate. 63. The method according to any one of Embodiments 42 to 61, wherein razertinib, or a pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate monohydrate. 64. The method according to any one of Embodiments 42 to 63, comprising administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, orally once daily at a dose of about 240 mg. 65. The method according to Embodiment 64, comprising administering razertinib or a pharmaceutically acceptable salt or hydrate thereof orally once daily at a dose of approximately 240 mg, starting on day 1 of cycle 5 or earlier, if carboplatin is discontinued early. 66. The method according to any one of Embodiments 42 to 65, comprising administering carboplatin at a dose of AUC5 on day 1 of each 21-day cycle for up to 4 cycles. 67. The method involves administering pemetrexed at approximately 500 mg / m². 2 The method according to any one of Embodiments 42 to 66, comprising administering pemetrexed in a dose on day 1 of each 21-day cycle for up to 4 cycles together with carboplatin, and then administering pemetrexed as maintenance therapy until disease progression. 68. The method is, a)(i) If the subject has a body weight of less than 80 kg, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, or (ii) If the subject has a body weight of less than 80 kg, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle, or (iii) If the subject has a body weight of 80 kg or more, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, or (iv) If the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody should be administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle. b) (i) Orally administer razertinib, or a pharmaceutically acceptable salt or hydrate thereof, at a dose of approximately 240 mg once daily, or (ii) If carboplatin is discontinued early, razertinib or a pharmaceutically acceptable salt or hydrate thereof should be administered orally once daily at a dose of approximately 240 mg, starting on day 1 of cycle 5 or earlier. c) Administer carboplatin at a dose equal to AUC5 on day 1 of each 21-day cycle for a maximum of 4 cycles. d) Pemetrexed, approximately 500 mg / m² 2 The drug is administered at this dose on day 1 of each 21-day cycle, along with carboplatin, for up to 4 cycles, followed by pemetrexed as maintenance therapy until disease progression. The method according to embodiment 67, including the method described in embodiment 67. 69. The method according to Embodiment 68, wherein the dose of bispecific anti-EGFR / c-Met antibody for day 1 of cycle 1 is administered as a divided dose over days 1 and 2. 70. The method according to any one of embodiments 42 to 69, wherein the combination therapy achieves an improvement in median PFS of at least two weeks. 71. The method according to embodiment 70, wherein the combination therapy achieves an improvement in median PFS for at least one month. 72. The method according to embodiment 71, wherein the combination therapy achieves an improvement in median PFS for at least 1.5 months. 73. The method according to embodiment 72, wherein the combination therapy achieves an improvement in median PFS for at least two months. 74. The method according to Embodiment 73, wherein at least one subject in the target population exhibits progression-free survival for at least 4.5 months. 75. The method according to Embodiment 74, wherein at least one subject in the target population exhibits progression-free survival for at least 5 months. 76. The method according to Embodiment 75, wherein at least one subject in the target population exhibits progression-free survival for at least 5.5 months. 77. The method according to Embodiment 76, wherein at least one subject in the target population exhibits progression-free survival for at least six months. 78. The method according to Embodiment 77, wherein at least one subject in the target population exhibits progression-free survival for at least 10 months. 79. The method according to Embodiment 78, wherein at least one subject in the target population exhibits progression-free survival for at least 12 months. 80. The method according to Embodiment 79, wherein at least one subject in the target population exhibits progression-free survival for at least 14 months. 81. The method according to any one of Embodiments 42 to 80, wherein the combination therapy achieves further improvement in objective response compared to the reference population (for example, the combination therapy achieves an ORR of at least about 60%, or at least about 61%, or at least about 62%). 82. The method according to any one of embodiments 42 to 81, wherein the combination therapy achieves further improvement in overall survival (OS) compared to the reference population. 83. The method according to any one of Embodiments 42 to 82, wherein the combination therapy achieves further improvement in duration of response (DoR) compared to the reference population (for example, the combination therapy achieves a median DoR of at least about 6 months, or at least about 7 months, or at least about 8 months, or at least about 9 months). 84. The method according to any one of Embodiments 42 to 83, wherein the combination therapy achieves further improvement in time to subsequent therapy (TTST) compared to the reference population (for example, 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). 85. The method according to any one of Embodiments 42 to 84, wherein the combination therapy achieves further improvement in PFS (PFS2) after the first subsequent therapy compared to the reference population (for example, the combination therapy achieves a median PFS2 of at least about 12 months, at least about 13 months, or at least about 14 months). 86. The method according to any one of Embodiments 42 to 85, wherein the combination therapy achieves further improvement in median intracranial PFS compared to the reference population (for example, 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). 87. The method according to any one of Embodiments 1 to 86, wherein the bispecific anti-EGFR / c-Met antibody is amivantamab. 88. The method according to any one of Embodiments 1 to 86, wherein the bispecific anti-EGFR / c-Met antibody is a biosimilar to amivantamab. 89. The method according to any one of Embodiments 1 to 41, wherein the combination therapy achieves further improvements in TTD, TTST, and PFS2 compared to the reference population (for example, the combination therapy achieves a median TTD of more 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; the combination therapy achieves a median TTST of more 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 the combination therapy achieves a median PFS2 of more than 11.3 months, or at least about 12 months, or at least about 13 months). 90. The method according to any one of Embodiments 1 to 41, wherein the combination therapy further achieves an improvement in time to disease progression (TTSP) (e.g., more than 13 months, or at least 13.5 months, or at least 14 months) compared to the reference population. 91. A method for improving the median overall survival (OS) in a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, and having non-small cell lung cancer (NSCLC) that has progressed during or after prior treatment with at least one tyrosine kinase inhibitor (TKI), wherein the target population... (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, (ii) A therapeutically effective dose of carboplatin, (iii) A therapeutically effective dose of pemetrexed, This includes administering combination therapy, Improvement in median OS was compared to the median OS of a reference population of subjects with NSCLC having one or more EGFR mutations that progressed during or after treatment with at least one previous TKI, and this reference population was administered carboplatin and pemetrexed but not bispecific anti-EGFR / c-Met antibodies. 92. The method according to Embodiment 91, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, the first domain comprising the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12. 93. The method according to Embodiment 91 or 92, wherein one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. 94. The method according to Embodiment 93, wherein one or more EGFR mutations include one or more exon 19 deletions. 95. The method according to Embodiment 93, wherein one or more EGFR mutations include an exon 21 L858R substitution. 96. The method according to any one of embodiments 91 to 95, wherein at least one prior TKI includes a first-generation EGFR TKI. 97. The method according to any one of embodiments 91 to 95, wherein at least one prior TKI includes a second-generation EGFR TKI. 98. The method according to any one of embodiments 91 to 95, wherein at least one prior TKI includes a third-generation EGFR TKI. 99. The method according to any one of embodiments 91 to 95, wherein the prior TKI comprises osimertinib. 100. The method according to any one of Embodiments 91 to 99, wherein the improvement in median OS at 18 months was greater in the group of subjects treated with combination therapy than in the reference group. 101. The method according to any one of embodiments 91 to 100, wherein the administration of the combination therapy is initiated on day 1 of cycle 1 of the first 21-day cycle and continued in the subsequent 21-day cycles. 102. The method according to any one of Embodiments 91 to 101, wherein a bispecific anti-EGFR / c-Met antibody is administered intravenously. 103. The method according to any one of Embodiments 91 to 101, wherein a bispecific anti-EGFR / c-Met antibody is administered subcutaneously. 104. The method according to any one of Embodiments 91 to 103, wherein the method comprises administering a bispecific anti-EGFR / c-Met antibody in an amount of approximately 140 mg to approximately 2240 mg. 105. The method according to Embodiment 104, wherein a bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 700 mg, 750 mg, 800 mg, 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. 