Use of an anti-EGFR / anti-MET antibody for treating gastric cancer or esophageal cancer

Abstract

The present disclosure provides a method for treating gastric cancer or esophageal cancer in a subject in need thereof by administering a therapeutically effective amount of a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

Description

Technical Field

[0001] (Reference to Electronically Submitted Sequence Listing) The sequence listing of this application is an XML-formatted sequence listing with the file name "JBI6733WOPCT1SEQLIST.xml", created on June 28, 2023, and having a size of 20 kilobytes (KB). It is submitted electronically through The United States Patent and Trademark Center Patent Center. This submitted sequence listing is part of this specification and is hereby incorporated by reference in its entirety into this specification.

[0002] (Field of the Invention) The present disclosure relates to a method for treating gastric cancer or esophageal cancer using a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

Background Art

[0003] Cancer is a major cause of death worldwide. Gastric cancer (GC) is the fifth most common cancer globally, with over 1 million new cases reported worldwide in 2018. Gastric cancer is highly prevalent in Asian countries, which account for approximately 75% of new cases in 2018, and is the third (male) / fourth (female) most prevalent cancer in Japan. Most patients exhibit adenocarcinoma tissue structure. Treatment regimens depend on the type of cancer (e.g., tissue structure), the stage of cancer at diagnosis, and the presence of molecular biomarkers (e.g., human epidermal growth factor receptor 2 (HER2) amplification, programmed death-ligand 1 (PD-L1) expression, and microsatellite instability). Treatment generally includes surgery and chemotherapy. In patients with metastatic disease, the National Comprehensive Cancer Network (NCCN) guidelines recommend HER2, programmed death-ligand 1 (PD-L1), and microsatellite instability testing (NCCN guidelines 2020). First-line treatment generally includes fluoropyrimidine + cisplatin or (depending on HER2 status) oxaliplatin + trastuzumab. The overall response rate observed for the initial treatment recommended by the guidelines varies widely (e.g., 35% - 68% for combination therapy with oral fluoropyrimidine (S-1) in Japan (Bang 2010; Kurokawa 2014)). The available treatment options after first-line treatment are limited. NCCN recommendations are chemotherapy as a single agent, ramucirumab + paclitaxel, immune checkpoint inhibitors, or fluorouracil + irinotecan. However, the overall response rate of second- and third-line treatments is limited, and the median progression-free survival is very low.

[0004] Esophageal cancer (EC) is the eighth most common cancer worldwide and ranks sixth among all cancers in terms of mortality in 2018. Similar to GC, EC is highly prevalent in Asian countries, accounting for more than 75% of new cases in 2018. Squamous cell carcinoma and adenocarcinoma are the two major histological structures of primary EC. However, the dominant EC histological structure varies between geographical regions. The dominant histological structure observed in the white population is adenocarcinoma, while the squamous histological structure is dominant in Asian countries. Treatments generally include surgery, radiotherapy, chemoradiotherapy, and chemotherapy. The NCCN guideline recommendations for first-line therapy are the same as those for the GC regimen due to the nature of histological similarity (NCCN Guidelines 2020). Clinical data on esophageal squamous cell carcinoma, which is the dominant histological structure in Asian countries, are mostly limited to phase II studies. The overall response rate of reported chemotherapy as a single agent is 15% - 40%. Other recommended treatments include fluorouracil + cisplatin and the PD-(L)1 inhibitor, pembrolizumab. However, the overall response rate observed for these treatments is very limited.

[0005] Accordingly, there is an unmet need in the art for improved therapies for the treatment of gastric or esophageal cancer.

Summary of the Invention

Means for Solving the Problems

[0006] In various aspects, provided herein is a method of treating gastric or esophageal cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

[0007] In one aspect, the present disclosure provides a method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody.

[0008] In some embodiments of the method for treating gastric cancer, 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 comprises 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.

[0009] In some embodiments of the method for treating gastric cancer, the first domain that specifically binds to EGFR comprises heavy chain variable region (VH) of SEQ ID NO: 13 and light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met comprises VH of SEQ ID NO: 15 and VL of SEQ ID NO: 16.

[0010] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0011] In some embodiments of the method for treating gastric cancer, 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.

[0012] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of about 1% to about 15%.

[0013] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is administered intravenously or subcutaneously to a subject.

[0014] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 3400 mg.

[0015] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, 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, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2100 mg, 2200 mg, 2240 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3360 mg, or 3400 mg.

[0016] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1600 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg.

[0017] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to a subject. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

[0018] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is administered intravenously to a subject. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously at a dose sufficient to achieve a therapeutic effect in the subject.

[0019] In some embodiments of the method for treating gastric cancer, 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. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week for four weeks and then once every two weeks. In some embodiments, the first dose of the bispecific anti-EGFR / c-Met antibody is administered over two days.

[0020] In some embodiments of the method for treating gastric cancer, one or more cells of the gastric cancer express EGFR and / or cMet.

[0021] In some embodiments of methods for treating gastric cancer, the subject has been previously treated. In some embodiments, the previous treatment includes chemotherapy, targeted therapy, immunotherapy, surgery, radiation therapy, chemoradiation therapy, or combinations thereof. In some embodiments, the chemotherapy includes fluoropyrimidine-based chemotherapy, platinum-based chemotherapy, paclitaxel, irinotecan, or combinations thereof. In some embodiments, the fluoropyrimidine is 5-fluorouracil or capecitabine. In some embodiments, the platinum-based chemotherapy is cisplatin, oxaliplatin, carboplatin, or nedaplatin. In some embodiments, the targeted therapy includes anti-HER2 therapy or anti-VEGF / VEGFR therapy. In some embodiments, the anti-HER2 antibody includes trastuzumab. In some embodiments, the anti-VEGF / VEGFR therapy includes bevacizumab or ramucirumab.

[0022] In some embodiments of methods for treating gastric cancer, the method further includes administering to the subject at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent includes glucocorticosteroids, antihistamines, antipyretics, H2 antagonists, antiemetics, opioids, or any combination thereof.

[0023] In some embodiments of methods for treating gastric cancer, the gastric cancer is advanced or metastatic cancer.

[0024] In some embodiments of methods for treating gastric cancer, the subject is human.

[0025] In one aspect, the present disclosure provides a method of treating esophageal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody.

[0026] In some embodiments of the method for treating esophageal cancer, 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 comprises the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12.

[0027] In some embodiments of the method for treating esophageal cancer, the first domain that specifically binds to EGFR comprises 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 comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0028] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0029] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0030] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure having a fucose content of about 1% to about 15%.

[0031] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is administered intravenously or subcutaneously to a subject.

[0032] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 3400 mg.

[0033] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, 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, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2100 mg, 2200 mg, 2240 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3360 mg, or 3400 mg.

[0034] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1600 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg.

[0035] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to a subject. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

[0036] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is administered intravenously to a subject. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously at a dose sufficient to achieve a therapeutic effect in the subject.

[0037] In some embodiments of the method for treating esophageal cancer, 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. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week for four weeks and then once every two weeks. In some embodiments, the first dose of the bispecific anti-EGFR / c-Met antibody is administered over two days.

[0038] In some embodiments of the method for treating esophageal cancer, one or more cells of the esophageal cancer express EGFR and / or cMet.

[0039] In some embodiments of the method for treating esophageal cancer, the subject has been previously treated. In some embodiments, the previous treatment includes chemotherapy, targeted therapy, immunotherapy, surgery, radiotherapy, chemoradiotherapy, or combinations thereof. In some embodiments, the chemotherapy includes fluoropyrimidine-based chemotherapy, platinum-based chemotherapy, paclitaxel, irinotecan, or combinations thereof. In some embodiments, the fluoropyrimidine is 5-fluorouracil or capecitabine. In some embodiments, the platinum-based chemotherapy is cisplatin, oxaliplatin, carboplatin, or nedaplatin. In some embodiments, the targeted therapy includes anti-HER2 therapy or anti-VEGF / VEGFR therapy. In some embodiments, the anti-HER2 antibody includes trastuzumab. In some embodiments, the anti-VEGF / VEGFR therapy includes bevacizumab or ramucirumab.

[0040] In some embodiments of the method for treating esophageal cancer, the subject is treatment-naive.

[0041] In some embodiments of the method for treating esophageal cancer, the method further includes administering to the subject at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is a glucocorticosteroid, antihistamine, antipyretic, H2 antagonist, antiemetic, opioid, or any combination thereof.

[0042] In some embodiments of the method for treating esophageal cancer, the esophageal cancer is advanced or metastatic cancer.

[0043] In some embodiments of the method for treating esophageal cancer, the subject is human. BRIEF DESCRIPTION OF THE DRAWINGS

[0044]

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Mode for Carrying Out the Invention

[0045] Receptor tyrosine kinases (RTKs) are involved in the regulation of many processes in mammalian development, cell function, and tissue homeostasis. Dysregulation of RTKs is involved in the development of numerous human cancers, and various RTKs are targets of both approved and experimental anticancer therapies.

[0046] The epidermal growth factor receptor (EGFR), an RTK of the HER family, is normally expressed in tissues of epithelial, mesenchymal, and neuronal origin. Binding of any of its seven ligands, including EGF, induces diverse cellular responses, including differentiation, proliferation, migration, and survival (Olayioye 2000). The mesenchymal-epithelial transition factor (cMet or mesenchymal-epithelial transition, MET) receptor is also an RTK, expressed in normal epithelial cells (Prat 1991) and having roles in growth and homeostasis, including embryonic development, angiogenesis, and wound healing (Sattler 2011). cMet is activated by a single specific ligand, hepatocyte growth factor (also known as scatter factor).

[0047] Overexpression and mutations of the EGFR and cMet receptors have been associated with tumor formation and malignancy, as well as poor prognosis in several types of cancer (Birchmeier 2003; Hyner 2005; Yano 2003). It has been reported that approximately 25% and 50% of gastric cancer (GC) patients express EGFR or cMet, respectively (Fuse 2016). Similarly, approximately 60% - 70% and 45% - 70% of esophageal cancer (EC) patients express EGFR or cMet, respectively (Hanawa 2006; Gibault 2005). Expression of EGFR or cMet is involved as a poor prognostic factor in GC (Aydin 2014; Gao 2013; Galizia 2007; Atmaca 2012; Fuse 2016) and EC (Wang 2007; Brand 2011; OZAWA 2015).

[0048] Despite the fact that numerous agents targeting EGFR (including anti-EGFR antibodies and EGFR tyrosine kinase inhibitors (TKIs)) have been used as standard treatments for many cancers, including colorectal cancer, non-small cell lung cancer (NSCLC), and head and neck cancer, there are no EGFR-directed therapies available for the stomach or EC. Previous studies have been unable to demonstrate the efficacy of cetuximab and panitumumab, anti-EGFR antibodies for the treatment of GC, or gefitinib, an EGFR tyrosine kinase inhibitor in EC in non-biomarker-selected populations (Lordick 2013; Waddell 2013; Dutton 2014). More recent studies evaluating nimotuzumab, an anti-EGFR antibody in combination with irinotecan for GC patients with EGFR expression have also been shown to be unsuccessful (Satoh 2015). The clinical experience with cMet-targeted therapies is not as extensive. Studies evaluating the efficacy of rilotumumab or onartuzumab, anti-cMet antibodies in GC have been unable to demonstrate a clinical benefit.

[0049] The present disclosure provides methods and compositions useful for treating gastric or esophageal cancer by targeting both EGFR and cMet.

[0050] Definitions The terms used herein are to be understood as being used for the purpose of describing particular embodiments only and are not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0051] Any methods and materials similar or equivalent to those described herein can be used in carrying 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.

[0052] When a list is presented, unless otherwise stated, each individual element of that list and all combinations of that list are to be understood as separate embodiments. For example, a list of embodiments presented as "A, B, or C" is to be construed as including the embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0053] As used in this specification and the appended "claims", the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes combinations of two or more cells and the like.

[0054] The connective term "and / or" between a plurality of recited 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. Any one of these options is included in the meaning and thus, when used herein, is understood to meet the requirements of the term "and / or". The simultaneous applicability of two or more of the options is also included in the meaning and thus is understood to meet the requirements of the term "and / or".

[0055] The transitional terms "comprising", "consisting essentially of", and "consisting of" are intended to imply the generally accepted meanings in patent terminology, i.e., (i) "comprising" is synonymous with "including", "containing", or "characterized by", is inclusive or non-limiting, and does not exclude additional unrecited elements or method steps; (ii) "consisting of" excludes any element, step, or component not specified in the claims; and (iii) "consisting essentially of" limits the scope of the claims to the specified materials or steps and those that do not substantially affect the basic and novel characteristics of the claimed invention. Embodiments described with the clause "comprising" (or its synonyms) also provide the embodiments independently described with "consisting of" and "consisting essentially of" as embodiments.

[0056] "Co-administration", "administered together", "administered in combination with", "in combination with", etc. 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.

[0057] "Treating," "being treated," or "treatment" of a disease or disorder such as cancer refers to achieving one or more of reducing the severity and / or duration of the disorder, inhibiting the worsening of symptoms characteristic of the disorder being treated, restricting or preventing recurrence of the disorder in a subject who previously had the disorder, or restricting or preventing recurrence of symptoms in a subject who was symptomatic for the previous disorder.

[0058] "Preventing," "being prevented," "prevention," or "prophylaxis" of a disease or disorder means preventing the disorder from occurring in a subject.

[0059] "Responsive," "responsiveness," or "likely to respond" refers to any kind of improvement or positive response, whether detectable or undetectable, such as reduction or recovery of one or more symptoms, decrease in the degree of the disease, a stabilized (i.e., non-worsening) disease state, prevention of spread of the disease, delay or deceleration of disease progression, recovery or alleviation of the disease state, and remission (partial or complete).

[0060] "Therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic result at the required dosage and for the required period. The therapeutically effective amount can vary depending on factors such as the condition of the individual, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to induce the desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improvement in the health of the patient, decrease or shrinkage in the size of a tumor, arrest or blunting of tumor growth, and / or absence of metastasis of cancer cells to other locations in the body.

