Treatment of gastric or esophageal cancer using anti-EGFR / anti-Met antibodies

Abstract

The present disclosure provides methods of 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

[0001] Reference sequence listing submitted electronically

[0002] The sequence listing of the present application is submitted electronically as an XML formatted sequence listing via the United States Patent and Trademark Center Patent Center, with a file name of "JBI6733WOPCT1SEQLIST.xml", a creation date of June 28, 2023, and a size of 20 kilobytes (KB). The submitted sequence listing is part of the present specification and is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to methods of treating gastric or esophageal cancer with a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody. Background Art

[0004] Cancer is the leading cause of death worldwide. Gastric cancer (GC) is the fifth most common cancer worldwide, and more than one million new cases were reported worldwide in 2018. GC is highly prevalent in Asian countries, accounting for approximately 75% of new cases in 2018, and is the third most common (male) / fourth most common (female) cancer in Japan. Most patients present with adenocarcinoma histology. Treatment options depend on the type of cancer (e.g., histology), the stage of the cancer at diagnosis, and the presence or absence of molecular biomarkers (e.g., human epidermal growth factor receptor 2 (HER2) amplification, programmed death ligand 1 (PD-L1) expression, and microsatellite instability). Treatment typically 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 typically includes a fluoropyrimidine plus cisplatin or oxaliplatin plus trastuzumab (depending on HER2 status). The observed overall response rates to guideline-recommended initial therapy vary widely (e.g., in Japan, overall response rates range from 35% to 68% for combination therapy with an oral fluoropyrimidine (S-1) (Bang 2010; Kurokawa 2014)). Available treatment options after first-line treatment are limited. The NCCN recommendations are chemotherapy as a single agent, ramucirumab plus paclitaxel, immune checkpoint inhibitors, or fluorouracil plus irinotecan. However, overall response rates to second- and third-line treatment are limited, and median progression-free survival is very low.

[0005] Esophageal cancer (EC) is the eighth most common cancer worldwide and ranked sixth in mortality among all cancers 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 main histologies of primary EC. However, the predominant EC histology varies between geographic regions. The predominant histology observed in the Caucasian population is adenocarcinoma, while squamous histology is predominant in Asian countries. Treatment generally includes surgery, radiotherapy, chemoradiotherapy, and chemotherapy. Due to the nature of histological similarities, the NCCN guideline recommendations for first-line therapy are the same as for GC regimens (NCCN Guidelines 2020). Clinical data for esophageal squamous cell carcinoma as the predominant histology in Asian countries are mainly limited to phase 2 studies. The reported overall response rate of chemotherapy as a single agent is 15%-40%. Other recommended treatments include fluorouracil plus cisplatin and the PD-(L)1 inhibitor, pembrolizumab. However, the observed overall response rates to these therapies are quite limited.

[0006] Therefore, there is an unmet need in the art for improved therapies for treating gastric or esophageal cancer. Summary of the invention

[0007] In various aspects, provided herein are methods of treating gastric cancer or esophageal cancer in a subject in need thereof, the methods 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.

[0008] 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.

[0009] 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 complementary determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementary determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; and wherein 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.

[0010] In some embodiments of the method for treating gastric cancer, 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.

[0011] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is of IgG1 isotype.

[0012] 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.

[0013] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure having a fucose content of between about 1% and about 15%.

[0014] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is administered intravenously or subcutaneously to the subject.

[0015] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 350 mg to about 3400 mg.

[0016] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is administered at 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.

[0017] 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.

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

[0019] In some embodiments of the method for treating gastric cancer, the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously at a dose sufficient to achieve a therapeutic effect in the subject.

[0020] 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 once every two weeks thereafter. In some embodiments, the first dose of the bispecific anti-EGFR / c-Met antibody is administered within two days.

[0021] In some embodiments of the method for treating gastric cancer, one or more cells of the gastric cancer express EGFR and / or cMet.