106. The method according to Embodiment 105, wherein, if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2. 107. The method according to Embodiment 106, wherein the dose of bispecific anti-EGFR / c-Met antibody for day 1 of cycle 1 is administered as a divided dose over days 1 and 2. 108. The method according to Embodiment 105, wherein, if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle. 109. The method according to Embodiment 105, wherein if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2. 110. The method according to Embodiment 109, wherein the dose of bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2. 111. The method according to Embodiment 105, wherein if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle. 112. The method according to any one of Embodiments 91 to 111, comprising administering carboplatin at a dose of AUC5 on day 1 of each 21-day cycle for up to 4 cycles. 113. The method involves administering pemetrexed at approximately 500 mg / m². 2 The method according to any one of Embodiments 91 to 112, comprising administering pemetrexed in a dose on day 1 of each 21-day cycle for up to 4 cycles together with carboplatin, and then administering pemetrexed as maintenance therapy until disease progression. 114. The method is, a)(i) If the subject has a body weight of less than 80 kg, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, or (ii) If the subject has a body weight of less than 80 kg, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle, or (iii) If the subject has a body weight of 80 kg or more, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2, or (iv) If the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody should be administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle. b) Administer carboplatin at a dose equal to AUC5 on day 1 of each 21-day cycle for a maximum of 4 cycles. c) Pemetrexed, approximately 500 mg / m² 2 The drug is administered at this dose on day 1 of each 21-day cycle, along with carboplatin, for up to 4 cycles, followed by pemetrexed as maintenance therapy until disease progression. The method according to Embodiment 113, including the method described in Embodiment 113. 115. The method according to Embodiment 114, wherein the dose of bispecific anti-EGFR / c-Met antibody for day 1 of cycle 1 is administered as a divided dose over days 1 and 2. 116. The method according to any one of embodiments 91 to 115, wherein a group of subjects treated with combination therapy achieves an improvement in median OS over at least two months compared to a reference group. 117. The method according to Embodiment 116, wherein a group of subjects treated with combination therapy achieves an improvement in median OS of at least approximately 2.2 months, 2.3 months, 2.4 months, 2.5 months, or 2.6 months compared to the reference group. 118. The method according to Embodiment 116, wherein a group of subjects treated with combination therapy achieves an improvement in median OS over approximately 2.4 months compared to the reference group. 119. The method according to Embodiment 116, wherein the population of subjects treated with combination therapy exhibits overall survival for at least 17 months. 120. The method according to Embodiment 119, wherein the subject exhibits an overall survival period of at least approximately 17.2 months, approximately 17.4 months, approximately 17.6 months, approximately 17.7 months, approximately 17.8 months, or approximately 18 months. 121. The method according to Embodiment 119, wherein the subjects exhibit an overall survival period of approximately 17.7 months. 122. The method according to any one of embodiments 91 to 121, wherein the group of subjects treated with combination therapy achieves further improvement in time to subsequent therapy (TTST) compared to the reference group. 123. The method according to any one of embodiments 91 to 121, wherein the group of subjects treated with combination therapy achieves further improvement in time to disease progression (TTSP) compared to the reference group. 124. The method according to any one of embodiments 91 to 121, wherein the group of subjects treated with combination therapy achieves further improvement in PFS (PFS2) after the first subsequent therapy compared to the reference group. 125. The method according to any one of embodiments 91 to 121, wherein the subject group administered the combination therapy achieves further improvement in time to discontinuation (TTD) compared to the reference group. 126. The method according to Embodiment 122, wherein a subject population administered combination therapy achieves an improvement in TTST of at least approximately 5 months, approximately 5.5 months, approximately 5.6 months, approximately 6 months, approximately 6.5 months, or approximately 7 months compared to the reference population. 127. The method according to Embodiment 122, wherein the population of subjects treated with combination therapy exhibits a TTST of at least approximately 12 months. 128. The method according to Embodiment 122, wherein the subject population administered combination therapy exhibits a TTST of approximately 12 months, approximately 12.2 months, or approximately 12.5 months. 129. The method according to Embodiment 122, wherein the subject population administered combination therapy exhibits a TTST of approximately 12.2 months. 130. The method according to Embodiment 122, wherein the group of subjects treated with combination therapy exhibits a TTST approximately twice as long as the reference group at 18 months. 131. The method according to Embodiment 123, wherein a group of subjects treated with combination therapy achieves an improvement in TTSP of at least about 4 months compared to the reference group. 132. The method according to Embodiment 123, wherein a group of subjects treated with combination therapy achieves an improvement in TTSP of approximately 4 months, approximately 4.2 months, or approximately 4.5 months compared to the reference group. 133. The method according to Embodiment 123, wherein a group of subjects treated with combination therapy achieves an improvement of approximately 4 months in TTSP compared to the reference group. 134. The method according to Embodiment 123, wherein a group of subjects treated with combination therapy achieves an improvement of approximately 4.2 months in TTSP compared to the reference group. 135. The method according to Embodiment 123, wherein the population of subjects treated with combination therapy exhibits a TTSP of at least approximately 16 months. 136. The method according to Embodiment 123, wherein the subject population administered combination therapy exhibits a TTSP of approximately 16 months. 137. The method according to Embodiment 123, wherein the subject population administered the combination therapy achieves a reduction of approximately 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% in TTSP compared to the reference population. 138. The method according to Embodiment 123, wherein the group of subjects treated with combination therapy achieves approximately a 27% reduction in TTSP at 18 months compared to the reference group. 139. The method according to Embodiment 124, wherein a subject population administered combination therapy achieves an improvement in PFS2 of at least approximately 4 months, approximately 4.2 months, approximately 4.4 months, approximately 4.5 months, approximately 4.6 months, approximately 4.8 months, or approximately 5 months compared to the reference population. 140. The method according to Embodiment 124, wherein a group of subjects treated with combination therapy achieves an improvement of approximately 4 months, 4.2 months, 4.4 months, 4.5 months, 4.6 months, 4.8 months, or 5 months in PFS2 compared to the reference group. 141. The method according to Embodiment 124, wherein a group of subjects treated with combination therapy achieves an improvement of approximately 4.4 months in PFS2 compared to the reference group. 142. The method according to Embodiment 124, wherein the subject exhibits a PFS2 of at least approximately 16 months. 143. The method according to Embodiment 124, wherein the subject exhibits a PFS2 of approximately 16 months. 144. The method according to Embodiment 124, wherein a population of subjects treated with combination therapy exhibits a greater PFS2 at 18 months compared to the reference population. 145. The method according to Embodiment 125, wherein a group of subjects treated with combination therapy achieves an improvement in TTD of at least approximately 5 months, approximately 5.3 months, approximately 5.5 months, approximately 5.7 months, approximately 5.9 months, or approximately 6 months compared to the reference group. 146. The method according to Embodiment 125, wherein a group of subjects treated with combination therapy achieves an improvement in TTD of approximately 5 months, 5.3 months, 5.5 months, 5.7 months, 5.9 months, or 6 months compared to the reference group. 147. The method according to Embodiment 125, wherein the subject population administered the combination therapy exhibits a TTD of at least approximately 10 months, approximately 10.2 months, approximately 10.4 months, approximately 10.6 months, approximately 10.8 months, or approximately 11 months. 148. The method according to Embodiment 125, wherein the subject population administered combination therapy exhibits a TTD of approximately 10 months, approximately 10.2 months, approximately 10.4 months, approximately 10.6 months, approximately 10.8 months, or approximately 11 months. 149. The method according to Embodiment 125, wherein the group of subjects receiving combination therapy has approximately five times more subjects receiving treatment at 18 months than the reference group. [Examples]