[0061] "Refractory" refers to a disease that does not respond to treatment. A refractory disease may be resistant to treatment before or at the start of treatment, or a refractory disease may become resistant during treatment.

[0062] "Recurrent" refers to the reopening of a disease or the signs and symptoms of a disease after a period of improvement following previous treatment with a therapeutic agent.

[0063] "Subject" includes any human or non-human animal. "Human animals" include all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" are used interchangeably herein.

[0064] "About" means within the allowable error range for a specific value determined by a person skilled in the art, which depends to some extent on the method by which the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular assay, result, or embodiment, unless otherwise explicitly stated elsewhere in the examples or this specification, "about" means the larger of either a standard deviation within 1 or a range up to 5% according to the practice of the art.

[0065] "Cancer" refers to the abnormal growth of cells that proliferate uncontrollably and, in some cases, tend to metastasize (spread) to other areas of the patient's body.

[0066] "EGFR or c-Met expressing cancer" refers to a cancer having detectable expression of EGFR or c-Met, or having a mutation or amplification of EGFR or c-Met. The expression, amplification, and mutation status of EGFR or c-Met can be detected using known methods such as sequencing, fluorescence in situ hybridization, immunohistochemical examination, flow cytometry, or Western blotting.

[0067] "Epidermal growth factor receptor" or "EGFR" refers to human EGFR having the amino acid sequence shown in GenBank accession number NP_005219 (also known as HER1 or ErbB1 (Ullrich et al., Nature 309:418-425, 1984)), as well as its naturally occurring variants.

[0068] As used herein, "hepatocyte growth factor receptor" or "c-Met" or "MET" refers to human c-Met having the amino acid sequence shown in GenBank accession number NP_001120972 and its natural variants.

[0069] "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 with respect to binding to EGFR and c-Met.

[0070] "Specific binding", or "specifically binds", or "specific binding", or "binds" refers to an antibody binding to an antigen or an epitope within an antigen with a higher affinity than to other antigens. Typically, the antibody typically has an equilibrium dissociation constant (K D ) that is at least 100-fold less than the K D for binding to non-specific antigens (e.g., BSA, casein), about 5 × 10 -8 M or less, e.g., 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 of K D and binds to the antigen or an 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 an antigen may have cross-reactivity with other related antigens, e.g., the same antigen (homolog) from other species such as human or monkey, e.g., 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.

[0071] "Antibody" has its broad meaning and includes monoclonal antibodies, including mouse, human, humanized, and chimeric monoclonal antibodies, antigen-binding fragments, multispecific antibodies such as bispecific, trispecific, and tetravalent antibodies, dimeric, tetrameric, or multimeric antibodies, single-chain antibodies, domain antibodies, and any other modified form of immunoglobulin molecules containing an antigen-binding site of the required specificity. "Full-length antibody" consists of two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain is composed of a heavy-chain variable region (VH) and a heavy-chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain is composed of a light-chain variable region (VL) and a light-chain constant region (CL). The VH region and VL region can be further subdivided into framework regions (FR) interspersed with hypervariable regions called complementarity determining regions (CDR). Each VH and VL is composed of three CDRs and four FR segments arranged in the order of FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from the amino terminus to the carboxy terminus.

[0072] "Complementary determining region (CDR)" is the region of an antibody that binds to an antigen. CDRs can be defined using various descriptions such as those of 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). The correspondence between the various descriptions and the numbering of the variable regions is described (see, for example, 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 resources, http: / / imgt_org). Available programs such as abYsis by UCL Business PLC can be used to describe CDRs. 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.

[0073] Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG, and IgM, according to the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subclassified as the isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Antibody light chains 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 their constant domain.

[0074] "Antigen-binding fragment" refers to a part of an immunoglobulin molecule that binds to an antigen. The antigen-binding fragment may be a synthetic polypeptide, a polypeptide obtainable by an enzyme, or a genetically recombinant polypeptide, such as VH, VL, VH and VL, Fab, F(ab’)2, Fd and Fv fragments, a domain antibody (dAb) consisting of one VH domain or one VL domain, a shark variable IgNAR domain, a camelized VH domain, a minimum recognition unit consisting of amino acid residues that reproduce the CDR of an antibody, such as an FR3-CDR3-FR4 moiety, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can be linked to each other via a synthetic linker to form various types of single-chain antibody designs. When the VH and VL domains are expressed by separate single-chain antibody constructs, the VH / VL domains can pair intramolecularly or intermolecularly to form a monovalent antigen-binding site, such as a single-chain Fv (scFv) or a diabody, which are described, for example, in WO 98 / 44001, WO 88 / 01649, WO 94 / 13804, and WO 92 / 01047.

[0075] A "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules that are identical except for possible well-known modifications such as removal of the C-terminal lysine from the antibody heavy chain, or post-translational modifications such as isomerization or deamidation of amino acids, oxidation of methionine, or deamidation of asparagine or glutamine, i.e., it means an individual antibody constituting the population. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific, or multispecific such as bispecific, and can be monovalent, bivalent, or multivalent.

[0076] "Recombinant" refers to DNA, antibodies, and other proteins that are prepared, expressed, created, or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies, or proteins.

[0077] "Bispecific" refers to an antibody that specifically binds to two different antigens, or two different epitopes within the same antigen. Bispecific antibodies can have cross-reactivity against other related antigens, e.g., the same antigen (homolog) from other species such as human or monkey, e.g., Macaca cynomolgus (e.g., cynomolgus or Pan troglodytes), or can bind to epitopes shared between two or more different antigens.

[0078] An "antagonist" or "inhibitor" refers to a molecule that, when bound to a cellular protein, suppresses at least one reaction or activity induced by the natural ligand of that protein. A molecule is an antagonist if at least one reaction or activity is suppressed by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than at least one reaction or activity that is suppressed in the absence of the antagonist (e.g., negative control), or if the suppression is statistically significant compared to the suppression in the absence of the antagonist.

[0079] A "PD-(L)1 axis inhibitor" refers to a molecule that inhibits PD-1 downstream signaling. A PD-(L)1 axis inhibitor can be a molecule that binds to PD-1, PD-L1, or PD-L2.

[0080] As used in this application, "low fucose" or "low fucose content" refers to an antibody having a fucose content of about 1% to 15%.

[0081] As used herein, "normal fucose" or "normal fucose content" refers to an antibody having a fucose content of greater than about 50%, typically greater than about 80% or greater than 85%.

[0082] The methods of the present disclosure One aspect of the present disclosure provides a method of treating gastric cancer or esophageal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody.

[0083] In some embodiments, the present disclosure provides a method of treating gastric cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody.

[0084] Gastric cancer as referred to in this specification includes cancers of the esophagogastric junction (GEJ). In some embodiments, the gastric cancer is adenocarcinoma. In some embodiments, the gastric cancer is advanced or metastatic cancer. For example, the gastric cancer may have metastasized to the esophagus, small intestine, lymph nodes, organs, bone, or a combination thereof.

[0085] In some embodiments, the present disclosure provides a method of treating esophageal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody.

[0086] In some embodiments, the esophageal cancer is adenocarcinoma. In some embodiments, the esophageal cancer is squamous cell carcinoma. In some embodiments, the esophageal cancer is advanced or metastatic cancer. For example, the esophageal cancer may have metastasized to the lung, small intestine, lymph nodes, organs, bone, or a combination thereof.

[0087] In some embodiments, the subject has been previously treated. The previous treatment may include chemotherapy, targeted therapy, immunotherapy, surgery, radiation therapy, chemoradiation therapy, or a combination thereof.

[0088] In some embodiments, the chemotherapy is fluoropyrimidine-based chemotherapy such as 5-fluorouracil or capecitabine.

[0089] In some embodiments, the chemotherapy is platinum-based chemotherapy. Exemplary platinum-based chemotherapies include, but are not limited to, cisplatin, oxaliplatin, carboplatin, or nedaplatin.

[0090] Further examples of chemotherapy can include taxanes (e.g., paclitaxel, docetaxel), topoisomerase inhibitors (e.g., irinotecan, camptothecin), or a combination thereof.

[0091] In some embodiments, the targeted therapy is anti-HER2 therapy or anti-VEGF / VEGFR therapy. Non-limiting examples of anti-HER2 therapy include trastuzumab. Non-limiting examples of anti-VEGF / VEGFR therapy include bevacizumab or ramucirumab.

[0092] In some embodiments, the previous treatment includes immunotherapy such as checkpoint inhibitors. In some embodiments, the immunotherapy includes a PD-(L)1 axis inhibitor or a CTLA-4 inhibitor. Non-limiting examples of PD-(L)1-based inhibitors include atezolizumab, nivolumab, pembrolizumab, camrelizumab, and tislelizumab. A non-limiting example of a CTLA-4 inhibitor is ipilimumab.

[0093] In some embodiments, the previous treatment includes anti-VEGF / VEGFR therapy. Non-limiting examples of anti-VEGF / VEGFR therapy include bevacizumab and ramucirumab.

[0094] In some embodiments, the previous treatment includes fluoropyrimidine and cisplatin.

[0095] In some embodiments, the previous treatment includes oxaliplatin and trastuzumab.

[0096] In some embodiments, the previous treatment includes ramucirumab and paclitaxel.

[0097] In some embodiments, the previous treatment includes fluorouracil and irinotecan.

[0098] In some embodiments, the previous treatment includes fluorouracil and cisplatin.

[0099] In some embodiments, the subject is treatment-naive.

[0100] In some embodiments, one or more cells of gastric cancer or esophageal cancer express EGFR and / or cMet. The expression of EGFR or c-Met can be detected using well-known methods such as fluorescence in situ hybridization, immunohistochemistry (IHC), flow cytometry, or Western blotting.

[0101] In some embodiments, the expression of EGFR and / or cMet is detected using immunohistochemistry (IHC) that measures the EGFR and / or cMet protein levels on the cell surface. As a non-limiting example, the membrane staining intensity score (0, 1+, 2+, or 3+) can be determined for each cell within a fixed field. Tumor samples can be fixed in formalin paraffin-embedded tissue (FFPE).

[0102] In some embodiments, a subject to whom a bispecific anti-EGFR / c-Met antibody is administered has a staining intensity score of 1+ or greater based on the EGFR and / or cMet expression in a tumor sample obtained from the subject as determined by an IHC assay.

[0103] In some embodiments, a subject to whom a bispecific anti-EGFR / c-Met antibody is administered has a staining intensity score of 2+ or greater based on the EGFR and / or cMet expression in a tumor sample obtained from the subject as determined by an IHC assay.

[0104] In some embodiments, a subject to whom a bispecific anti-EGFR / c-Met antibody is administered has a staining intensity score of 3+ based on the EGFR and / or cMet expression in a tumor sample obtained from the subject as determined by an IHC assay.

[0105] In some embodiments, as a semi - quantitative approach useful for the analysis of immunohistochemical examination results, an H - score (or tissue score) can be assigned to a tumor sample (Hirsch FR et al., J Clin Oncol 21:3798 - 3807, 2003; John T et al., Oncogene 28:S14 - S23, 2009, the entire text of which is incorporated herein by reference). In some embodiments, the H - score can be based on the dominant staining intensity. In some embodiments, the H - score can include the sum of the individual H - scores for each intensity level seen. As a non - limiting example, the percentage of cells at each staining intensity level can be calculated, and finally, the H - score can be assigned using the following exemplary formula: [1×(% cells 1 +)+2×(% cells 2 +)+3×(% cells 3 +)]. The final calculated H - score in the range of 0 - 300 can give more relative weight to higher - intensity membrane staining in a given tumor sample. In some embodiments, a tumor sample can be considered either positive or negative based on a specific identification threshold.

[0106] In some embodiments, a "composite H - score" can be generated by adding the H - score calculated from the analysis of one biomarker (e.g., EGFR expression) to the H - score calculated from the analysis of a second biomarker (e.g., MET expression). Thus, the composite H - score can have a range of 0 - 600.

[0107] Administration The bispecific anti-EGFR / c-Met antibody can be administered in a pharmaceutically acceptable carrier. "Carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the present invention is co-administered. Such vehicles may be water and oils, including those derived from petroleum, animal, plant, or synthetic sources, such as liquid peanut oil, soybean oil, mineral oil, sesame oil, etc. For example, the bispecific anti-EGFR / c-Met antibody may be formulated using 0.4% saline and 0.3% glycine. These solutions are sterilized and generally contain no 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. Injectable suspensions or solutions may also be prepared using an aqueous carrier with appropriate additives. For subcutaneous administration, recombinant human hyaluronidase such as rHuPH20 (CAS registration number 757971-58-7) can be used. 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, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, and in particular pp. 958-989 should be referred to.

[0108] The administration mode uses tablets, capsules, liquids, powders, gels, particle formulations to deliver the bispecific anti-EGFR-c-Met antibody to the host by any suitable route, such as parenteral administration like intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous, or it may be via the lung, transmucosal (oral, intranasal, intravaginal, intrarectal). The formulation may be contained in a syringe, implant device, osmotic pump, cartridge, micropump, 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 intratumoral, intra-articular, intratracheal, intra-abdominal, intra-articular capsule, intra-cartilage, intra-cavity, intracerebellar, intraventricular, intra-colon, endocervical, intragastric, intrahepatic, intramyocardial, intra-bone, intra-pelvic, intra-pericardial, intraperitoneal, intra-pleural, intra-prostatic, intrapulmonary, intrarectal, intra-renal, intra-retinal, intraspinal, intra-synovial sac, intrathoracic, intra-uterine, intra-vascular, intra-bladder, intralesional, intravaginal, intrarectal, intra-oral, sublingual, intranasal, or transdermal delivery.

[0109] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously. An exemplary intravenous formulation is disclosed in U.S. Patent Application Publication No. 2022-0064307(A1).

[0110] 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 can be administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject. An exemplary subcutaneous formulation is disclosed in U.S. Patent Application Publication No. 2022-0395573(A1).

[0111] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 3340 mg.