[0192] To further illustrate some of the embodiments disclosed herein, the following examples are provided. These examples are illustrative and not limiting to the embodiments of the present disclosure.

[0193] Example 1. CHRYSALIS-2 Clinical Trial CHRYSALIS-2 (NCT04077463) is an open-label Phase 1 / 1b trial to evaluate the safety and pharmacokinetics of razertinib as monotherapy or in combination with amivantamab in participants with advanced non-small cell lung cancer. The trial includes multiple cohorts. Results for the LACP (razertinib, amivantamab, carboplatin, pemetrexed) cohort of 20 patients are provided below.

[0194] method: The LACP cohort of the CHRYSALIS-2 trial enrolled patients with relapsed / refractory EGFR-mutated NSCLC whose disease had progressed during or after treatment with EGFR TKIs as last-line therapy (up to three prior treatment lines). Patients received amivantamab 1400 mg (1750 mg for patients weighing ≥80 kg) intravenously weekly for the first four weeks, and then 1750 mg (2100 mg for patients weighing ≥80 kg) every three weeks starting in cycle 3, in addition to 240 mg of lazertinib orally daily and pemetrexed (500 mg / m²). 2 Patients received ) along with carboplatin (AUC5 for the first four cycles) in 21-day cycles. Responses were assessed by the principal investigator according to RECIST v1.1.

[0195] result: Of the 20 patients enrolled, the median age was 61 years (range, 38–76), 55% were female, 55% were Asian, and 40% were Caucasian. The median number of previous treatment lines was 2 (70% had previously received osimertinib, and 45% had previously received first-generation / second-generation EGFR TKIs). The objective response rate was 50%, and the median duration of response was not estimable (median follow-up was 13.1 months [range, 2.4–17.5 months]). Eight of the 10 responders had a response duration of 6 months or longer. Eleven patients (55%) are continuing treatment. The median progression-free survival (PFS) was 14.0 months (95% CI, 4.3–not estimable). A total of five patients were treated beyond disease progression with a median treatment duration of escalating 4.2 months (range, 3.1–7.1 months). Among the 12 patients with a history of brain metastases, the median PFS was 6.7 months (95% CI, 1.4–not estimable). The most frequent therapeutic adverse events (TEAEs) were rash (100%), neutropenia (90%), and infusion-related reactions (65%). The most common grade 3 or higher TEAEs were neutropenia (70%), thrombocytopenia (25%), and fatigue (25%). Of the grade 3 or higher TEAEs—neutropenia, febrile neutropenia, and thrombocytopenia—all but two cases of neutropenia resolved completely by day 1 of the subsequent cycle. Of the 20 patients, 15 (75%) experienced cytopenic events during the first four cycles, while of the 17 patients, 2 (12%) experienced cytopenic events from cycle 5 onward. Of the 7 patients treated with colony-stimulating factors for neutropenia, 5 did not experience recurrent episodes of neutropenia. Treatment-related interruptions, reductions, and discontinuations of any of the study drugs occurred in 18 (90%), 14 (70%), and 8 (40%) patients, respectively. No patients discontinued all study drugs due to TEAEs.

[0196] Conclusion: In patients with EGFR-mutated progressive NSCLC who experienced disease progression with EGFR TKIs, amivantamab, lazertinib plus chemotherapy demonstrated meaningful and sustained response rates.

[0197] Example 2. MARIPOSA-2 Clinical Trial MARIPOSA-2 is a randomized, open-label, active-controlled, parallel-group, multi-center, Phase 3 trial designed 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 non-squamous NSCLC that progressed during or after treatment with osimertinib. The trial identification numbers include NCT04988295, CR109061, 2021-001825-33 (EudraCT), and 61186372NSC3002.

[0198] The objective of this study is to evaluate the efficacy of adding lazertinib to amivantamab, carboplatin, and pemetrexed (LACP / ACP-L dosing regimen), and the efficacy of adding lazertinib to amivantamab, carboplatin, and pemetrexed (ACP), compared with addition to carboplatin and pemetrexed (CP), in participants with epidermal growth factor receptor (EGFR)-positive exon 19 del or exon 21 L858R substitution non-small cell lung cancer (NSCLC) that has progressed locally or metastasized after osimertinib failure. The objective of the expansion cohort is to further characterize the safety and efficacy of the ACP-L dosing schedule versus ACP using additional data.

[0199] Trial Design The original study design of MARIPOSA-2 provided three arms with a randomization ratio of 2:2:1 for LACP, CP, and ACP respectively, for the primary goal of comparing LACP, CP versus ACP in a study to demonstrate the contribution of lazertinib. A decision was made to amend MARIPOSA-2 to test the dual primary hypotheses of comparing ACP versus CP and LACP versus CP.

[0200] Cohort A was ultimately modified to withhold lazertinib during carboplatin administration. The modified dosing schedule, where lazertinib is initiated after completion of treatment with carboplatin, is referred to as ACP-L. The prior dosing schedule before modification (i.e., the dosing schedule where participants initiated lazertinib from the start of treatment) is designated as LACP. The primary statistical analysis compared all randomized participants between Cohort A and Cohort B, and between Cohort C and Cohort B, based on treatment regardless of dosing schedule.

[0201] To further characterize the safety and efficacy of the modified ACP-L dosing schedule relative to ACP, a separate open-label randomized extension cohort was added to the trial. Enrollment of participants into the extension cohort commenced after enrollment into the main study was completed. The extension cohort had the same eligibility criteria and study procedures as the main study and was conducted at the same trial sites. It was planned that participants would be randomly assigned in a 2:1 ratio to the study treatment groups (Cohort A2 and Cohort C2, respectively) in the extension cohort.

[0202] Data from the extension cohort were not included in the primary analysis. The primary analysis of Cohort A, pre-specified in the Statistical Analysis Plan (SAP), pools data from participants treated with LACP and ACP-L. Due to limited follow-up for participants administered ACP-L in the main study and the extension cohort, a full comparison of ACP-L versus CP is not within the scope of this analysis. A diagram of the study design is provided in Figure 1.

[0203] Inclusion / Exclusion Criteria. Eligible patients were 18 years of age or older, had locally advanced or metastatic NSCLC with disease progression during or after osimertinib monotherapy (as the most recent line of treatment), and had an EGFR Ex19 deletion or L858R mutation. Patients with brain metastases were eligible provided that their intracranial disease was stable, asymptomatic, and they had not changed their steroid dose. Additional information regarding the criteria is provided below.

[0204] Inclusion Criteria: Participants must have at least one measurable lesion according to the Response Evaluation Criteria (RECIST) v1.1 for previously unirradiated solid tumors. Participants must have non-squamous non-small cell lung cancer (NSCLC) that has been histologically or cytologically confirmed and characterized by an epidermal growth factor receptor (EGFR) exon 19 del or exon 21 L858R mutation at the time of or after diagnosis of locally advanced or metastatic disease. Participants with a history of brain metastases must have been treated for all lesions as clinically demonstrated (i.e., there is no current indication for further definitive local treatment). Any definitive local treatment for brain metastases must have been completed at least 14 days prior to randomization, and participants may be receiving 10 milligrams (mg) or less of prednisone or its equivalent daily for the treatment of intracranial disease. Participants must have a status of 0 or 1 in the Eastern Cooperative Oncology Group (ECOG). • Toxicity from previous systemic anticancer therapy must be resolved to meet the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Grade 1 or baseline level (excluding alopecia [any grade], peripheral neuropathy of grade 2 or less, or hypothyroidism of grade 2 or less that is stable with hormone replacement). Women who may become pregnant must have negative serum pregnancy tests at the time of screening and within 72 hours of the first dose of the study treatment, and must consent to further serum or urine pregnancy tests during the study. Participants must have experienced disease progression during or after osimertinib monotherapy as their most recent line of treatment. Osimertinib must have been administered as first-line treatment for locally advanced or metastatic disease, or as second-line treatment after prior treatment with a first- or second-generation EGFR tyrosine kinase inhibitor (TKI) as monotherapy. Participants who have received any type of neoadjuvant and / or adjuvant therapy are eligible if progression to locally advanced or metastatic disease occurs at least 12 months after the last dose of such therapy, and the participant subsequently progresses to locally advanced or metastatic disease during or after osimertinib. Treatment with osimertinib must be discontinued at least 8 days prior to randomization (4 times the half-life) (i.e., the last dose must be no later than day 8).