[0112] In some embodiments, the bispecific anti-EGFR / c-Met antibody is 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,administered at a dose of about 1510 mg, about 1520 mg, about 1530 mg, about 1540 mg, about 1550 mg, about 1560 mg, about 1570 mg, about 1580 mg, about 1590 mg, about 1600 mg, about 1610 mg, 1620 mg, about 1630 mg, about 1640 mg, about 1650 mg, about 1660 mg, about 1670 mg, about 1680 mg, about 1690 mg, about 1700 mg, about 1710 mg, about 1720 mg, about 1730 mg, about 1740 mg, about 1750 mg, about 1760 mg, about 1770 mg, about 1780 mg, about 1790 mg, about 1800 mg, about 1810 mg, about 1820 mg, about 1830 mg, about 1840 mg, about 1850 mg, about 1860 mg, about 1870 mg, about 1880 mg, 1890 mg, about 1900 mg, about 1910 mg, about 1920 mg, about 1930 mg, about 1940 mg, about 1950 mg, about 1960 mg, about 1970 mg, about 1980 mg, about 1990 mg, about 2000 mg, about 2010 mg, about 2020 mg, about 2030 mg, about 2040 mg, about 2050 mg, about 2060 mg, about 2070 mg, about 2080 mg, about 2090 mg, about 2100 mg, about 2110 mg, about 2120 mg, about 2130 mg, about 2140 mg, about 2150 mg, about 2160 mg, about 2170 mg, about 2180 mg, about 2190 mg, about 2200 mg, about 2210 mg, about 2220 mg, about 2230 mg, about 2240 mg, about 2250 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3360 mg, or about 3400 mg.

[0113] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, about 700 mg, about 1050 mg, about 1400 mg, about 1575 mg, about 1600 mg, about 1750 mg, about 2100 mg, about 2240 mg, about 2400 mg, or about 3360 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 800 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 850 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 900 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 950 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1000 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1050 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1150 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1200 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1250 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1300 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1575 mg.In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1600 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 2100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 2400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 3360 mg.

[0114] In some embodiments, when the subject's weight is less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. In some embodiments, when the subject's weight is 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg.

[0115] When the subject's weight is 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

[0116] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, about 1050 mg of the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, about 1400 mg of the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, about 1600 mg of the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, about 1750 mg of the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, in some embodiments, about 2100 mg of the bispecific anti-EGFR / c-Met antibody is administered once a week.

[0117] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, about 1050 mg of the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, about 1400 mg of the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, about 1600 mg of the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, about 1750 mg of the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, about 2100 mg of the bispecific antibody is administered once every two weeks.

[0118] In some embodiments, when the subject's weight is less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1575 mg. In some embodiments, when the subject's weight is 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg.

[0119] In some embodiments, when the subject's weight is less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1600 mg. In some embodiments, when the subject's weight is 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered weekly for the first 4 weeks and then once every two weeks.

[0120] In some embodiments, when the subject's weight is less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg. In some embodiments, when the subject's weight is 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered weekly for the first 3 weeks and then once every three weeks.

[0121] 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.

[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 is administered once a week for four weeks and then once every two weeks.

[0124] In some embodiments, the first dose of the bispecific anti-EGFR / c-Met antibody is administered over two days. As a non-limiting example, the first dose of the bispecific anti-EGFR / c-Met antibody may be divided over two days on day 1 (350 mg) and day 2 (700 mg if body weight < 80 kg or 1050 mg if body weight ≥ 80 kg).

[0125] In some embodiments, the method further comprises administering to the subject at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is a glucocorticoid, antihistamine, antipyretic, H2 antagonist, antiemetic, opioid, or any combination thereof.

[0126] In some embodiments, the at least one additional therapeutic agent is administered prior to one or more therapeutic doses.

[0127] In some embodiments, the glucocorticoid is dexamethasone, beclomethasone, betamethasone, budesonide, cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, or triamcinolone. In some embodiments, the glucocorticoid is dexamethasone or methylprednisolone. For example, the glucocorticoid is dexamethasone (10 mg) or methylprednisolone (40 mg).

[0128] The glucocorticoid (e.g., dexamethasone, methylprednisolone) can be administered intravenously (IV) about 45 - 60 minutes before the administration of the bispecific anti-EGFR / c-Met antibody. Alternatively, the glucocorticoid (e.g., dexamethasone, methylprednisolone) can be administered orally 60 - 90 minutes before the administration of the bispecific anti-EGFR / c-Met antibody.

[0129] In some embodiments, the antihistamine is diphenhydramine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexchlorpheniramine, dimenhydrinate, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine, or fexofenadine. In some embodiments, the antihistamine is diphenhydramine. For example, the antihistamine can be diphenhydramine (about 25 - 50 mg) or an equivalent.

[0130] In some embodiments, the antihistamine is administered orally about 30 - 60 minutes before the administration of the bispecific anti-EGFR / c-Met antibody. In some embodiments, the antihistamine is administered intravenously about 15 - 30 minutes before the administration of the bispecific anti-EGFR / c-Met antibody.

[0131] In some embodiments, the antipyretic is acetaminophen, ibuprofen, naproxen, ketoprofen, and nimesulide, aspirin, choline salicylate, magnesium salicylate, sodium salicylate, or phenazone (antipyrine). In some embodiments, the antipyretic is acetaminophen. For example, the antipyretic can be acetaminophen (about 650 mg to 1,000 mg) or an equivalent.

[0132] In some embodiments, the antipyretic is administered intravenously about 15 to 30 minutes before the administration of the bispecific anti-EGFR / c-Met antibody, or orally about 30 to 60 minutes before.

[0133] In some embodiments, the H2-antagonist is ranitidine, cimetidine, famotidine, or nizatidine. In some embodiments, the H2-antagonist is ranitidine. For example, the H2-antagonist can be ranitidine (about 50 mg) or an equivalent.

[0134] In some embodiments, the H2-antagonist is administered intravenously about 15 to 30 minutes before the administration of the bispecific anti-EGFR / c-Met antibody, or orally about 60 minutes before the administration of the bispecific anti-EGFR / c-Met antibody.

[0135] In some embodiments, the antiemetic is ondansetron, meclizine, dimenhydrinate, prochlorperazine, promethazine, vitamin B6, droperidol, granisetron, metoclopramide, aprepitant, dolasetron, palonosetron, rolapitant. In some embodiments, the antiemetic is ondansetron. For example, the antiemetic can be ondansetron (about 16 mg) or an equivalent.

[0136] In some embodiments, the antiemetic is administered intravenously about 15 to 30 minutes before the administration of the bispecific anti-EGFR / c-Met antibody, or orally about 15 to 30 minutes before the administration of the bispecific anti-EGFR / c-Met antibody.

[0137] In some embodiments, at least one additional therapeutic agent described herein is administered after one or more therapeutic doses. The at least one additional therapeutic agent can be administered up to 48 hours after one or more therapeutic doses, if clinically indicated.

[0138] As non-limiting examples, glucocorticoids (e.g., dexamethasone (10 mg)), antihistamines (e.g., diphenhydramine (25 - 50 mg)), antipyretics (e.g., acetaminophen (650 - 1,000 mg)), and / or opiates (e.g., meperidine (25 - 100 mg)) can be administered intravenously or orally, as needed, after administration of one or more therapeutic doses of the bispecific anti-EGFR / c-Met antibody. Additionally, an antiemetic can be administered intravenously (e.g., ondansetron (8 - 16 mg)) or orally (e.g., ondansetron (8 mg)) to the subject, as needed, after one or more therapeutic doses.

[0139] Generation of the anti-EGFR / c-Met antibody An exemplary bispecific anti-EGFR / c-Met antibody that can be used in the methods of the present disclosure is amivantamab. Amivantamab is an IgG1 anti-EGFR / c-Met bispecific antibody described in U.S. Patent No. 9,593,164, which is hereby incorporated by reference in its entirety.

[0140] Amivantamab is a low-fucose, fully human immunoglobulin G1 (IgG1)-based bispecific antibody against the EGFR and MET receptors, and shows preclinical activity against tumors with overexpressed wild-type EGFR and activation of the MET pathway. Unlike EGFR TKIs that bind to the intracellular portion of EGFR, amivantamab targets the extracellular domains of both EGFR and MET. Amivantamab may have at least three potential mechanisms of action, including 1) inhibition of ligand-dependent signaling, 2) downregulation of EGFR and MET expression levels, and 3) initiation of antibody-dependent cellular cytotoxicity (ADCC). Amivantamab is produced with low levels of fucosylation, which leads to enhanced levels of ADCC activity. The human FcγIIIa receptor, which is important for ADCC, binds more strongly to low-fucose antibodies, resulting in more potent and effective ADCC killing of target cancer cells (Satoh, 2006). By targeting the extracellular domains of EGFR and MET, amivantamab is hypothesized to be able to inhibit receptors that show primary resistance to EGFR TKIs (exon 20 insertions), or receptors that have acquired either an EGFR resistance mutation (T790M or C797S) or secondary activation of the MET pathway (MET amplification).

[0141] Amivantamab is characterized by the following amino acid sequences. EGFR binding group >SEQ ID NO: 1 (HCDR1, EGFR binding group) TYGMH >SEQ ID NO: 2 (HCDR2, EGFR binding group) VIWDDGSYKYYGDSVKG >SEQ ID NO: 3 (HCDR3, EGFR binding group) DGITMVRGVMKDYFDY >SEQ ID NO: 4 (LCDR1, EGFR binding group) RASQDISSALV >SEQ ID NO: 5 (LCDR2, EGFR binding group) DASSLES >SEQ ID NO: 6 (LCDR3, EGFR binding group) QQFNSYPLT >SEQ ID NO: 7 (HCDR1, c-Met binding group) SYGIS >SEQ ID NO: 8 (HCDR2, c-Met binding group) WISAYNGYTNYAQKLQG >SEQ ID NO: 9 (HCDR3, c-Met binding group) DLRGTNYFDY >SEQ ID NO: 10 (LCDR1, c-Met binding group) RASQGISNWLA >SEQ ID NO: 11 (LCDR2, c-Met binding group) AASSLLS >SEQ ID NO: 12 (LCDR3, c-Met binding group) QQANSFPIT >SEQ ID NO: 13 (VH, EGFR binding group) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS >SEQ ID NO: 14 (VL, EGFR binding group) AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK >SEQ ID NO: 15 (VH, c-Met binding group) QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS >SEQ ID NO: 16 (VL, c-Met binding group) DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK >SEQ ID NO: 17 HC1 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >SEQ ID NO: 18 LC1 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID NO: 19 HC2 QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK > Sequence number 20 LC2 DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0142] 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 comprises 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 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.

[0143] In some embodiments, the first domain that specifically binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0144] In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0145] 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.

[0146] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises one or more Fc silencing mutations.

[0147] In one embodiment, the one or more Fc silencing mutations reduce the affinity for Fcγ receptors.

[0148] In one embodiment, the one or more Fc silencing mutations comprise V234A / G237A / P238S / H268A / V309L / A330S / P331S.

[0149] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure having a fucose content of about 1% to about 15%. Antibodies with reduced fucose content can be produced using various methods that have been reported to be successful in expressing relatively highly defucosylated antibodies with biantennary complex-type Fc oligosaccharides, such as control of culture osmotic pressure (Konno et al., Cytotechnology 64(:249-65,2012), application of the mutant CHO cell line Lec13 as the host cell line (Shields et al., J Biol Chem 277:26733-26740,2002), application of the mutant CHO cell line EB66 as the host cell line (Olivier et al., MAbs;2(4),2010; Epub ahead of print; PMID:20562582), application of the 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 against the α1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng88:901-908,2004), or co-expression with β-1,4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II, or kifunensine, a potent α-mannosidase I inhibitor (Ferrara et al., J Biol Chem281:5032-5036,2006, Ferrara et al., Biotechnol Bioeng 93:851-861,2006; Xhou et al., Biotechnol Bioeng 99:652-65,2008). Generally, by reducing the fucose content in the glycans of the antibody, antibody-mediated cellular cytotoxicity (ADCC) is enhanced.

[0150] As described in U.S. Patent No. 9,593,164, other bispecific anti-EGFR / c-Met antibodies may be used in the methods of the present disclosure as long as they exhibit similar characteristics when compared to amivantamab. The bispecific anti-EGFR / c-Met antibodies that can be used in the methods of the present disclosure can also be generated by combining an EGFR-binding VH / VL domain and 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.

[0151] The bispecific anti-EGFR / c-Met antibodies used in the methods of the present disclosure can be generated, for example, using Fab-arm exchange (or half-molecule exchange) between two monospecific bivalent antibodies by introducing substitutions at the heavy chain CH3 interface in each half-molecule such that heterodimers of two antibody half-molecules with different specificities are more readily formed in a cell-free environment in vitro or using co-expression. The Fab-arm exchange reaction is a result of disulfide bond isomerization reaction and dissociation-association of the CH3 domain. The heavy chain disulfide bond in the hinge region of the parental monospecific antibody is reduced. One of the resulting free cysteines of the parental monospecific antibody forms an intra-heavy chain disulfide bond with a cysteine residue of the second parental monospecific antibody molecule, and at the same time, the CH3 domain of the parental antibody is released and reformed by dissociation-association. The CH3 domains of the Fab-arms can be engineered to be more favorable for heterodimerization than homodimerization. The resulting product is a bispecific antibody having two Fab-arms or half-molecules that bind to different epitopes, i.e., an epitope on EGFR and an epitope on c-Met, respectively. For example, the bispecific antibodies of the present invention can be generated using the techniques described in International Publication No. WO 2011 / 131746. In the case of IgG1 antibodies, the mutations F405L in one heavy chain and K409R in the other heavy chain can be used. In IgG2 antibodies, wild-type IgG2 and IgG2 antibodies having F405L and R409K substitutions may be used. In IgG4 antibodies, wild-type IgG4 and IgG4 antibodies having F405L and R409K substitutions may be used. To generate the bispecific antibody, a first monospecific bivalent antibody and a second monospecific bivalent antibody are engineered to have the aforementioned mutations in the Fc region, and the antibodies are incubated together under sufficient reducing conditions such that the cysteine in the hinge region can undergo disulfide bond isomerization, whereby the bispecific antibody is generated by Fab-arm exchange. The incubation conditions can optimally be returned to non-reducing conditions.Exemplary reducing agents that can be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol. For example, an incubation of at least 90 minutes can be used at a temperature of at least 20° C. in the presence of at least 25 mM of 2-MEA or in the presence of at least 0.5 mM of dithiothreitol, at pH 5 to 8, such as pH 7.0 or pH 7.4.

[0152] The bispecific anti-EGFR / c-Met antibodies used in the methods of the present disclosure can also be generated using designs such as knob-in-hole or knob-into-hole (Genentech), CrossMAb (Roche) and electrostatically-matched (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), and Biclonic (Merus).

[0153] In the "knob-in-hole" approach (see, e.g., WO 2006 / 028936), the selected amino acids that form the interface of the CH3 domain of human IgG can be mutated at positions that affect CH3 domain interactions in order to promote heterodimer formation. An amino acid with a small side chain (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 (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 the preferential interaction between the heavy chain with the "hole" and the heavy chain with 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 modified position in the first CH3 domain of the first heavy chain / the modified position in the second CH3 domain of the second heavy chain).

[0154] In addition to the use of the "knob-in-hole" approach for the promoter of Fab arm exchange, the CrossMAb technology utilizes CH1 / CL domain exchange in one of the halves to ensure correct light chain pairing of the resulting bispecific antibody (see, e.g., US Pat. No. 8,242,247).

[0155] The full-length bispecific antibodies of the present invention may also be generated by using other cross-over techniques to exchange variable or constant, or both domains, in one or both groups, between the heavy and light chains or within the heavy chain of the bispecific antibody. Examples of such exchanges include VH-CH1 and VL-CL, VH and VL, CH3 and CL, and CH3 and CH1 as described in, for example, WO 2009 / 080254, WO 2009 / 080251, WO 2009 / 018386, and WO 2009 / 080252.

[0156] Other approaches, such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues on one CH3 surface and negatively charged residues on a second CH3 surface, may be used as described in US Patent Application Publication No. 2010 / 0015133, US Patent Application Publication No. 2009 / 0182127, US Patent Application Publication No. 2010 / 028637, or US Patent Application Publication No. 2011 / 0123532. In other approaches, heterodimerization can be promoted by the following substitutions, as described in US Patent Application Publication No. 2012 / 0149876 or US Patent Application Publication No. 2013 / 0195849: L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W (represented as the modified positions in the first CH3 domain of the first heavy chain / the modified positions in the second CH3 domain of the second heavy chain).

[0157] The bispecific antibodies of the present invention may be generated using SEEDbody technology. SEEDbodies have selected IgG residues substituted with IgA residues in their constant domains to promote heterodimerization, as described in US Patent Application Publication No. 2007 / 0287170.

[0158] Mutations are typically made at the DNA level to molecules such as the constant domains of antibodies using standard methods.

[0159] Exemplary Embodiments 1. A method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody. 2. 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 comprises the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12, the method according to embodiment 1. 3. The first domain that specifically binds to EGFR comprises 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 comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16, the method according to embodiment 2. 4. The bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype, the method according to embodiment 2 or 3. 5. The bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20, the method according to any one of embodiments 1 to 4. 6. The bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of about 1% to about 15%, the method according to any one of embodiments 1 to 5. 7. The bispecific anti-EGFR / c-Met antibody is administered intravenously or subcutaneously to a subject, the method according to any one of embodiments 1 to 6. 8. The bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 2000 mg, the method according to embodiment 7. 9. The method according to embodiment 8, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, 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, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2100 mg, 2200 mg, 2240 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3360 mg, or 3400 mg. 10. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. 11. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg. 12. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1600 mg. 13. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1750 mg. 14. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg. 15. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg. 16. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg. 17. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg. 18. The method according to any one of embodiments 10 to 15, wherein the bispecific anti-EGFR / c-Met antibody is administered weekly for the first 4 weeks and then once every 2 weeks. 19. The method according to embodiment 16 or 17, wherein the bispecific anti-EGFR / c-Met antibody is administered weekly for the first three weeks and then once every three weeks. 20. The method according to any one of embodiments 10-19, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously. 21. The method according to embodiment 18, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously. 22. The method according to any one of embodiments 1-6, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to a subject. 23. The method according to embodiment 22, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to a subject at a dose sufficient to achieve a therapeutic effect. 24. The method according to any one of embodiments 1-23, wherein 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. 25. The method according to embodiment 24, wherein the bispecific anti-EGFR / c-Met antibody is administered once a week for four weeks and then once every two weeks. 26. The method according to embodiment 25, wherein the first dose of the bispecific anti-EGFR / c-Met antibody is administered over two days. 27. The method according to any one of embodiments 1-26, wherein one or more cells of gastric cancer express EGFR and / or cMet. 28. The method according to any one of embodiments 1-27, wherein the subject has been previously treated. 29. The method according to embodiment 28, wherein the previous treatment includes chemotherapy, targeted therapy, immunotherapy, surgery, radiotherapy, chemoradiotherapy, or a combination thereof. 30. The method according to embodiment 29, wherein the chemotherapy includes fluoropyrimidine-based chemotherapy, platinum-based chemotherapy, paclitaxel, irinotecan, or a combination thereof. 31. The method according to embodiment 30, wherein the fluoropyrimidine is 5-fluorouracil or capecitabine. 32. The method according to embodiment 30, wherein the platinum-based chemotherapy is cisplatin, oxaliplatin, carboplatin, or nedaplatin. 33. The method according to embodiment 29, wherein the targeted therapy comprises anti-HER2 therapy or anti-VEGF / VEGFR therapy. 34. The method according to embodiment 33, wherein the anti-HER2 therapy comprises trastuzumab. 35. The method according to embodiment 34, wherein the anti-VEGF / VEGFR therapy comprises bevacizumab or ramucirumab. 36. The method according to any one of embodiments 1 to 27, wherein the subject is treatment-naive. 37. The method according to any one of embodiments 1 to 36, wherein the method further comprises administering to the subject at least one additional therapeutic agent. 38. The method according to embodiment 37, wherein the additional therapeutic agent comprises a glucocorticosteroid, an antihistamine, an antipyretic, an H2 antagonist, an antiemetic, an opioid, or any combination thereof. 39. The method according to any one of embodiments 1 to 38, wherein the gastric cancer is advanced cancer or metastatic cancer. 40. The method according to any one of claims 1 to 39, wherein the subject is human. 41. A method for treating esophageal cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody. 42. 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 comprises the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12. The method according to embodiment 41. 43. The method according to embodiment 42, wherein the first domain specifically binding to EGFR comprises 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 specifically binding to c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16. 44. The method according to embodiment 42 or 43, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. 45. The method according to any one of embodiments 41 to 44, wherein the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20. 46. The method according to any one of embodiments 41 to 45, wherein the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of about 1% to about 15%. 47. The method according to any one of embodiments 41 to 46, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously or subcutaneously to a subject. 48. The method according to embodiment 47, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 2000 mg. 49. The method according to embodiment 48, wherein the bispecific anti-EGFR / c-Met antibody met antibody is administered at a dose of about 350 mg, 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, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, or 2100 mg, 2200 mg, 2240 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3360 mg, or 3400 mg. 50. The method according to embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. 51. The method according to embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg. 52. The method according to embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1600 mg. 53. The method according to embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1750 mg. 54. The method according to embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg. 55. The method according to embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg. 56. The method according to embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg. 57. The method according to embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg. 58. The method according to any one of embodiments 50 to 55, wherein the bispecific anti-EGFR / c-Met antibody is administered weekly for the first 4 weeks and then once every 2 weeks. 59. The method according to embodiment 56 or 57, wherein the bispecific anti-EGFR / c-Met antibody is administered weekly for the first 3 weeks and then once every 3 weeks. 60. The method according to embodiment 58, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously. 61. The method according to embodiment 59, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously. 62. The method according to any one of embodiments 50 to 59, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously. 63. The method according to any one of embodiments 41 to 57, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. 64. The method according to embodiment 63, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in a subject. 65. The method according to any one of embodiments 41-64, wherein 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. 66. The method according to embodiment 65, wherein the bispecific anti-EGFR / c-Met antibody is administered once a week for four weeks and then once every two weeks. 67. The method according to embodiment 66, wherein the first dose of the bispecific anti-EGFR / c-Met antibody is administered over two days. 68. The method according to any one of embodiments 41-67, wherein one or more cells of esophageal cancer express EGFR and / or cMet. 69. The method according to any one of embodiments 41-68, wherein the subject has been previously treated. 70. The method according to embodiment 69, wherein the previous treatment includes chemotherapy, targeted therapy, immunotherapy, surgery, radiotherapy, chemoradiotherapy, or a combination thereof. 71. The method according to embodiment 70, wherein the chemotherapy includes fluoropyrimidine-based chemotherapy, platinum-based chemotherapy, paclitaxel, irinotecan, or a combination thereof. 72. The method according to embodiment 71, wherein the fluoropyrimidine is 5-fluorouracil or capecitabine. 73. The method according to embodiment 71, wherein the platinum-based chemotherapy is cisplatin, oxaliplatin, carboplatin, or nedaplatin. 74. The method according to embodiment 70, wherein the targeted therapy includes anti-HER2 therapy or anti-VEGF / VEGFR therapy. 75. The method according to embodiment 74, wherein the anti-HER2 therapy includes trastuzumab. 76. The method according to embodiment 74, wherein the anti-VEGF / VEGFR therapy includes bevacizumab or ramucirumab. 77. The method according to any one of embodiments 41-68, wherein the subject is treatment-naive. 78. The method according to any one of embodiments 41 to 77, further comprising administering to the subject at least one additional therapeutic agent. 79. The method according to embodiment 78, wherein the additional therapeutic agent is a glucocorticosteroid, an antihistamine, an antipyretic, an H2 antagonist, an antiemetic, an opioid, or any combination thereof. 80. The method according to any one of embodiments 41 to 79, wherein the esophageal cancer is advanced cancer or metastatic cancer. 81. The method according to any one of claims 41 to 80, wherein the subject is a human.

Examples

[0160] To further illustrate some of the embodiments disclosed herein, the following examples are provided. These examples are intended to be illustrative and not to limit the embodiments of the present disclosure.

[0161] Example 1. Phase 2 Open-Label Study of Amivantamab in Subjects with Previously Treated Advanced or Metastatic Gastric or Esophageal Cancer Rationale for the Study Gastric cancer (GC) and esophageal cancer (EC) are known to express EGFR and cMet, and the expression of these proteins correlates with poor prognosis. Although many agents targeting EGFR are part of the standard treatment for many tumor types, anti-EGFR or anti-cMet therapies are not approved for GC or EC. As a bispecific duo-body that can bind to the extracellular domains of both the EGFR receptor and the cMet receptor, amivantamab has a unique mechanism of action that suggests the potential to control GC and EC patients expressing EGFR and / or cMet. Amivantamab demonstrated in vitro and in vivo preclinical activity against tumors using GC and EC models with amplified EGFR or cMet (Vijayaraghavan 2020). Furthermore, the clinical experience of amivantamab in NSCLC has shown clinical benefit against a broad spectrum of EGFR and cMet abnormalities, including EGFR protein overexpression and cMet amplification.

[0162] This study aims to evaluate the clinical activity of amivantamab as monotherapy in GC (including GEJ cancer) and EC patients who have received at least two prior lines of standard therapy (GC / GEJ participants) or one prior line of therapy (EC participants). The Phase 2a cohort aims to first investigate the antitumor activity of amivantamab in participants with documented expression of EGFR, cMet, or both, as evaluated by immunohistochemistry (IHC). Approximately 30 participants with any expression level of the EGFR, cMet, or both proteins will be enrolled in each of the Phase 2a cohorts. However, based on previous experience investigating anti-EGFR and anti-cMet antibodies in gastroesophageal cancer, at least 20 participants who express IHC 2+ or higher (defined as participants who express EGFR IHC 2+ or higher and / or cMet IHC 2+ or higher) will be enrolled. To achieve this minimum enrollment, additional enrollment into the Phase 2a cohorts may be permitted. Furthermore, at least 10 participants who express cMet protein at any level will be enrolled in each of the Phase 2a cohorts to better characterize the contribution of cMet to amivantamab activity. If activity is demonstrated in the Phase 2a cohorts, participants who do not express EGFR and cMet may be enrolled into a Phase 2a expansion cohort to investigate. The Phase 2b cohort will investigate the clinical activity of amivantamab in a patient population selected based on Phase 2a data.

[0163]

Table 1

[0164] Benefit / Risk Assessment Risks of Study Participation The safety and tolerability of amivantamab monotherapy were demonstrated in the Phase 1 study 61186372EDI1001 in NSCLC patients. Amivantamab was generally well tolerated without any occurrence of dose limiting toxicity (DLT). However, considering that the available clinical data are limited to NSCLC participants, unexpected safety risks related to study treatment may occur in GC or EC participants. This study protocol includes the following elements to reduce the risks to study participants. · Participants are closely monitored for safety throughout the study according to the scheduled assessments outlined in the activity schedule (Table 1) (see Safety Assessment section). · Dose modification guidelines are provided to manage toxicity that occurs during the study, including specific guidelines for infusion-related reaction (IRR), rash, interstitial lung disease (ILD), liver test abnormalities, or paronychia (see Dose Delay Guidelines section and Dose Modification Guidelines section).

[0165] Amivantamab is generally safe and well tolerated based on the above data.

[0166] Benefits of Study Participation Many drugs targeting EGFR have been approved and are part of the standard treatment for many tumor types, but anti-EGFR or anti-cMet therapies are not approved in GC or EC. Amivantamab has demonstrated significant activity as a monotherapy for the treatment of NSCLC and has received Breakthrough Therapy Designation from the US FDA and the China Center for Drug Evaluation, which is based on an overall response rate of 41% in subjects with EGFR Exon20ins disease and after previous treatment with platinum-based chemotherapeutic agents. Consistent with the unique mechanism of action of amivantamab, activity was observed in subjects with diverse EGFR mutations, as well as in subjects with MET amplification and overexpressed EGFR.