[0205] Exclusion criteria: • Participants had received radiotherapy for palliative care of NSCLC less than 14 days prior to randomization. Participants with symptomatic or progressive brain metastases. Participants must have a history of piatric disease or current evidence of such disease, or have spinal cord compression that has not been definitively treated with surgery or radiation. • Participants are familiar with small cell transformation. Participants have a history of interstitial lung disease (ILD) / pneumonia, including drug-induced ILD or radiation pneumonitis. Participants have a history of clinically significant cardiovascular disease (but not limited to) diagnosed within 4 weeks prior to randomization, including but not limited to: deep vein thrombosis or pulmonary embolism, myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary / peripheral artery bypass grafting, or acute coronary syndrome. Participants have a significant genetic predisposition to venous thromboembolic events. Participants have a history of venous thromboembolic events and have not received appropriate therapeutic anticoagulation therapy in accordance with National Comprehensive Cancer Network or local guidelines.

[0206] Duration of treatment / duration of clinical trial: This trial included a screening phase, a treatment phase, and a follow-up phase. Participants had to complete the screening procedure within 28 days prior to randomization. The treatment phase began on day 1 of cycle 1 and continued in 21-day cycles until the end of treatment visit, whichever came first, within 30 days of discontinuation of the study treatment or before the initiation of subsequent systemic therapy. Participants who discontinued the study treatment for any reason were followed up in the follow-up phase for survival and disease progression. The follow-up phase began after the end of treatment visit and continued until death, inability to follow up, or withdrawal of consent, whichever came first.

[0207] Main research areas: Group A Administration Schedule 1 (LACP): • Lazertinib: 240 mg, administered orally once daily. • Amivantamab: Administered intravenously (IV) in 21-day cycles. Administer 1,400 mg (1,750 mg if weighing 80 kg or more) on days 1 / 2 (divided dose), 8, and 15 of Cycle 1, and on day 1 of Cycle 2. Start with cycle 3, administering 1,750 mg (2,100 mg for patients weighing over 80 kg) on ​​day 1 of each 21-day cycle. Carboplatin and pemetrexed: Same as in Group B.

[0208] Administration schedule 2 (ACP-L): • Lazertinib: 240 mg, administered orally once daily, starting on day 1 of cycle 5, or earlier if carboplatin is discontinued earlier. • Amivantamab: Administered via intravenous infusion in 21-day cycles. Administer 1,400 mg (1,750 mg if weighing 80 kg or more) on days 1 / 2 (divided dose), 8, and 15 of Cycle 1, and on day 1 of Cycle 2. Start with cycle 3, administering 1,750 mg (2,100 mg for patients weighing over 80 kg) on ​​day 1 of each 21-day cycle. Carboplatin and Pemetrexed: same as Group B.

[0209] Group B (CP): • Carboplatin: administered at a dose of AUC5 on Day 1 of each 21-day cycle, for up to 4 cycles • Pemetrexed: 500 mg / m 2 administered at the dose on Day 1 of each 21-day cycle; carboplatin is administered for up to 4 cycles, followed by administration as maintenance therapy until disease progression

[0210] Group C (ACP): • Amivantamab: administered according to the schedule in Group A • Carboplatin and Pemetrexed: administered in the same manner as in Group B

[0211] [Table 1]

[0212] Results: As described above, MARIPOSA-2 (NCT04988295) is a randomized, open-label phase 3 trial evaluating the efficacy and stability of two dosing regimens: RYBREVANT® (amivantamab) and a chemotherapy agent. Patients with locally advanced or metastatic EGFR ex19 deletion or L858R substitution NSCLC who had experienced disease progression during or after osimertinib administration were randomized to receive either RYBREVANT® plus a chemotherapy agent or RYBREVANT® plus a chemotherapy agent with razertinib or a chemotherapy agent alone. Using a dual primary endpoint, progression-free survival (PFS) (using RECIST v1.1 guidelines), assessed by blinded independent central review (BICR), was compared to chemotherapy alone for each experimental group. Secondary endpoints included objective response, overall survival (OS), duration of response (DoR), time to follow-up therapy, progression-free survival (PFS2) after the first follow-up therapy, and intracranial PFS, as assessed by BICR. All study participants underwent sequential brain imaging to enable robust assessment of brain endpoints and to evaluate central nervous system (CNS) activity of RYBREVANT® with and without rasertinib. Since brain metastases can result in significant burden and poor outcomes for patients, this aspect of the study design provides important information in an area of ​​highly unmet needs. The study enrolled 657 participants with locally advanced or metastatic EGFR exon 19 deletion (ex19 deletion) or L858R replacement non-small cell lung cancer (NSCLC) at or after disease progression with osimertinib.

[0213] The following is a summary of the positive top-line results from the Phase 3 MARIPOSA-2 trial evaluating RYBREVANT® (amivantamab) administered in combination with and without razertinib in combination with chemotherapy agents (carboplatin and pemetrexed). The trial met its dual primary endpoint and demonstrated a statistically significant and clinically meaningful improvement in PFS compared to chemotherapy alone in both experimental treatment groups. No new safety signals were found regarding the addition of RYBREVANT® to chemotherapy.

[0214] A total of 657 participants (ACP: 131; LACP / ACP-L: 263; CP: 263) were randomized in the primary study and included in this primary analysis. The primary efficacy results are summarized in Table 1A. At the clinical cutoff (CCO), 371 PFS events were observed by BICR at a median study follow-up of 8.74 months.

[0215] [Table 2]

[0216] Results of effectiveness: The median progression-free survival, as determined by a blinded, independent central review, was 6.3 months (95% CI, 5.55–8.4) with amivantamab-chemotherapy, 8.3 months (95% CI, 6.8–9.1) with amivantamab-razertinib-chemotherapy, and 4.2 months (95% CI, 4.0–4.4) with chemotherapy alone. The hazard ratio for disease progression or death was 0.48 (95% CI, 0.36–0.64; P<0.001) for amivantamab-chemotherapy versus chemotherapy, and was similar in degree to amivantamab-razertinib-chemotherapy versus chemotherapy (0.44; 95% CI, 0.35–0.56; P<0.001).

[0217] The median progression-free survival as assessed by the principal investigator was 8.2 months (95% CI, 6.8–10.9) for amivantamab-chemotherapy and 8.3 months (95% CI, 7.1–9.9) for amivantamab-lasertinib-chemotherapy, compared to 4.2 months (95% CI, 4.0–4.5) for chemotherapy alone, corresponding to similar hazard ratios of 0.41 and 0.38 for disease progression or death, respectively (P<0.001 for both chemotherapy-based approaches).

[0218] The progression-free survival benefit was consistent across specified subgroups for amivantamagb-chemotherapy, including subgroups based on history of brain metastases, line of treatment with osimertinib, and EGFR mutation type, and was similar in degree to that of amivantamagb-razertinib-chemotherapy.

[0219] The objective response rates were 64% (95% CI, 55-72) for amivantamab-chemotherapy, 63% (95% CI, 57-69) for amivantamab-lazertinib-chemotherapy, and 36% (95% CI, 30-42) for chemotherapy alone. A similar significant improvement was observed for amivantamab-chemotherapy compared to chemotherapy (odds ratio, 3.10; 95% CI, 2.00-4.80; P<0.001), and a similar significant improvement was observed for amivantamab-lazertinib-chemotherapy as well (odds ratio, 2.97; 95% CI, 2.08-4.24; P<0.001). Among patients with confirmed responses, the median duration of response was 6.9 months (95% CI, 5.5 to unpredictable) for amivantamab-chemotherapy, 9.4 months (95% CI, 6.9 to unpredictable) for amivantamab-lazertinib-chemotherapy, and 5.55 months (95% CI, 4.2 to 9.6) for chemotherapy alone.

[0220] In this study, 161 deaths were observed, but there was a favorable trend toward improved overall survival with amivantamab-chemotherapy versus chemotherapy (hazard ratio for death, 0.77; 95% CI, 0.49–1.21). Non-adverse effects were observed with amivantamab-lazertinib-chemotherapy versus chemotherapy (hazard ratio for death, 0.96; 95% CI, 0.67–1.35).

[0221] The median intracranial progression-free survival was 12.45 months (95% CI, 10.8–not estimable) for amivantamab-chemotherapy, 12.8 months (95% CI, 11.1–14.3) for amivantamab-lasertinib-chemotherapy, and 8.3 months (95% CI, 7.3–11.3) for chemotherapy alone. The improvement over chemotherapy was significant for amivantamab-chemotherapy (hazard ratio for disease progression or death, 0.55; 95% CI, 0.38–0.79; P=0.001) and similar in degree to amivantamab-lasertinib-chemotherapy versus chemotherapy alone (hazard ratio for disease progression or death, 0.58; 95% CI, 0.44–0.78; P<0.001).

[0222] Based on the limited follow-up of participants who received ACP-L in the main study and extension cohort to date, a comparison between ACP-L and CP is not within the scope of this analysis and will be further evaluated if additional data becomes available.

[0223] Consideration Amivantamab-chemotherapy and amivantamab-lasertinib-chemotherapy significantly extended progression-free survival compared to chemotherapy alone, reducing the risk of disease progression or death by 52% and 56%, respectively. Early separation of the curves was observed between both amivantamab-chemotherapy and amivantamab-lasertinib-chemotherapy and chemotherapy alone. The benefit in progression-free survival was consistent across the given subgroups. The degree of improvement compared to chemotherapy was similar for amivantamab-chemotherapy and amivantamab-lasertinib-chemotherapy.

[0224] Amivantamab is a high molecular weight and was not expected to easily cross the blood-brain barrier. This was one of the key driving forces for including lasertinib, a known CNS-active TKI, in the amivantamab-lasertinib-chemotherapy group. Therefore, it is noteworthy that amivantamab-chemotherapy showed an intracranial progression-free survival advantage over chemotherapy, similar to that of amivantamab-lasertinib-chemotherapy. These findings suggest that amivantamab exerts an intracranial antitumor effect, and it is unclear whether this occurs through direct involvement with intracranial metastases or indirectly through immune-based mechanisms. Despite the frequent use of continued TKIs due to concerns about CNS progression, no previous promising trials have shown improved clinical outcomes with this approach.

[0225] Resistance to osimertinib is diverse, polyclonal, and difficult to treat. Currently, there are no approved targeted therapies for the post-osimertinib situation. Two recent studies of immunotherapy-chemotherapy regimens have failed to demonstrate efficacy in the TKI-resistant situation. There are currently six other phase 3 trials (NCT05261399, NCT04765059, NCT05089734, NCT05338970, NCT04656652, NCT05184712) investigating targeted therapy combinations with chemotherapy as a second-line (or later) treatment in EGFR-mutated progressive NSCLC, highlighting an unmet need in this patient population.

[0226] In summary, progression-free survival was significantly longer with amivantamab chemotherapy and amivantamab-razertinib chemotherapy compared to chemotherapy in patients with EGFR-mutated progressive NSCLC whose disease progressed during or after osimertinib monotherapy.

[0227] Update Data: Post-operative outcomes and additional safety data from MARIPOSA-2 The outcomes following progression from MARIPOSA-2 and additional safety data were evaluated as described below.

[0228] Methods: The following analyses focus on 131 patients randomized to amivantamaib-chemotherapy (safety set: n=130) and 263 patients randomized to chemotherapy (safety set: n=243). A third treatment group (amivantamaib-lazertinib-chemotherapy) was modified during the study and will be reported later. Post-progression endpoints were time to discontinuation (TTD), time to follow-up therapy (TTST), and progression-free survival (PFS2) after the first follow-up therapy.

[0229] Results: At a median follow-up period of 8.7 months (mo), 55 / 130 (42%) patients (pts) in the chemotherapy group and 173 / 243 (71%) in the chemotherapy group had progressive disease (PD). Of the patients with PD, 19 / 55 (35%) in the amivantamab-chemotherapy group and 28 / 173 (16%) in the chemotherapy group were treated for more than 4 weeks beyond progression, with median post-progression treatment durations (95% CI) of 18.3 (9.0-NE) weeks and 9.0 (6.0-16.4) weeks, respectively. Compared to chemotherapy, amivantamab-chemotherapy significantly prolonged TTD (median 11.0 months compared to 4.5 months for chemotherapy; HR, 0.37 [95% CI 0.28~0.50]; P<0.0001), TTST (median 12.1, compared to 6.6 months for chemotherapy; HR, 0.42 [95% CI, 0.30~0.59]; P<0.0001), and PFS2 (median 13.9, compared to 11.3 months for chemotherapy; HR, 0.60 [95% CI 0.40~0.92]; P=0.017). Among patients with PD, 75% (41 / 55) in the amivantamab-chemotherapy group discontinued treatment after progression. In contrast, 93% (161 / 173) of patients with chemotherapy discontinued treatment after progression. Initial systemic therapy was initiated in 63% (26 / 41) of patients who had received amivantamab-chemotherapy and in 63% (101 / 161) of patients who had received chemotherapy. The most common follow-up therapies in both groups were osimertinib and docetaxel. In amivantamab-chemotherapy patients, the initial onset of adverse events such as cytopenia, skin, and fatigue was highest in the first four months and decreased over time.

[0230] Conclusion: Amivantamab-chemotherapy significantly extended TTD, TTST, and PFS2 compared to chemotherapy alone. Amivantamab-chemotherapy represents a new standard of care for patients with EGFR-mutated progressive NSCLC after disease progression with osimertinib.

[0231] Update data: Secondary analysis of patient-related endpoints from MARIPOSA-2 Below, we present an evaluation of time to disease progression (TTSP) and patient-reported outcomes (PRO) from MARIPOSA-2.

[0232] Methods: The following analysis included 131 patients randomized to amivantamab-chemotherapy and 263 patients randomized to chemotherapy (intent-to-treat analysis population [ITT]). TTSP was defined as the time from randomization to the onset of new / worsening lung cancer symptoms requiring a change in anticancer therapy or death, whichever came first. Patient-reported outcomes (PROs) were measured using the EORTC-QLQ-C30, NSCLC-SAQ, and PROMIS-PF 8c instruments.

[0233] Results: At a median follow-up period of 8.7 months, a trend toward improvement in median TTSP was observed with amivantamab-chemotherapy compared to chemotherapy alone (14.9 months vs. 13.0 months; HR, 0.74 [95% CI, 0.51-1.07]; P=0.10).

[0234] The median treatment duration was 3.7 months for chemotherapy compared to 6.3 months for amivantamab-chemotherapy. At 6 months (189 days), the percentage of ITT patients who continued treatment and had improved or stable physical function compared to baseline was 21% for chemotherapy compared to 37% for amivantamab-chemotherapy. A higher percentage of patients with improved or stable emotional function (38% vs. 21%), cognitive function (38% vs. 20%), role function (30% vs. 19%), and overall health (40% vs. 19%) were present in amivantamab-chemotherapy compared to chemotherapy.

[0235] Based on data from EORTC-QLQ-C30, over 6 months, 28% of patients in the amivantamab-chemotherapy group and 13% in the chemotherapy group reported no dyspnea, 23% in the amivantamab-chemotherapy group and 15% in the chemotherapy group reported no pain, and 10% in the amivantamab-chemotherapy group and 5% in the chemotherapy group, respectively. According to EORTC-QLQ-C30, more patients in the amivantamab-chemotherapy group reported improved / stable function or absence of significant symptoms in response to chemotherapy.

[0236] According to the NSCLC-SAQ, amivantamab-chemotherapy substantially extended the time patients could tolerate worsening lung cancer symptoms compared to chemotherapy alone (11.6 months vs. 8.5 months).

[0237] According to PROMIS-PF 8c, amivantamab-chemotherapy numerically extended the time that physical function declined compared to chemotherapy (11.6 months vs. 9.4 months).