[0167] Using this targeted therapy approach with amivantamab as a single agent in any progressive GC (including GEJ cancer) or EC participant is expected to provide benefit to these participants.

[0168] Benefit-Risk Assessment for Study Participation Considering the means taken to minimize risks to participants in this study (see Risks in the Study Participation section), the potential risks of amivantamab are justified by the expected benefits that can be given to participants with progressive GC or EC (see Benefits in the Study Participation section).

[0169]

Table 2

[0170] Hypothesis Amivantamab is expected to demonstrate anti-tumor activity in participants with GC or EC expressing any level of EGFR, cMet, or both proteins.

[0171] Study Design Overall Design This is an open-label, multi-center, multi-arm phase 2 interventional study in participants 20 years of age or older (or the legal age of consent in the jurisdiction where the study is conducted) with previously treated advanced or unresectable GC or EC. Participants are Japanese with GC / GEJ or EC and express varying degrees of EGFR, cMet, or both, as determined locally or centrally by IHC, and are enrolled in the GC cohort or the EC cohort. If activity is demonstrated in the phase 2a cohort, participants who do not express EGFR and cMet can be enrolled in the phase 2a expansion cohort to investigate them. If activity is observed within the phase 2a cohort, the corresponding phase 2b GC or EC expansion cohort can be initiated to evaluate the antitumor activity of amivantamab in selected GC and EC participants based on the forward-looking evaluation of IHC during phase 2a (Figure 1).

[0172] If the efficacy observed in both of the Phase 2a cohorts guarantees full enrollment into their respective Phase 2b cohorts, up to approximately 282 participants will be enrolled into the combined Phase 2a and Phase 2b populations. Approximately 30 evaluable participants will be enrolled into each of the Phase 2a GC and EC groups. However, based on previous experience investigating anti-EGFR and anti-cMet antibodies in gastroesophageal cancer, at least 20 participants who express IHC 2+ or higher (defined as participants who express either EGFR IHC 2+ or higher or cMet IHC 2+ or higher) will be enrolled. Additionally, at least 10 participants who express any level of cMet protein (IHC 1+ or higher) will be enrolled into each Phase 2a cohort to better characterize the contribution of cMet in amivantamab activity. If these criteria are not met in the first 30 evaluable subjects, additional enrollment may be allowed in the Phase 2a cohorts to achieve this minimum enrollment. If activity is demonstrated in the Phase 2a cohorts, up to 11 participants who do not have expression of either EGFR or cMet can be enrolled into a Phase 2a expansion cohort to investigate. The Phase 2b GC expansion cohort or EC expansion cohort will evaluate the tumor activity of amivantamab in GC and EC patients using biomarker selection based on the Phase 2a results. If activated, approximately 100 participants will be enrolled into each of the Phase 2b cohorts.

[0173] The study includes a screening phase (screening phase (pre-screening and full screening) section), a treatment phase (treatment phase section), and a follow-up phase (follow-up phase (applicable only to Phase 2b) section).

[0174] Screening Phase (Pre-Screening and Full Screening) During the entire screening period, participants are evaluated for eligibility to participate in the study. Participants complete all screening procedures within 28 days of C1D1. For all participants in Phase 2a and Phase 2b, pretreatment biopsies are collected. If the report of the central tumor IHC results is not completed within the 28-day screening period, the screening period can be extended by 14 days. However, all other evaluations still meet the timing criteria for C1D1 or are repeated.

[0175] An optional pre-screening period is provided to facilitate molecular characterization of the stored tumor biopsy samples. Participants may submit stored samples prior to completion of previous treatment.

[0176] Treatment Phase The treatment phase of the participant starts at C1D1 and continues as 28-day cycles until approximately 30 days after the end of study treatment (end-of-treatment, EOT) visit. This study is conducted in the outpatient setting. However, inpatient observation from C1D1 to C1D8 is permitted in Phase 2a (including the Phase 2a expansion cohort) to enable close monitoring. Study treatment continues until disease progression is documented by clinical or radiological (RECIST version 1.1) assessment or the participant meets another criterion for discontinuation of study treatment.

[0177] Disease evaluations are performed as close as possible to the start of treatment (baseline screening scan), 6 weeks (+1 week) after the first dose of study treatment, then every 6 weeks (±1 week) for the first 12 months, then every 12 weeks (±1 week) until objective radiological disease progression or withdrawal of consent.

[0178] At each study visit during the treatment phase, participants receive a safety assessment that includes a physical examination and an evaluation of adverse events (AEs), vital signs, concomitant medications, and clinical laboratory parameters. Participants also have blood samples drawn at selected visits for the evaluation of PK and immunogenicity parameters and biomarker evaluation. Post-treatment biopsies, circulating tumor DNA (ctDNA), and biomarkers according to the activity schedule section at C2D15 are collected from all Phase 2a participants at C2D15 (+1 week).

[0179] Follow-up phase (applicable only to Phase 2b) Participants who discontinue study treatment are followed for subsequent treatment, disease status (applicable only for participants who discontinue treatment for reasons other than progressive disease to confirm the date of disease progression), and survival during the follow-up phase. This phase begins with the EOT visit assessment, which is conducted every 12 weeks (±14 days) after the last dose of study treatment or disease progression (whichever occurs first), and continues until either the end of the study, death, loss to follow-up, or withdrawal of consent to participate in the study occurs first.

[0180] A diagram of the study design is provided in Figure 1.

[0181] Reasons for the dose being justified Amivantamab was generally well tolerated up to a dose of 1750 mg in the Phase 1 study (Study 61186372EDI1001), with no dose-limiting toxicities reported during dose escalation, and no maximum tolerated dose was identified in lung cancer participants. Based on the overall exposure, safety, and efficacy data, the recommended Phase 2 dose was determined to be 1050 mg for body weight <80 kg and 1400 mg for body weight ≥80 kg, administered by IV infusion every 2 weeks in subsequent cycles after a 28-day cycle, i.e., once weekly (split dose on Days 1–2) in Cycle 1. The recommended Phase 2 dose achieved complete soluble target saturation through dosing for EGFR and cMet in lung cancer participants. The observed safety profile of amivantamab was consistent with EGFR and cMet inhibition, and most of the treatment emergent adverse events (TEAEs) that occurred under treatment were Grade 1–2 in severity. Therefore, it is considered appropriate to administer the same dosing regimen to GC or EC participants.

[0182] Study population Eligible participants are screened within 28 days prior to administration of study treatment.

[0183] The inclusion and exclusion criteria for enrolling participants in this study are described below.

[0184] Inclusion criteria Each potential participant must meet all of the following criteria to be enrolled in the study. 1. The participant is 20 years of age or older (or the legal age of consent in the jurisdiction where the study is being conducted). 2. The tumors of the participants express EGFR, cMet, or both, as determined by either a local or central IHC assay (IHC 1+ or greater). If a local IHC test is used for eligibility determination, a copy of the unidentified pathology report for IHC analysis is submitted during the screening period. Phase 2a Expansion Cohort: The participant tumors lack the expression of EGFR and MET, as determined by either a local or central IHC evaluation. If a local IHC test is used for eligibility determination, a copy of the unidentified pathology report for IHC analysis is submitted during the screening period. 3. The participant has histologically or cytologically confirmed gastric (including GEJ) or EC that is locally advanced, unresectable, or metastatic and is not eligible for curative treatment. Gastric cancer or GEJ cancer only: The participant is refractory or ineligible to at least two previous standard treatment options for systemic therapy. Previous treatments include fluoropyrimidine and platinum-based chemotherapy. Participants with known HER2 expression have received HER2-targeted therapy as part of previous therapy. If progression occurs within 24 weeks of previous adjuvant or neoadjuvant chemotherapy, this therapy is considered one previous systemic therapy option for the purpose of meeting eligibility criteria. Esophageal cancer only: (a) The participant is refractory or intolerant to at least one prior selected systemic therapy. Prior therapies include fluoropyrimidines and platinum-based chemotherapy (including chemoradiation given in a stage IV setting). (b) Participants who have undergone extensive resection in combination with neoadjuvant / adjuvant therapy and chemotherapy including chemoradiation (including participants who have undergone salvage surgery if there is residual tumor after chemoradiation), and in whom recurrence has been confirmed by imaging within 24 weeks after the last administration of chemotherapy, are considered to have received one selected prior systemic therapy for the purpose of meeting the eligibility criteria. If a prior combination therapy was discontinued due to an AE and then one of the agents was continued, this is considered to be "one prior selection" and not "two prior selections". A change in dosage form (IV administration, oral administration) or a dose reduction without progression is considered to be "one prior selection" and not "two prior selections". 4. The participant has measurable disease as measured according to RECIST version 1.1. If there is only one measurable lesion, it can be used for screening biopsy if the baseline tumor assessment scan is performed more than 7 days after the biopsy. 5. The participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Eastern Cooperative Oncology Group (ECOG) Performance Status). 6. The participant has appropriate organ and bone marrow function as follows and must not have a history of red blood cell or platelet transfusion within 7 days prior to the clinical examination. a. Hemoglobin ≥ 8 g / dL b. Absolute neutrophil count ≥ 1500 / mm 3 and has not used granulocyte colony stimulating factor (G-CSF) within 10 days prior to the test c. Platelets ≥ 75,000 / mm 3 d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN). If liver metastases are present, ≤ 5 × ULN e. Total bilirubin ≤ 1.5 × ULN (Participants with Dubin-Johnson syndrome can be enrolled if direct bilirubin is within the normal range). f. Glomerular filtration rate calculated or measured using the Modification of Diet in Renal Disease (MDRD) equation (see MDRD equation for eGFR) ≥ 40 mL / min 7. Participants have a tumor lesion suitable for biopsy and consent to the protocol-defined mandatory biopsy.

[0185] Exclusion Criteria Potential participants who meet any of the following criteria are excluded from participating in the study. 1. Participants have an uncontrolled medical condition including, but not limited to, the following. a. Diabetes b. Active or ongoing bacterial infection (including infections requiring treatment with antibacterial therapy [participants need to complete antibiotics 1 week prior to enrollment]), symptomatic viral infection, or any other clinically significant infection c. Active bleeding diathesis d. Psychiatric / social situation that limits compliance with study requirements 2. Participants have received prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within either 2 weeks before the first dose of study treatment or within the longer of 4 times the half-life, or have received radiation therapy within 4 weeks before the first dose of study treatment. For drugs with a long half-life, the maximum period from the last required dose is 28 days. Toxicities from prior anticancer therapy must have resolved to baseline level or grade 1 or less (excluding alopecia or skin changes after radiation [any grade], grade ≤ 2 peripheral neuropathy, and grade ≤ 2 hypothyroidism stabilized with hormone replacement therapy). 3. Participants have a history of untreated brain metastases (participants with metastases that are clinically stable, asymptomatic, and have been finally locally treated with corticosteroid therapy for at least 2 weeks prior to the first administration of study treatment are eligible), leptomeningeal disease or spinal cord compression that has not been finally treated with surgery or radiation. If brain metastases are diagnosed on screening imaging, the participant may be re-screened for eligibility after definitive treatment. 4. Participants have a history of (non-infectious) ILD / pneumonia that requires steroids, or currently have ILD / pneumonia, or if a suspected ILD / pneumonia cannot be excluded by imaging at screening. Esophageal cancer participants with a history of radiation pneumonitis that has completely resolved (defined as stable on chest X-ray for 3 months prior to enrollment without any treatment) can be enrolled. 5. Participants have an active malignancy other than the disease being treated under the study (i.e., progressing in the past 12 months or requiring a treatment change). The only permitted exceptions are as follows. a. Non-muscle invasive bladder cancer treated within the past 24 months that is considered to be completely cured. b. Skin cancer (non-melanoma or melanoma) treated within the past 24 months that is considered to be completely cured. c. Non-invasive cervical cancer treated within the past 24 months that is considered to be completely cured. d. Localized prostate cancer (N0M0): · Having a Gleason score of 6, treated within the past 24 months or not treated and under active surveillance, · Having a Gleason score of 3+4, treated 6 months ahead of full study screening and considered to have a very low risk of recurrence, · Or having a history of localized prostate cancer, receiving androgen deprivation therapy, and considered to have a very low risk of recurrence. e. Breast cancer: · Appropriately treated lobular carcinoma in situ or ductal carcinoma in situ, · Or has a history of localized breast cancer, is receiving antihormonal agents, and is considered to have a very low risk of recurrence. f. Malignancies considered to be cured with minimal risk of recurrence. g. For Phase 2a participants only: Participants with a second malignancy may enroll if they are considered not to require any systemic treatment for at least 6 months after enrollment. 6. Participants have a history of clinically significant cardiovascular disease, including but not limited to the following. a. Diagnosis of deep vein thrombosis or pulmonary embolism within 4 months prior to the first dose of study treatment, or diagnosis of any of the following within 6 months prior to the first dose of study treatment: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary / peripheral artery bypass graft, or any acute coronary syndrome. Clinically insignificant thromboses such as non-occlusive catheter-related clots are not excluded. b. Prolongation of the QTcF interval exceeding 480 milliseconds, or clinically significant arrhythmia, or electrophysiological disease (e.g., implantation of an implantable cardioverter-defibrillator, or atrial fibrillation with uncontrolled heart rate). Participants with a clinically stable cardiac pacemaker are eligible. c. Uncontrolled (persistent) hypertension: systolic blood pressure > 180 mmHg, diastolic blood pressure > 100 mmHg. d. Hospitalization defined as congestive heart failure according to New York Heart Association (NYHA) class III-IV or congestive heart failure (any NYHA class) (New York Heart Association Criteria) within 6 months of study enrollment. e. Pericarditis / clinically significant pericardial effusion. f. Myocarditis. 7. Participants have a known allergy, hypersensitivity, or intolerance to the excipients of amivantamab. 8. Participants have received study treatment (including investigational vaccines) within 6 weeks prior to enrollment, except for the anticancer therapies described in exclusion criterion No. 2. 9. Participants have or are expected to have any of the following. a. Invasive surgical treatment involving entry into the body cavity within the first 4 weeks before C1D1 or not fully recovered. Thoracentesis and percutaneous biopsy of baseline tumor tissue samples, if necessary, can be performed less than 4 weeks before C1D1, at the discretion of the principal investigator, as long as the participant has fully recovered from the procedure before the first administration of the study treatment. b. Severe traumatic injury within 3 weeks before the start of C1D1 (unless all wounds are fully healed prior to day 1). c. Major surgery is scheduled during the administration of the investigational drug or within 6 months after the final administration of the study treatment. 10. Participants have the following at screening. a. Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg). Participants with a history of HBV demonstrated by positive hepatitis B core antibody are eligible at screening if they have 1) negative HBsAg and 2) HBV DNA (viral load) below the lower limit of quantification by local testing. Participants with positive HBsAg due to recent vaccination are eligible if the HBV DNA (viral load) is below the lower limit of quantification by local testing. b. Positive hepatitis C antibody (anti-HCV [hepatitis C virus]). Participants with a history of HCV who have completed antiviral treatment and subsequently had HCV RNA recorded as below the lower limit of quantification by local testing are eligible. c. Other clinically active infectious or non-infectious liver diseases 11. Participants known to be positive for human immunodeficiency virus (HIV) having one or more of the following. a. Not receiving highly active antiretroviral therapy (ART). b. ART was changed within 6 months before the start of screening. c. Receiving ART that may interfere with the study treatment. d. CD4 count less than 350 at screening. e. Acquired immunodeficiency syndrome (AIDS) that defines opportunistic infections within 6 months of the start of screening. Without consenting to initiate ART, in addition to having received > 4 weeks of ART, having an HIV viral load of < 400 copies / mL at the end of the 4-week period (to ensure that ART is tolerated and HIV is controlled). 12. Participants have received prior EGFR or cMet-directed therapy.