[0238] Conclusion: Compared to chemotherapy, amivantamab-chemotherapy numerically extended the time to disease progression. More patients in the ITT population reported improved or stable function and absence of lung cancer-related symptoms with amivantamab-chemotherapy compared to chemotherapy. In patients with EGFR-mutated progressive NSCLC after progression with osimertinib, the PFS benefit of amivantamab-chemotherapy was achieved while maintaining low disease symptom burden and high levels of function.

[0239] Example 3. Amivantamab + chemotherapy vs. chemotherapy: Second interim overall survival in EGFR-mutated advanced non-small cell lung cancer after disease progression in osimertinib treatment. Background: In the Phase 3 MARIPOSA-2 trial (NCT04988295), amivantamab (ami)-chemo (chemo; carboplatin / pemetrexed) demonstrated superior progression-free survival (PFS) compared to chemotherapy in patients (pts) with advanced EGFR-mutated non-small cell lung cancer (NSCLC) after progression on osimertinib (osi) (HR, 0.48; 95% CI, 0.36-0.64; P<0.001). In the first preliminary analysis (IA) of overall survival (OS) (median follow-up: 8.7 months), a favorable trend was observed between amivantamab-chemotherapy and chemotherapy (HR, 0.77; 95% CI, 0.49-1.21). We report the results of the second IA (IA2) and post-disease OS analysis.

[0240] Methods: MARIPOSA-2 enrolled patients with EGFR-mutated (Ex19 deletion / L858R substitution) progressive NSCLC post-osi following osimertinib. The primary endpoint was PFS. IA2 of OS was pre-specified to occur when approximately 75% of all OS events were observed. OS was assessed using a two-sided alpha of 0.0142 (O'Brien-Fleming alpha-paying approach performed by the Lan-DeMets method). Other endpoints were time to discontinuation (TTD), time to follow-up therapy (TTST), and PFS after the first follow-up therapy (PFS2).

[0241] Results: In IA2, 208 OS events were observed across both groups. After an 18.1-month follow-up period, OS was numerically improved in amivantamab-chemotherapy compared to chemotherapy alone (median, 17.7 months vs. 15.3 months; HR, 0.73; 95% CI, 0.54–0.99; P=0.039), but did not reach the pre-specified significance threshold. At 18 months, 50% and 40% of patients survived in amivantamab-chemotherapy and chemotherapy, respectively. The OS benefit of amivantamab-chemotherapy versus chemotherapy was generally consistent across pre-defined subgroups. PFS2 was significantly prolonged with amivantasamab-chemotherapy versus chemotherapy alone (median, 16.0 months vs. 11.6 months; HR, 0.64; 95% CI, 0.48–0.85; P=0.002), and further improved over time, supporting the findings in OS. TTD and TTST were significantly prolonged with amivantasamab-chemotherapy (Table 2).

[0242] [Table 3]

[0243] Figure 2 shows the study design for MARIPOSA-2. Reported secondary / exploratory efficacy endpoints were: overall survival (OS); time to disease progression (TTSP); time to treatment discontinuation (TTD); time to follow-up therapy (TTST); and progression-free survival (PFS2) after the first follow-up therapy. A second interim analysis of OS was pre-specified to occur when approximately 75% of the planned OS events were observed. The significance level for the second interim analysis of OS was determined based on an O'Brien-Fleming α expenditure approach (two-sided α: 0.0142) performed by the Lan-DeMets method.

[0244] Figure 3 shows overall survival. Amivantamab-chemotherapy showed a clear and improved OS trend compared to chemotherapy alone. P-values ​​were calculated using a log-rank test stratified by osimertinib treatment line (first line vs. second line), history of brain metastases (yes or no), and Asian race (yes or no). OS was assessed with a two-sided alpha of 0.0142.

[0245] Figure 4 shows time to disease progression (TTSP, time from randomization to the onset of a new symptom or worsening of symptoms that the researchers considered to be related to lung cancer and required a change in either anticancer treatment or / or clinical intervention to manage the symptoms). TTSP was significantly improved with amivantamab-chemotherapy versus chemotherapy. b-In a previous analysis, amivantamab-chemotherapy numerically improved TTSP compared to chemotherapy alone (HR, 0.74; 95% CI, 0.51–1.07; P=0.10). P-values ​​were calculated using a log-rank test stratified by osimertinib treatment line (first line vs. second line), history of brain metastases (yes or no), and Asian race (yes or no).

[0246] Figure 5 shows time to discontinuation (TTD, time from randomization to discontinuation of all study treatments for any reason, including disease progression, treatment toxicity, or death). b- In a previous analysis, amivantamab-chemotherapy significantly prolonged TTD compared to chemotherapy (HR, 0.37; 95% CI, 0.28–0.50; P<0.0001). 1 cP values ​​are from log-rank tests stratified by osimertinib treatment line (first line vs. second line), history of brain metastases (yes or no), and Asian race (yes or no).

[0247] Figure 6 shows the time to follow-up therapy (time from the randomization date to the start of follow-up anticancer therapy after discontinuation of the study treatment or death, whichever occurred first). The TTST was significantly longer in amivantamab-chemotherapy compared to chemotherapy. b-In a previous analysis, the TTST was significantly longer in amivantamab-chemotherapy compared to chemotherapy (HR, 0.42; 95% CI, 0.30-0.59; P<0.0001). The P value was determined using a log-rank test stratified by osimertinib treatment line (first line vs. second line), history of brain metastases (yes or no), and Asian race (yes or no).

[0248] Figure 7 shows PFS after the first subsequent therapy (PFS2, defined as the time from randomization to the second objective disease progression date after the initiation of subsequent anticancer therapy, based on the earlier of investigator assessment (after PFS was used) or death). PFS2 was significantly prolonged with amivantamab-chemotherapy compared with chemotherapy. b-In a previous analysis, amivantamab-chemotherapy significantly prolonged PFS2 compared with chemotherapy (HR, 0.60; 95% CI, 0.40-0.92; P=0.017). The P-value was calculated using a log-rank test stratified by osimertinib treatment line (first line vs. second line), history of brain metastases (yes or no), and Asian race (yes or no). No single therapy class was identified as the most prominent subsequent therapy, highlighting limited options in the context of a third treatment choice.

[0249] Conclusion: Amivantamab-chemotherapy numerically improved overall survival (OS) and significantly prolonged post-progression outcomes in advanced NSCLC with EGFR mutations compared to chemotherapy alone, following osimertinib. At a median follow-up period of 18.1 months, data continued to support amivantamab-chemotherapy over chemotherapy, demonstrating a promising OS trend in the post-osimertinib situation (median, 17.7 months vs. 15.3 months; HR, 0.73; P=0.039).

[0250] In the post-disease endpoint, amivantamab-chemotherapy showed significantly and sustained improvement compared to chemotherapy alone. - Time to disease progression (HR, 0.73; P=0.026) - Time until treatment is discontinued (HR, 0.42; P<0.0001) - Time to follow-up therapy (HR, 0.51; P<0.0001) - Progression-free survival after the initial follow-up therapy (HR, 0.64; P=0.002)

[0251] The multi-target MoA and immune cell-targeting activity of amivantamab, combined with the antitumor effects of chemotherapy, may contribute to the observed persistence.

[0252] These MARIPOSA-2 follow-up results confirm the superior outcomes of amivantamab-chemotherapy compared to chemotherapy alone in advanced NSCLC with EGFR mutations following disease progression during osimertinib treatment. * * *

[0253] The present invention is not limited to the specific embodiments described herein. In fact, various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to be within the scope of the appended claims.

[0254] All patents, applications, publications, test methods, documents, and other materials cited herein are incorporated herein by reference in their entirety as if they were physically present herein.

Claims

1. A method for improving the median progression-free survival (PFS) in a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, and having non-small cell lung cancer (NSCLC) that has progressed during or after prior treatment with at least one tyrosine kinase inhibitor (TKI), wherein the target population... (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, (ii) A therapeutically effective dose of carboplatin, and (iii) Therapeutic dose of pemetrexed, This includes administering combination therapy, The improvement in median PFS is compared to the median PFS of a reference population of subjects having NSCLC with one or more EGFR mutations that progressed during or after treatment with at least one TKI, wherein the reference population was administered carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody.

2. The method according to claim 1, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, the first domain comprising the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO:

12.

3. The method according to claim 1 or claim 2, wherein the one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

4. The method according to claim 3, wherein the one or more EGFR mutations include one or more exon 19 deletions.

5. The method according to claim 3, wherein one or more EGFR mutations include an exon 21 L858R substitution.

6. The method according to any one of claims 1 to 5, wherein the aforementioned at least one TKI includes a first-generation EGFR TKI.

7. The method according to any one of claims 1 to 5, wherein the aforementioned at least one TKI includes a second-generation EGFR TKI.

8. The method according to any one of claims 1 to 5, wherein the aforementioned at least one TKI includes a third-generation EGFR TKI.

9. The method according to any one of claims 1 to 5, wherein the aforementioned at least one TKI comprises osimertinib.

10. The method according to any one of claims 1 to 9, wherein the administration of the combination therapy is initiated on the first day of cycle 1 of a first 21-day cycle and continued in subsequent 21-day cycles.

11. The method according to any one of claims 1 to 10, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

12. The method according to any one of claims 1 to 10, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

13. The method according to any one of claims 1 to 12, wherein the method comprises administering the bispecific anti-EGFR / c-Met antibody in an amount of about 140 mg to about 2240 mg.

14. The method according to claim 13, wherein the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 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.

15. The method according to claim 14, wherein 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 approximately 1400 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2.

16. The method according to claim 15, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

17. The method according to claim 14, wherein 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 approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle.

18. The method according to claim 14, wherein if the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2.

19. The method according to claim 18, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

20. The method according to claim 14, wherein if the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle.

21. The method according to any one of claims 1 to 20, wherein the method comprises administering the carboplatin at a dose of AUC5 on day 1 of each 21-day cycle for up to 4 cycles.

22. The above method involves distributing pemetrexed at approximately 500 mg / m². ２ The method according to any one of claims 1 to 21, comprising administering the pemetrexed in the specified dose on day 1 of each 21-day cycle for up to four cycles, and then administering the pemetrexed as maintenance therapy until disease progression.

23. The aforementioned method, a) (i) If the subject has a body weight of less than 80 kg, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2, or (ii) If the subject has a body weight of less than 80 kg, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle, or (iii) If the subject has a body weight of 80 kg or more, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2, or (iv) If the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle. b) Administering the carboplatin at an AUC5 dose on day 1 of each 21-day cycle for a maximum of 4 cycles. c) Approximately 500 mg / m² of pemetrexed ２ The drug is administered at the specified dose along with carboplatin on day 1 of each 21-day cycle for up to four cycles, followed by the administration of pemetrexed as maintenance therapy until disease progression. The method according to claim 22, including the method described in claim 22.

24. The method according to claim 23, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

25. The method according to any one of claims 1 to 24, wherein the combination therapy achieves an improvement in the median PFS for at least two weeks.

26. The method according to claim 25, wherein the combination therapy achieves an improvement in the median PFS for at least one month.

27. The method according to claim 26, wherein the combination therapy achieves an improvement in the median PFS for at least 1.5 months.

28. The method according to claim 27, wherein the combination therapy achieves an improvement in the median PFS for at least two months.

29. The method according to claim 28, wherein the subject exhibits a progression-free survival period of at least 4.5 months.

30. The method according to claim 29, wherein the subject exhibits a progression-free survival period of at least five months.

31. The method according to claim 30, wherein the subject exhibits a progression-free survival period of at least 5.5 months.

32. The method according to claim 31, wherein the subject exhibits a progression-free survival period of at least six months.

33. The method according to claim 32, wherein the subject exhibits a progression-free survival period of at least 10 months.

34. The method according to claim 33, wherein the subject exhibits a progression-free survival period of at least 12 months.

35. The method according to claim 34, wherein the subject exhibits a progression-free survival period of at least 14 months.

36. The method according to any one of claims 1 to 35, wherein the combination therapy further achieves an improvement in objective response compared to the reference population.

37. The method according to any one of claims 1 to 36, wherein the combination therapy further achieves an improvement in overall survival (OS) compared to the reference population.

38. The method according to any one of claims 1 to 37, wherein the combination therapy further achieves an improvement in duration of response (DoR) compared to the reference population.

39. The method according to any one of claims 1 to 38, wherein the combination therapy further achieves an improvement in the time to subsequent therapy compared to the reference population.

40. The method according to any one of claims 1 to 39, wherein the combination therapy further achieves an improvement in PFS (PFS2) after the first subsequent therapy compared to the reference population.

41. The method according to any one of claims 1 to 40, wherein the combination therapy further achieves an improvement in the median intracranial PFS compared to the reference population.

42. A method for improving the median progression-free survival (PFS) in a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, and having non-small cell lung cancer (NSCLC) that has progressed during or after prior treatment with at least one tyrosine kinase inhibitor (TKI), wherein the target population... (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, (ii) A therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, (iii) A therapeutically effective dose of carboplatin, and (iv) A therapeutically effective dose of pemetrexed, This includes administering combination therapy that includes, A method in which the improvement in median PFS is compared to the median PFS of a reference population of subjects having NSCLC with one or more EGFR mutations, during or after treatment with at least one previous TKI, wherein the reference population was administered carboplatin and pemetrexed, but not the bispecific anti-EGFR / c-Met antibody, the razertinib, or any pharmaceutically acceptable salts or hydrates thereof.

43. The method according to claim 41, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, the first domain comprising the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO:

12.

44. The method according to claim 42 or 43, wherein the one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

45. The method according to claim 44, wherein the one or more EGFR mutations include one or more exon 19 deletions.

46. The method according to claim 44, wherein one or more EGFR mutations include an exon 21 L858R substitution.

47. The method according to any one of claims 42 to 46, wherein the aforementioned prior TKI includes a first-generation EGFR TKI.

48. The method according to any one of claims 42 to 46, wherein the aforementioned at least one TKI includes a second-generation EGFR TKI.

49. The method according to any one of claims 42 to 46, wherein the aforementioned at least one TKI includes a third-generation EGFR TKI.

50. The method according to any one of claims 42 to 46, wherein the aforementioned at least one TKI comprises osimertinib.

51. The method according to any one of claims 42 to 50, wherein the administration of the combination therapy is initiated on the first day of cycle 1 of a first 21-day cycle and continued in subsequent 21-day cycles.

52. The method according to any one of claims 42 to 51, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

53. The method according to any one of claims 42 to 51, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

54. The method according to any one of claims 42 to 53, wherein the method comprises administering the bispecific anti-EGFR / c-Met antibody in an amount of about 140 mg to about 2240 mg.

55. The method according to claim 54, wherein the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 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.

56. The method according to claim 55, wherein 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 approximately 1400 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2.

57. The method according to claim 56, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

58. The method according to claim 55, wherein 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 approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle.

59. The method according to claim 55, wherein if the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2.

60. The method according to claim 59, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

61. The method according to claim 55, wherein if the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle.

62. The method according to any one of claims 42 to 61, wherein the razertinib, or a pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate.

63. The method according to any one of claims 42 to 61, wherein the razertinib, or a pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate monohydrate.

64. The method according to any one of claims 42 to 63, comprising administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, orally once daily at a dose of about 240 mg.

65. The method according to claim 64, wherein if carboplatin is discontinued early, razertinib or a pharmaceutically acceptable salt or hydrate thereof is administered orally once daily at a dose of about 240 mg, starting on day 1 of cycle 5 or earlier.

66. The method according to any one of claims 42 to 65, comprising administering the carboplatin at a dose of AUC5 on day 1 of each 21-day cycle for up to four cycles.