[0186] Active Participants will consent to use sun protection measures (hats, sunglasses, protective clothing, sunscreen, etc.), limit long-term exposure to natural sunlight, and avoid artificial sunlight (tanning beds or phototherapy) from baseline until the last dose of study treatment. Use a broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a sun protection factor ≥ 15.

[0187] Administered study treatment Amivantamab will be supplied for this study in glass vials containing 350 mg / vial at a concentration of 50 mg / mL in 7 mL vials. IV infusion will be prepared on-site in 250 mL of diluent.

[0188] The initial dose of amivantamab is based on the participant's weight at screening: 1050 mg (if weight < 80 kg) or 1400 mg (if weight ≥ 80 kg). Amivantamab will be administered as an IV infusion in 28-day cycles as follows. Cycle 1: Once a week (divide the first dose into 350 mg on day 1 and 700 mg on day 2 if weight < 80 kg, or 1050 mg on day 2 if weight ≥ 80 kg). Cycle 2+: Days 1 and 15 of each cycle.

[0189] Amivantamab can be administered at higher doses based on body weight: 1750 mg for body weight < 80 kg and 2100 mg for body weight ≥ 80 kg can be administered as an IV infusion in 28-day cycles as follows. Cycle 1: Once a week (the first dose is divided between Day 1 [350 mg] and Day 2 [1400 mg if body weight < 80 kg or 1750 mg if body weight ≥ 80 kg]). Cycle 2+: Days 1 and 15 of each cycle.

[0190] Amivantamab is administered intravenously using a ramped infusion rate regimen. The product is infused via a peripheral vein for all Cycle 1 doses. Infusion via a central line is enabled for subsequent dosing starting with the C2D1 dose.

[0191] Administer amivantamab according to the clinical protocol. Additional guidance is provided below. · On Day 1 of each cycle, review the results of hematological and chemistry test evaluations prior to administering study treatment. · Amivantamab is diluted prior to infusion · Amivantamab is not mixed or diluted with other drugs. · Amivantamab is not administered as an IV push or bolus.

[0192] Dose and administration schedule may be adjusted during the course of this study.

[0193] Responsibilities for Preparation / Handling / Storage / Instructions Preparation / Handling / Storage All study treatment is stored at a controlled temperature according to the requirements on the label. Protect amivantamab from light prior to use.

[0194] Means to Minimize Bias: Randomization and Blinding Treatment Allocation Procedure for Randomization: Randomization is not used in this study. Participants are assigned to treatment in the order in which they are eligible for this study.

[0195] Blind study Since this is a non-blind study, the blind procedure is not applicable.

[0196] Drug administration delay guidelines If treatment delay is indicated, treatment with amivantamab may be delayed until recovery of toxicity to a level that allows continuation of treatment. Participants with treatment delays are evaluated at least weekly to ensure appropriate supportive care is being provided and to assess for improvement in toxicity. For the majority of clinically significant toxicities, dose withholding and dose modification may be done according to the guidelines described below (Dose Modification Guidelines section).

[0197] The following section provides additional guidelines for the prevention, monitoring, and management of toxicities reported with amivantamab.

[0198] Infusion-related reactions Infusion-related reactions are commonly observed during treatment with amivantamab, mainly on the first exposure to C1D1, typically within the first 90 minutes of the infusion. The majority of IRRs are grade 1 or 2. The guidelines described herein pertain to the safe administration of amivantamab during the first dose.

[0199] During amivantamab infusion, participants are clinically monitored at regular intervals (including the pre-infusion assessment). Monitoring includes measurement of heart rate, blood pressure, body temperature, respiratory rate, and oxygen saturation.

[0200] Drugs before and after amivantamab infusion Drugs before amivantamab infusion Summarize the required and optional drugs before amivantamab infusion for IRR in Table 3.

[0201] [Table 3] C = Cycle, D = Day X, IV = Intravenous. a. If the agents listed in this table are not locally available, similar agents and dosages may be substituted and administered in accordance with local guidelines. b. Participants for whom the required agent is contraindicated can investigate alternative agents with their study physicians. If the alternative agent is not suitable for the above intent, the participant need not take the corresponding agent. c. If clinically indicated for participants who experience infusion-related reactions to C1D8, C1D1, or C1D2 starting from C1D8, optional pre-dose steroids may be administered.

[0202] Agents after amivantamab infusion If clinically indicated as shown in Table 4, optional agents after amivantamab infusion may be prescribed and continued up to 48 hours after infusion.

[0203]

Table 4

[0204] Prohibited or restricted agents and treatments The following concomitant medications and therapies are not used during the study. · Any chemotherapy, systemic anti-cancer therapy, or experimental therapy (other than study treatment). Hormone therapy as specified in Exclusion 5 is permitted. · Radiation therapy for tumor lesions that are evaluated for tumor response prior to progression by X-ray · The use of live vaccines or live attenuated vaccines is prohibited · Due to the potential for hypomagnesemia associated with EGFR inhibitors, concomitant medications that can decrease serum magnesium are avoided if possible.

[0205] Study evaluations and procedures Overview The schedule of the active section summarizes the frequency and timing of the measurements applicable to this study.

[0206] The total blood volume collected for the study is approximately 25 mL (screening), 105 mL (cycle 1), 75 mL (cycle 2), and 30 mL (for cycle 3 and each cycle beyond EOT).

[0207] Repeat or unscheduled samples may be taken for safety reasons or due to technical problems with the sample.

[0208] Evaluation of Efficacy and Immunogenicity Evaluation of Disease Disease evaluation is performed as described in the activity schedule (Table 1) regardless of any dose modifications. More frequent radiological evaluations may be possible if clinically indicated.

[0209] If clinically indicated, computed tomography scans of the chest (including supraclavicular regions), abdomen, pelvis, and any other disease sites are performed using IV contrast agent. Participants who cannot receive a CT scan with IV contrast agent (e.g., due to allergy or renal insufficiency) may have non-contrast CT of the chest and MRI of the abdomen and pelvis using IV contrast agent at baseline and during the study. The same methodology is used for disease evaluation at baseline and throughout the course of the study to characterize each identified and reported lesion and record the disease status. Technologies other than CT or MRI may be used based on local standard of care and RECIST version 1.1 guidelines for the use of these alternative technologies.

[0210] Baseline disease assessment is performed as close as possible to the start of treatment, but within 28 days prior to the first dose. Subsequent assessments are performed 6 weeks (+1 week) after the start of study treatment administration, then every 6 weeks (±1 week) for the first 12 months, and then every 12 weeks (±1 week) until objective radiographic disease progression. The timing of each disease assessment is relative to the first dose of study treatment administration and continues until disease progression, regardless of dose modification. Any other sites where new disease is suspected are also imaged.

[0211] If a participant achieves a partial response (PR) or complete response (CR), the response is confirmed at a time close to 4 weeks after entering PR or CR, instead of the pre-defined 6 weeks.

[0212] Particularly if it is unclear whether progression has occurred in response to the emergence of non-target lesions or new lesions, treatment is continued until the next scheduled assessment (or earlier if clinically indicated), and the participant's status is re-evaluated. If repeated scans confirm progression, the date of the first scan is declared the date of progression. To achieve "definite progression" based on non-target lesions, there must be an overall substantial worsening in the non-target lesions such that, even if there is stable disease or PR in the target lesions, the overall tumor burden has increased sufficiently to warrant discontinuation of treatment. A slight "increase" in the size of one or more non-target lesions is usually not sufficient to qualify as definite progression. If worsening of symptoms (based on an overall worsening of the health status) is recorded as the basis for determining disease progression, the clinical findings used to make the determination are specified. Radiographic progression is recorded, if possible, prior to subsequent treatment, even after treatment has been discontinued due to symptomatic worsening. For participants who discontinue study treatment for reasons other than toxicity or objective progressive disease, tumor assessments continue according to the schedule until radiographic progressive disease is recorded.

[0213] Participants undergo a brain MRI scan (or, if MRI is contraindicated, a CT scan with contrast to determine the presence of brain lesions) at screening to identify any untreated brain metastases (Exclusion Criterion #3). Brain scans are not required at each subsequent disease assessment regardless of previous history of brain metastases, but are performed according to local guidelines and practice if clinically indicated.

[0214] If a participant is deriving clinical benefit and treatment beyond documented disease progression is approved, disease assessments continue as scheduled clinical benefit following each disease assessment review.

[0215] Safety Assessments Clinically significant abnormalities that persist at study end / early termination are followed until resolved or until a clinically stable state is reached.

[0216] This study includes the following assessments of safety and tolerability according to the time points indicated in the Activity Schedule section.

[0217] Physical Examinations The screening physical examination includes at least an examination of the participant's height, weight, and general appearance, as well as the skin, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system. On Day 1 of each cycle, perform the indicated physical examinations of the involved organs and other body systems as shown, and obtain the participant's weight using a calibrated scale.

[0218] Vital Signs Vital sign measurements include the following assessments as shown in the Activity Schedule (Table 1). · Body temperature · Heart rate · Respiratory rate · Oxygen saturation · Blood pressure

[0219] Blood pressure and heart rate measurements were evaluated in the supine position using a fully automated device. Manual techniques were used only when an automated device was not available.

[0220] Prior to blood pressure and heart rate measurements, the subject was rested quietly in a quiet environment free from distractions (e.g., television, mobile phone) for at least 5 minutes.

[0221] Electrocardiogram A locally performed triplicate electrocardiogram (ECG) was collected at screening to determine eligibility. During ECG collection, the participant was in a quiet environment free from distractions (e.g., television, mobile phone). The participant was rested in the supine position for at least 5 minutes prior to ECG collection and refrained from talking or moving the arms or legs. If blood sampling or vital sign measurement was scheduled at the same time as ECG recording, the procedures were performed in the order of ECG, vital signs, and blood sampling.

[0222] Three individual ECG tracings were obtained in succession as close together as possible at approximately 2 - minute intervals. The ECG, including the ECG morphology, was reviewed for immediate management.

[0223] QTcF was calculated using Fridericia's formula: QTcF = QT / (RR)^0.33.

[0224] ECOG Performance Status The Eastern Cooperative Oncology Group Performance Status Score was evaluated during the screening phase to determine eligibility.

[0225] Clinical Safety Laboratory Assessments Clinical laboratory assessments were performed locally. Clinical laboratory tests were performed as described in Table 5.

[0226]

Table 5

[0227] More frequent clinical tests may be performed as indicated by the overall clinical condition of the participants or abnormalities warranting more frequent monitoring.

[0228] Pharmacokinetics Blood samples are used to evaluate the PK of amivantamab. Serum collected for PK may be further used to evaluate aspects of safety or efficacy to address concerns arising during or after the study period. Evaluation

[0229] Blood samples are collected for measurement of amivantamab in serum for PK analysis. The PK profile of amivantamab is based on serum concentration data obtained from time points around the first and fifth dose administrations collected from at least 10 participants of each cancer type in Phase 2a. At all other dose administrations from Phase 2a and Phase 2b participants, and before and after the start of the infusion for all participants, sparse PK blood samples are also obtained. Analytical procedures

[0230] Pharmacokinetics: Serum samples are analyzed to determine the concentration of amivantamab using a validated specific and sensitive enzyme-linked immunosorbent assay (ELISA) method.

[0231] Furthermore, serum PK samples can be stored for future analysis of other co-therapies.

[0232] Pharmacokinetic parameters and evaluation The primary PK endpoints include the maximum serum concentration (C max ), T max , AUC( t1-t2 ) (e.g., AUC Day1-8 ), AUC tau , the plasma / serum concentration (C trough ) immediately prior to the next study treatment administration, t 1 / 2 , CL, the steady-state volume of distribution (V SS) and accumulation ratio, among others, although not limited thereto. Population PK modeling can be performed to evaluate the potential effects of endogenous and exogenous factors on the PK of amivantamab.

[0233] Biomarker Using the collected tumor tissue samples, the tumor surface levels of EGFR and cMet protein expression are evaluated by the centrally conducted IHC assay to determine patient eligibility. However, the records of previously performed local IHC results can be submitted for the purpose of demonstrating the eligibility of the study implementation. Nevertheless, all statistical analyses and biomarker analyses utilize the results of the centrally conducted IHC assay that classifies patients as 0, 1+, 2+, or 3+ based on the highest staining of either EGFR or cMet. The tumor tissue collected at screening can also be analyzed by tumor next-generation sequencing to evaluate molecular alterations and track responses to treatment. Tumor samples collected after treatment and at progression can also be evaluated by IHC and next-generation sequencing to track responses to amivantamab. The tissue can also be used to determine biomarkers related to GC / EC and / or analyzed to confirm ctDNA results.

[0234] Screening blood samples from all participants undergo ctDNA analysis to evaluate the pre-treatment mutation status of EGFR, cMet, and other important cancer genes to characterize the tumor. Additional blood samples are collected during the study and evaluated for ctDNA to assess changes in the levels or types of genetic alterations observed over time and monitor the emergence of potential markers of resistance to amivantamab.

[0235] Blood samples are also collected at time points and can be analyzed for circulating factors (e.g., hepatocyte growth factor) related to disease biology.

[0236] To analyze PD markers (e.g., soluble EGFR and cMet) in samples collected before and after exposure to amivantamab, blood samples were collected from at least 10 participants in each cancer type at selected time points to investigate whether complete soluble target saturation was achieved throughout dosing.

[0237] For the provision of biopsy tissue samples, formalin-fixed, paraffin-embedded (FFPE) tissue samples are required and evaluated for cancer-related biomarkers (DNA, RNA, and / or protein).

[0238] Immunogenicity assessment Serum samples are collected for the immunogenicity assessment of amivantamab (anti-drug antibodies to amivantamab). Detection and characterization of antibodies to amivantamab are performed using validated immunoassays.

[0239] Serum samples are screened for antibodies that bind to amivantamab and serum titers are determined from positive samples. Antibodies can be further characterized and / or evaluated for their ability to neutralize the activity of the study treatment. All samples collected for immunogenicity analysis are also evaluated for amivantamab concentration in serum to ensure appropriate interpretation of immunogenicity data. Other immunogenicity analyses may be performed to further characterize any immune responses that occur.

[0240] Statistical considerations A general description of the statistical methods used to analyze efficacy and safety data is outlined below.

[0241] Statistical hypotheses The hypotheses to be tested in Phase 2a are not planned.

[0242] The statistical hypothesis in the 2b phase is that amivantamab monotherapy leads to an objective response rate (ORR) higher than 15% (i.e., H0≦15% vs H a >15%) in patients with GC or EC selected based on the expression of EGFR, cMet, or both. This threshold is based on past studies (11.2% - 13.6%) for the approved 3L regimen for GC and the reported efficacy (approximately 15%) of the approved 2L regimen for EC.

[0243] Determination of Sample Size In the 2a phase, approximately 30 evaluable participants with tumors expressing EGFR, cMet, or both, as determined by central IHC, are enrolled in the GC and EC cohorts. 20 participants are enrolled with IHC 2+ / 3+, which provides approximately a 90% probability of observing a post - hoc probability of (ORR>22.5%)≧40% (similar to ORR≧20%) assuming an ORR of 30% for the sub - population. By enrolling 10 participants with IHC 1+, the probability of observing a post - hoc probability of (ORR>22.5%)≧40% is 80%. Up to 11 participants can be enrolled in each 2a - phase expansion cohort. If no response or stable disease is observed for more than 6 weeks among the first 6 participants for futility in each 2a - phase expansion cohort, enrollment is stopped. If two or more responses are observed in each 2a - phase expansion cohort, additional participants can be enrolled for further characterization.

[0244] In the 2b - phase cohort, approximately 100 participants are enrolled in each of the GC and EC expansion cohorts. Eligible participants are determined based on the results of the 2a - phase portion. Assuming an overall ORR of 30% for amivantamab, 100 participants in the 2b - phase portion provide a power of approximately 90% to reject the null hypothesis using a two - sided z - test with α = 0.05 for an ORR of 15%.

[0245] Population of the Analysis Set For the purposes of the analysis, the following populations are defined. (1) All treatment populations: All participants who receive at least one dose of the study treatment (2) Response evaluable population: All participants who meet the following criteria · Receive at least one dose of the study treatment · Have at least a second post-baseline efficacy disease assessment, or discontinued treatment for any reason, or the disease progressed / died before the second post-baseline disease assessment (3) Safety population: All participants who receive at least one dose of the study treatment (4) Pharmacokinetic population: All participants who receive at least one dose of the study treatment and have at least one evaluable post-baseline measurement (5) Immunogenicity population: All participants who receive at least one dose of the study treatment and have at least one evaluable post-baseline measurement.

[0246] General considerations All continuous variables are summarized using the number of participants (n), mean, standard deviation (SD), median, minimum, and maximum. Discrete variables are summarized as numbers and percentages. The Kaplan-Meier product-limit method is used to estimate time-to-event variables, including the median survival time. Unless otherwise specified, ratios and groups are analyzed separately.

[0247] Analysis of the ORR and disease control rate (DCR) is performed on the response evaluable population. Other efficacy analyses are performed on all treatment populations. Central IHC data are used for statistical analysis purposes.

[0248] At the end of the Phase 2a portion, the results are reviewed and it is determined which subpopulations should be included in the Phase 2b portion.

[0249] Primary endpoint Objective response rate. Primary estimate: · Population: Participants with GC or EC expressing EGFR and / or MET · Variable: Overall response, CR or PR · Investigational drug: Amivantamab monotherapy · Interventional event: Subsequent anti-cancer therapy. Treatment policy: Response after this interventional event is not included. · Summary: ORR

[0250] The primary efficacy measure is ORR. Objective response rate is defined as the proportion of participants achieving either CR or PR as determined by the assessment of the investigator responsible for the trial using RECIST version 1.1. Confirmation of ORR by the investigator responsible for the trial can be performed via IRC in the Phase 2b.

[0251] For the Phase 2a part, there is no formal hypothesis testing. ORR is calculated descriptively for the response evaluable population.

[0252] For the Phase 2b part, ORR is compared to 15% using a z-test by normal approximation. The multiplicity caused by subgroup selection in the interim analysis (see section on interim analysis) is controlled by a closed testing procedure and weighted statistics. ORR and its 95% confidence interval (CI) are also calculated.

[0253] Secondary endpoint Disease control rate: The disease control rate is defined as the percentage of participants achieving complete or partial response or stable disease for at least 6 weeks as defined by RECIST version 1.1. DCR and its 95% CI by the Clopper-Pearson method are also calculated.

[0254] Duration of Response: The duration of response (DoR) is defined as the time from the date of the first recorded response (CR or PR) to the date of recorded progression or death (whichever is earlier). The end of the response coincides with the date of progression or death due to any cause used for the PFS endpoint. If the participant does not progress after response, their duration of response uses the PFS cut-off time. The median DoR with Kaplan-Meier plot and 95% confidence interval (calculated from the Kaplan-Meier estimates) is presented. Confirmation of DoR by the Investigator can be done via the IRC in Phase 2b.

[0255] Progression-Free Survival: Progression-free survival is defined as the time from the first administration to the earlier of the date of objective disease progression or death (due to any cause if there is no progression) based on the assessment of the Investigator using RECIST version 1.1. Participants who have not progressed or died at the time of analysis are censored at the last date of assessment from the last evaluable RECIST version 1.1 assessment. PFS is analyzed using the same methodology as the analysis of DoR.

[0256] Overall Survival: Overall survival is defined as the time from the first administration date to the date of death due to any cause. Any participant whose death is not known at the time of analysis is censored based on the last recorded date when the participant was known to be alive. OS is analyzed using the same methodology as the analysis of DoR.

[0257] Other Analyses Pharmacokinetic Analysis PK analysis uses the PK population. Serum amivantamab concentrations are summarized for each cancer type and the overall population in a table of mean, SD, median, and range over time as required. PK parameters are estimated for individuals and descriptive statistics are calculated for each cancer type and the overall population.

[0258] Participants will be excluded from PK analysis if their data do not allow for an accurate assessment of PK (e.g., incomplete administration of study treatment, missing information on administration and sampling times, concentration data not sufficient for PK parameter calculation).

[0259] Pharmacokinetics / Pharmacodynamics Analysis If data permit, an exposure-response relationship between amivantamab exposure and key efficacy and safety parameters can be investigated. Further, this relationship can be characterized using an exposure-response model.

[0260] Immunogenicity Analysis Summarize the incidence of anti-amivantamab antibodies for the immunogenicity population.

[0261] Screen serum samples for antibodies that bind to amivantamab and report the titers of confirmed positive samples. Other analyses can be performed to further characterize the immunogenicity of amivantamab.

[0262] Pharmacodynamics Analysis and Biomarker Analysis Biomarker analysis uses the biomarker population. The analysis is planned to investigate PD and other biomarkers that may indicate the mechanism of action of the drug or predict potential mechanisms of efficacy and resistance to amivantamab.

[0263] The association between biomarker positivity and clinical response or time-to-event endpoints is evaluated using appropriate statistical methods (e.g., analysis of variance, categorical, or survival models) for each endpoint. A correlation between baseline biomarker expression levels and clinical response or time-to-event endpoints associated is performed to identify responder (or resistant) subpopulations.

[0264] To better understand the mechanisms of disease and response or resistance to amivantamab, additional biomarkers (DNA, RNA, and / or protein) related to GC / EC can also be evaluated in blood and tissue samples collected during the study.

[0265] Interim analysis In the second part of Phase 2b, approximately 12 weeks after the first infusion of the 50 participants, an interim futility analysis will be planned in each of the GC and EC groups. The interim futility analysis is based on the best response rate for each pre-specified subpopulation (e.g., IHC 2+ / 3+ and IHC 1+) selected at the end of Phase 2a and pre-specified before the start of Phase 2b. Enrollment of each subpopulation may be terminated for futility if the posterior probability (ORR>22.5%) is <40%.

[0266] Results Participants in the Phase 2a gastric cancer (GC) cohort and esophageal cancer (EC) cohort received intravenous (IV) infusions of amivantamab at a body weight-based dose on a 28-day cycle. Participants weighing less than 80 kilograms (kg) received an IV infusion of 1050 milligrams (mg) of amivantamab, and participants weighing 80 kg or more received an IV infusion of 1400 mg of amivantamab once a week in Cycle 1 and then every two weeks (on Days 1 and 15 of each cycle) in subsequent cycles. The enrollment status is shown in Table 6. Demographics and disease characteristics are shown in Table 7. An overview of the overall safety of treatment-emergent adverse events (TEAEs) is shown in Table 8. TEAEs related to Grade 3 or higher are shown in Table 9.

[0267] [Table 6]

[0268] [Table 7]

[0269] [Table 8]

[0270]

Table 9

[0271] The observed incidence of infusion-related reactions (IRR) was similar to that in other amivantamab monotherapy studies. The incidence of hypoalbuminemia in the gastric cohort was slightly higher than that in the esophageal cohort. Stomach (n = 29): All grades: 12 (41.4%), ≥ grade 3: 3 (10.3%). Esophagus (n = 30): All grades: 10 (33.3%), ≥ grade 3: 3 (10.0%)

[0272] Next, the response to treatment was evaluated. The "all-treated" patient population consisted of patients who received at least one dose of study treatment. The "response evaluable" patient population consisted of (1) patients who received at least one dose of study treatment, (2) patients who met all eligibility criteria of the study, and (3) patients who had a baseline and at least one post-baseline efficacy disease assessment, or patients who had disease progression / died due to disease progression before the first post-baseline disease assessment. Table 10 shows an overview of the objective response rate based on the RECIST version 1.1 criteria by pre-screening of the IHC score (central) in the response evaluable population. Table 11 shows an overview of the objective response rate based on the RECIST version 1.1 criteria by pre-screening of the IHC score (central) in all treated populations.

[0273]

Table 10

[0274]

Table 11

[0275] The overall response for gastric cancer patients in the response evaluable population is shown in Figure 6. The overall response for gastric cancer patients in all treatment populations is shown in Figure 7. The overall response for esophageal cancer patients in the response evaluable population is shown in Figure 8. The overall response for esophageal cancer patients in all treatment populations is shown in Figure 9.

[0276] In summary, the safety profile in the gastric / esophageal cancer cohort is consistent with the reported experience of other amivantamab monotherapy studies. The gastric cancer cohort had 1 partial response and 5 stable disease patients (disease control rate (DCR): 25.0%) among 24 response evaluable patients. The esophageal cancer cohort had 3 partial responses and 16 stable disease patients (DCR: 67.9%) among 28 response evaluable patients.

[0277] A higher dose of amivantamab, 1750 mg, was evaluated in three patients with esophageal cancer. All three participants weighed less than 80 kilograms (kg) and received an intravenous infusion of 1750 mg of amivantamab once weekly in Cycle 1, with a first dose divided into 350 mg and 1400 mg on Days 1 and 2, respectively, and then every two weeks (on Days 1 and 15 of each cycle) in subsequent cycles. Table 12 shows the demographic data and disease characteristics in patients treated with 1750 mg of amivantamab. Table 13 shows the overall safety profile of TEAE in patients treated with 1750 mg of amivantamab. Grade 3 or higher TEAE was not observed in the 1750 mg amivantamab group.

[0278]

Table 12

[0279]

Table 13

[0280] Efficacy was evaluated in three patients treated with 1750 mg of amivantamab. One patient had stable disease, one had a partial response, and one had progressive disease. Figure 10 shows the best overall response in patients evaluable for response.

[0281] Example 2. Evaluation of Amivantamab in an Esophageal Patient-Derived Xenograft (PDX) Model Expressing Wild-Type EGFR To evaluate the efficacy of amivantamab in a series of esophageal PDX models (n = 12, provided by CrownBio) bearing wild-type EGFR, tumor fragments were harvested from stock tumor-bearing mice and inoculated into designated experimental mice. A designated tumor fragment (2 - 3 mm in diameter) was subcutaneously inoculated into the right flank of each mouse to generate a tumor. Detailed esophageal PDX inoculation information is listed in Table 14.