67. The aforementioned pemetrexed is administered at approximately 500 mg / m². ２ The method according to any one of claims 42 to 66, comprising administering the pemetrexed in a dose such as the carboplatin on day 1 of each 21-day cycle for up to four cycles, and then administering the pemetrexed as maintenance therapy until disease progression.

68. The method described above is a) (i) If the subject has a body weight of less than 80 kg, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2, or (ii) If the subject has a body weight of less than 80 kg, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle, or (iii) If the subject has a body weight of 80 kg or more, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2, or (iv) If the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle. b) (i) Orally administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, once daily at a dose of approximately 240 mg, or (ii) If carboplatin is discontinued early, razertinib or a pharmaceutically acceptable salt or hydrate thereof shall be administered orally once daily at a dose of approximately 240 mg, starting on day 1 of cycle 5 or earlier. c) Administering the carboplatin at an AUC5 dose on day 1 of each 21-day cycle for a maximum of 4 cycles. d) Approximately 500 mg / m² of pemetrexed ２ The drug is administered at the specified dose along with carboplatin on day 1 of each 21-day cycle for up to four cycles, followed by the administration of pemetrexed as maintenance therapy until disease progression. The method according to claim 67, including the method described in claim 67.

69. The method according to claim 68, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

70. The method according to any one of claims 42 to 69, wherein the combination therapy achieves an improvement in the median PFS for at least two weeks.

71. The method according to claim 70, wherein the combination therapy achieves an improvement in the median PFS for at least one month.

72. The method according to claim 71, wherein the combination therapy achieves an improvement in the median PFS for at least 1.5 months.

73. The method according to claim 72, wherein the combination therapy achieves an improvement in the median PFS for at least two months.

74. The method according to claim 73, wherein the subject exhibits a progression-free survival period of at least 4.5 months.

75. The method according to claim 74, wherein the subject exhibits a progression-free survival period of at least five months.

76. The method according to claim 75, wherein the subject exhibits a progression-free survival period of at least 5.5 months.

77. The method according to claim 76, wherein the subject exhibits a progression-free survival period of at least six months.

78. The method according to claim 77, wherein the subject exhibits a progression-free survival period of at least 10 months.

79. The method according to claim 78, wherein the subject exhibits a progression-free survival period of at least 12 months.

80. The method according to claim 79, wherein the subject exhibits a progression-free survival period of at least 14 months.

81. The method according to any one of claims 42 to 80, wherein the combination therapy further achieves an improvement in objective response compared to the reference population.

82. The method according to any one of claims 42 to 81, wherein the combination therapy further achieves an improvement in overall survival (OS) compared to the reference population.

83. The method according to any one of claims 42 to 82, wherein the combination therapy further achieves an improvement in duration of response (DoR) compared to the reference population.

84. The method according to any one of claims 42 to 83, wherein the combination therapy further achieves an improvement in the time to subsequent therapy compared to the reference population.

85. The method according to any one of claims 42 to 84, wherein the combination therapy further achieves improvement in PFS (PFS2) after the first subsequent therapy compared to the reference population.

86. The method according to any one of claims 42 to 85, wherein the combination therapy further achieves an improvement in the median intracranial PFS compared to the reference population.

87. A method for improving the median overall survival (OS) in a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, and having non-small cell lung cancer (NSCLC) that has progressed during or after prior treatment with at least one tyrosine kinase inhibitor (TKI), wherein the target population includes: (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, (ii) A therapeutically effective dose of carboplatin, and (iii) Therapeutic dose of pemetrexed, This includes administering combination therapy, The improvement in median OS is compared to the median OS of a reference population of subjects with NSCLC having one or more EGFR mutations that progressed during or after treatment with at least one previous TKI, wherein the reference population was administered carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody.

88. The method according to claim 87, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, the first domain comprising the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO:

12.

89. The method according to claim 87 or 88, wherein the one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

90. The method according to claim 89, wherein the one or more EGFR mutations include one or more exon 19 deletions.

91. The method according to claim 89, wherein one or more EGFR mutations include an exon 21 L858R substitution.

92. The method according to any one of claims 87 to 91, wherein the aforementioned at least one TKI includes a first-generation EGFR TKI.

93. The method according to any one of claims 87 to 91, wherein the aforementioned at least one TKI includes a second-generation EGFR TKI.

94. The method according to any one of claims 87 to 91, wherein the aforementioned at least one TKI includes a third-generation EGFR TKI.

95. The method according to any one of claims 87 to 91, wherein the aforementioned at least one TKI comprises osimertinib.

96. The method according to any one of claims 87 to 95, wherein the administration of the combination therapy is initiated on the first day of cycle 1 of a first 21-day cycle and continued in subsequent 21-day cycles.

97. The method according to any one of claims 87 to 96, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

98. The method according to any one of claims 87 to 96, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

99. The method according to any one of claims 87 to 98, wherein the method comprises administering the bispecific anti-EGFR / c-Met antibody in an amount of about 140 mg to about 2240 mg.

100. The method according to claim 99, wherein the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 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.

101. The method according to claim 100, wherein if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1400 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2.

102. The method according to claim 101, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

103. The method according to claim 100, wherein 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 approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle.

104. The method according to claim 100, wherein if the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2.

105. The method according to claim 104, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

106. The method according to claim 100, wherein if the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle.

107. The method according to any one of claims 87 to 106, comprising administering the carboplatin at a dose of AUC5 on day 1 of each 21-day cycle for up to four cycles.

108. The above method involves distributing pemetrexed at approximately 500 mg / m². ２ The method according to any one of claims 87 to 107, comprising administering the pemetrexed in the specified dose together with carboplatin on day 1 of each 21-day cycle for up to four cycles, and then administering the pemetrexed as maintenance therapy until disease progression.

109. The aforementioned method, a) (i) If the subject has a body weight of less than 80 kg, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2, or (ii) If the subject has a body weight of less than 80 kg, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg, starting from cycle 3, on day 1 of each 21-day cycle, or (iii) If the subject has a body weight of 80 kg or more, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg on day 1, day 8, and day 15 of cycle 1, and on day 1 of cycle 2, or (iv) If the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 2100 mg, starting from cycle 3, on day 1 of each 21-day cycle. b) Administering the carboplatin at an AUC5 dose on day 1 of each 21-day cycle for a maximum of 4 cycles. c) Approximately 500 mg / m² of pemetrexed ２ The drug is administered at the specified dose along with carboplatin on day 1 of each 21-day cycle for up to four cycles, followed by the administration of pemetrexed as maintenance therapy until disease progression. The method according to claim 108, including the method described in claim 108.

110. The method according to claim 109, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a divided dose over days 1 and 2.

111. The method according to any one of claims 87 to 110, wherein the subject group administered the combination therapy achieves an improvement in the median OS for at least two months compared to the reference group.

112. The method according to claim 111, wherein the group of subjects administered the combination therapy achieves an improvement in the median OS for at least 2.4 months compared to the reference group.

113. The method according to claim 111, wherein the group of subjects administered the combination therapy achieves an improvement in the median OS of approximately 2.4 months compared to the reference group.

114. The method according to claim 111, wherein the subject who was administered the combination therapy exhibits an overall survival period of at least 17 months.

115. The method according to claim 114, wherein the subject who was administered the combination therapy exhibits an overall survival period of at least about 17.7 months.

116. The method according to claim 114, wherein the subject who was administered the combination therapy exhibits an overall survival period of approximately 17.7 months.

117. The method according to any one of claims 87 to 116, wherein the combination therapy further achieves an improvement in time to disease progression (TTSP) compared to the reference population.

118. The method according to any one of claims 87 to 116, wherein the combination therapy further achieves an improvement in time to subsequent therapy (TTST) compared to the reference population.

119. The method according to any one of claims 87 to 116, wherein the combination therapy further achieves improvement in PFS (PFS2) after the first subsequent therapy compared to the reference population.

120. The method according to any one of claims 87 to 116, wherein the combination therapy further achieves an improvement in time to discontinuation (TTD) compared to the reference population.

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