[0282]

Table 14

[0283] After the establishment of palpable lesions, tumor growth was measured twice a week. After the average tumor volume reached approximately 150 mm 3 animals were randomly assigned to the relevant study groups to obtain 8 mice per group. Randomization was performed according to the tumor size of each group, and the day of randomization was designated as day 0. Treatment was initiated on the same day as randomization according to the study design in Table 15.

[0284]

Table 15

[0285] The endpoint of the study was to compare tumor growth in each group at the end of treatment and subsequent tumor growth after discontinuation of administration. Tumor size was measured twice a week in two dimensions using calipers, and the formula: V = 0.5 × L × W 2 (where V is the tumor volume, L is the length of the tumor (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L)) was used to express the tumor volume in mm 3 and is shown in Figures 2A - 2L as the tumor growth curve over time (expressed as mean ± SEM).

[0286] Tumor growth inhibition (TGI%) is an indicator of antitumor activity and was calculated as TGI% = (1 - (T - T0) / (C - C0)) × 100%. T and C were the mean tumor volumes (TV) of the treatment group and the control group, respectively, on the day when the mean tumor volume of the control group ended according to the study design. Tumor growth inhibition is summarized in Table 16.

[0287]

Table 16

[0288]

Number

[0289] As shown in FIGS. 2A-2L and Table 16, 7 out of 12 esophageal PDX tumors responded to amivantamab monotherapy. Among these, amivantamab induced tumor regression in ES3431 (TGI% 112.7%) and ES0178 (TGI% 100.4%), strongly inhibited tumor growth in ES0110 (TGI% 90.8%) and ES11079 (TGI% 94.5%), and showed moderate responses in ES0026, ES3862, and ES11062 (TGI% 58.6%, 49.4%, and 45.5%, respectively).

[0290] Example 3. Evaluation of Amivantamab Monotherapy or Combination with Chemotherapeutic Agents or Capmatinib in the Treatment of Gastric PDX Tumors To evaluate the antitumor activity of amivantamab, a panel of gastric PDX models was selected for treatment with amivantamab alone, or the c-Met inhibitor capmatinib (Selleck), and in combination with gastric chemotherapy regimens such as 5-FU (Shanghai Xudong Haipu Pharm) + cisplatin (Qilu Pharm) or paclitaxel (Beijing Union Pharm).

[0291] Tumor fragments were collected from stock tumor-bearing mice and inoculated into BALB / c nude mice. A designated tumor fragment (2-3 mm in diameter) was subcutaneously inoculated into the right flank of each mouse to generate a tumor. Detailed gastric PDX information is listed in Table 17.

[0292]

Table 17

[0293] After the establishment of palpable lesions, tumor growth was measured twice a week. After the average tumor volume reached approximately 150 mm 3 reached, animals were randomly assigned to the relevant study groups, with 8 mice in each group. Randomization was performed according to the tumor size of each group, and the day of randomization was designated as day 0. Treatment was initiated on the same day as randomization according to the dosing regimen in Table 18 as needed.

[0294] [Table 18] i.p.: intraperitoneal, i.v.: intravenous (ly), p.o.: oral administration. QW = once a week, BIW: twice a week (day 0, three times a week), BID: twice a day at 12-hour intervals, QD, five days a week: once a day on days 0 - 5 of the week. * : GA0046 was used to treat groups 1, 2, 7, and 8. GA0075 and GA0152 were used to treat groups 1 - 6 (15 mg / kg paclitaxel). GA3121 was used to treat groups 1, 2, 5, and 6 (10 mg / kg paclitaxel). GA2254 and GA3236 were used to treat groups 1 - 2.

[0295] The study endpoint was to compare tumor growth in each group at the end of treatment and subsequent tumor elongation after dosing cessation. Tumor size was measured twice a week in two dimensions using calipers, and the formula: V = 0.5×L×W 2 (where V is the tumor volume, L is the tumor length (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L)) was used to express the tumor volume in mm 3 represented. The tumor growth curves over time (expressed as mean ± SEM) are shown in Figures 3A - 3F.

[0296] Tumor growth inhibition (TGI%) is an indicator of antitumor activity and was calculated as TGI% = (1 - (T - T0) / (C - C0))×100%. T and C were the mean tumor volumes (TV) of the treatment group and the control group, respectively, on the day when the mean TV of the control group ended according to the study design. Tumor growth inhibition is summarized in Table 19.

[0297]

Table 19

[0298]

Number

[0299] As shown in Figures 3A - 3F and Table 19, amivantamab monotherapy (10 mg / kg BIW) inhibited tumor growth in 3 out of 6 PDX models, and strong antitumor activity was observed in GA0046 (TGI% 121.31%) and GA0075 (101.17%).

[0300] In GA0046 (Figure 3A), complete tumor regression was observed with amivantamab monotherapy. In comparison, the c-Met inhibitor capmatinib (10 mg / kg BID) showed no effect on tumor growth (TGI%: 5.93% on day 28).

[0301] The standard treatment chemotherapy regimen was also evaluated in this study. As shown in Figure 3B, 5-FU (10 mg / kg QD, 5 days / week) + cisplatin (4 mg / kg QW), or paclitaxel (10 / 15 mg / kg, QW) showed moderate activity, 43.35% and 66.09% on day 28 in GA0075. Surprisingly, the combination of amivantamab induced potent and sustained tumor growth inhibition in the same model (104.92% and 111.54% respectively). A similar synergistic effect between amivantamab and paclitaxel was observed in another model, GA0152, where the TGI% was improved from 27.29% to 70.13% (Figure 3E).

[0302] Example 4. Relationship between Receptor Expression and In Vivo Efficacy of Amivantamab in Esophageal and Gastric PDX Tumors To further investigate the antitumor activity of amivantamab against receptor levels, an immunohistochemistry assay was performed to examine the membrane expression of both EGFR and c-Met. Paraffin-embedded tissues were cut into 4-μm slides and placed in an automated staining system (Leica or Ventana). After a series of pre-set procedures (dewaxing, peroxide block, primary antibody incubation, secondary antibody incubation, DAB reaction), the stained slides (using either an EGFR antibody, clone 5B7 from Ventana or SP84 from Abcam, or a c-Met antibody, clone SP44 from Ventana or Abcam) were further scanned at high resolution into a photograph using an imaging system (NanoZoomer) for review and scoring by a pathologist.

[0303] The intensity of EGFR or c-Met membrane staining from each slide was scored at four levels: 0, 1+, 2+, and 3+. A further H score was calculated based on the percentage of cells at different intensity levels using the following formula. The relative EGFR and c-Met H scores in the esophageal and gastric PDX models tested were listed in Table 20, Figure 4, and Table 21, Figure 5, respectively, together with the antitumor activity of amivantamab. In esophageal tumors, high EGFR levels appear to be associated with tumor growth inhibition (TGI%), and in gastric tumors, high levels of EGFR and / or cMet appear to be associated with amivantamab TGI%.

[0304]

Number

[0305]

Table 20

[0306]

Table 21

[0307] The present invention is not limited to the specific embodiments described herein. Indeed, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to be within the scope of the appended claims.

[0308] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present herein.

Claims

**Claim 1** A method for treating gastric cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a bispecific anti-epidermal growth factor receptor (EGFR) / c-Met antibody. **Claim 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 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. **Claim 3** The method according to claim 2, wherein the first domain that specifically binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met comprises VH of SEQ ID NO: 15 and VL of SEQ ID NO:

16. **Claim 4** The method according to claim 2 or 3, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. **Claim 5** The method according to any one of claims 1 to 4, wherein the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO:

20. **Claim 6** The method according to any one of claims 1 to 5, wherein the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure having a fucose content of about 1% to about 15%. **Claim 7** The method according to any one of claims 1 to 6, wherein the bispecific anti-EGFR / c-Met antibody is administered to the subject intravenously or subcutaneously. **Claim 8** The method according to claim 7, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 3400 mg. **Claim 9** The method according to claim 8, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, 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, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2100 mg, 2200 mg, 2240 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3360 mg, or 3400 mg.

10. The method according to claim 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg.

11. The method according to claim 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

12. The method according to claim 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1600 mg.

13. The method according to claim 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1750 mg.

14. The method according to claim 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg.

15. The method according to claim 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg.

16. The method according to claim 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg.

17. The method according to claim 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg.

18. The method according to any one of claims 9 to 17, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject.

19. The method according to any one of claims 9 to 17, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject.

20. The method according to any one of claims 1 to 19, wherein the bispecific anti-EGFR / c-Met antibody is administered once every two weeks, once a week, once every two weeks, once every three weeks, or once every four weeks.

21. The method according to claim 20, wherein the bispecific anti-EGFR / c-Met antibody is administered once a week for 4 weeks and then once every two weeks.

22. The method according to claim 21, wherein the first dose of the bispecific anti-EGFR / c-Met antibody is administered over 2 days.

23. The method according to any one of claims 1 to 22, wherein one or more cells of the gastric cancer express EGFR and / or cMet.

24. The method according to any one of claims 1 to 23, wherein the subject has been previously treated.

25. The method according to claim 24, wherein the previous treatment includes chemotherapy, targeted therapy, immunotherapy, surgery, radiotherapy, chemoradiotherapy, or a combination thereof.

26. The method according to claim 25, wherein the chemotherapy includes fluoropyrimidine-based chemotherapy, platinum-based chemotherapy, paclitaxel, irinotecan, or a combination thereof.

27. The method according to claim 26, wherein the fluoropyrimidine is 5-fluorouracil or capecitabine.

28. The method according to claim 26, wherein the platinum-based chemotherapy is cisplatin, oxaliplatin, carboplatin, or nedaplatin.

29. The method according to claim 25, wherein the targeted therapy includes anti-HER2 therapy or anti-VEGF / VEGFR therapy.

30. The method according to claim 29, wherein the anti-HER2 therapy includes trastuzumab.

31. The method according to claim 30, wherein the anti-VEGF / VEGFR therapy includes bevacizumab or ramucirumab.

32. The method according to any one of claims 1 to 23, wherein the subject is treatment-naive.

33. The method according to any one of claims 1 to 32, further comprising administering at least one additional therapeutic agent to the subject.

34. wherein the additional therapeutic agent comprises a glucocorticosteroid, an antihistamine, an antipyretic, an H ２ - antagonist, an antiemetic, an opioid, or any combination thereof, the method according to claim 33.

35. The method according to any one of claims 1 to 34, wherein the gastric cancer is advanced cancer or metastatic cancer.

36. The method according to any one of claims 1 to 35, wherein the subject is human.

37. A method for treating esophageal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific anti-epidermal growth factor receptor (EGFR) / c-Met antibody.

38. The method according to claim 37, 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, and the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the second domain that binds to c-Met comprises an HCDR1 of SEQ ID NO: 7, an HCDR2 of SEQ ID NO: 8, an HCDR3 of SEQ ID NO: 9, an LCDR1 of SEQ ID NO: 10, an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO:

12.

39. The method according to claim 38, wherein the first domain that specifically binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO:

16.

40. The method according to claim 38 or 39, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

41. The method according to any one of claims 37 to 40, wherein the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO:

20.

42. The method according to any one of claims 37 to 41, wherein the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of about 1% to about 15%.

43. The method according to any one of claims 37 to 42, wherein the bispecific anti-EGFR / c-Met antibody is administered to the subject intravenously or subcutaneously.

44. The method according to claim 43, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 3400 mg.

45. The method according to claim 44, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, 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, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2100 mg, 2200 mg, 2240 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3360 mg, or 3400 mg.

46. The method according to claim 45, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg.

47. The method according to claim 45, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

48. The method according to claim 45, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1600 mg.

49. The method according to claim 45, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1750 mg.

50. The method according to claim 45, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg.

51. The method according to claim 45, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg.

52. The method according to claim 45, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg.

53. The method according to claim 45, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg.

54. The method according to any one of claims 37 to 53, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject.

55. The method according to any one of claims 46 to 53, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject.

56. The method according to any one of claims 37 to 55, wherein 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.

57. The method according to claim 56, wherein the bispecific anti-EGFR / c-Met antibody is administered once a week for 4 weeks and then once every two weeks.

58. The method according to claim 57, wherein the first dose of the bispecific anti-EGFR / c-Met antibody is administered over 2 days.

59. The method according to any one of claims 37 to 58, wherein one or more cells of the esophageal cancer express EGFR and / or c-Met.

60. The method according to any one of claims 37 to 59, wherein the subject has been previously treated.

61. The method according to claim 60, wherein the previous treatment includes chemotherapy, targeted therapy, immunotherapy, surgery, radiotherapy, chemoradiotherapy, or a combination thereof.

62. The method according to claim 61, wherein the chemotherapy includes fluoropyrimidine-based chemotherapy, platinum-based chemotherapy, paclitaxel, irinotecan, or a combination thereof.

63. The method according to claim 62, wherein the fluoropyrimidine is 5-fluorouracil or capecitabine.

64. The method according to claim 62, wherein the platinum-based chemotherapy is cisplatin, oxaliplatin, carboplatin, or nedaplatin.

65. The method according to claim 61, wherein the targeted therapy includes anti-HER2 therapy or anti-VEGF / VEGFR therapy.

66. The method according to claim 65, wherein the anti-HER2 therapy includes trastuzumab.

67. The method according to claim 65, wherein the anti-VEGF / VEGFR therapy includes bevacizumab or ramucirumab.

68. The method according to any one of claims 37 to 59, wherein the subject is treatment-naive.

69. The method according to any one of claims 37 to 68, further comprising administering at least one additional therapeutic agent to the subject.

70. wherein the additional therapeutic agent is a glucocorticosteroid, an antihistamine, an antipyretic, an H ２ - antagonist, an antiemetic, an opioid, or any combination thereof, the method according to claim 69.

71. The method according to any one of claims 37 to 70, wherein the esophageal cancer is advanced cancer or metastatic cancer.

72. The method according to any one of claims 37 to 71, wherein the subject is human.

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