[0022] In some embodiments of the method for treating gastric cancer, the subject has received previous treatment. In some embodiments, previous treatment includes chemotherapy, targeted therapy, immunotherapy, surgery, radiotherapy, chemoradiotherapy, or a combination thereof. In some embodiments, chemotherapy includes fluoropyrimidine-based chemotherapy, platinum-based chemotherapy, paclitaxel, irinotecan, or a combination thereof. In some embodiments, fluoropyrimidine is 5-fluorouracil or capecitabine. In some embodiments, platinum-based chemotherapy is cisplatin, oxaliplatin, carboplatin, or nedaplatin. In some embodiments, targeted therapy includes anti-HER2 therapy or anti-VEGF / VEGFR therapy. In some embodiments, anti-HER2 therapy includes trastuzumab. In some embodiments, anti-VEGF / VEGFR therapy includes bevacizumab or ramucirumab.

[0023] In some embodiments of the method for treating gastric cancer, the method further comprises administering to the subject at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises a glucocorticoid, an antihistamine, an antipyretic, an H2-antagonist, an antiemetic, an opiate, or any combination thereof.

[0024] In some embodiments of the method for treating gastric cancer, the gastric cancer is an advanced or metastatic cancer.

[0025] In some embodiments of the method for treating gastric cancer, the subject is a human.

[0026] In one aspect, the present disclosure provides a method of treating esophageal 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.

[0027] 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 a heavy chain complementary determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementary determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; and wherein the second domain that binds to c-Met comprises a HCDR1 of SEQ ID NO: 7, a HCDR2 of SEQ ID NO: 8, a HCDR3 of SEQ ID NO: 9, a LCDR1 of SEQ ID NO: 10, a LCDR2 of SEQ ID NO: 11, and a LCDR3 of SEQ ID NO: 12.

[0028] In some embodiments of the method for treating esophageal cancer, 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.

[0029] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is of IgG1 isotype.

[0030] In some embodiments of the method for treating esophageal 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.

[0031] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure having a fucose content of between about 1% and about 15%.

[0032] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is administered intravenously or subcutaneously to the subject.

[0033] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 350 mg to about 3400 mg.

[0034] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is administered at 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.

[0035] 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.

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

[0037] In some embodiments of the method for treating esophageal cancer, the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously at a dose sufficient to achieve a therapeutic effect in the subject.

[0038] 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 once every two weeks thereafter. In some embodiments, the first dose of the bispecific anti-EGFR / c-Met antibody is administered within two days.

[0039] In some embodiments of the method for treating esophageal cancer, one or more cells of the esophageal cancer express EGFR and / or cMet.

[0040] In some embodiments of the method for treating esophageal cancer, the subject has received previous treatment. In some embodiments, previous treatment includes chemotherapy, targeted therapy, immunotherapy, surgery, radiotherapy, chemoradiotherapy, or a combination thereof. In some embodiments, chemotherapy includes fluoropyrimidine-based chemotherapy, platinum-based chemotherapy, paclitaxel, irinotecan, or a combination thereof. In some embodiments, fluoropyrimidine is 5-fluorouracil or capecitabine. In some embodiments, platinum-based chemotherapy is cisplatin, oxaliplatin, carboplatin, or nedaplatin. In some embodiments, targeted therapy includes anti-HER2 therapy or anti-VEGF / VEGFR therapy. In some embodiments, anti-HER2 therapy includes trastuzumab. In some embodiments, anti-VEGF / VEGFR therapy includes bevacizumab or ramucirumab.

[0041] In some embodiments of the method for treating esophageal cancer, the subject is treatment naive.

[0042] In some embodiments of the method for treating esophageal cancer, the method further comprises administering to the subject at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is a glucocorticoid, an antihistamine, an antipyretic, an H2-antagonist, an antiemetic, an opiate, or any combination thereof.

[0043] In some embodiments of the method for treating esophageal cancer, the esophageal cancer is an advanced or metastatic cancer.

[0044] In some embodiments of the methods for treating esophageal cancer, the subject is a human. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 One aspect of the Phase 2 study described in Example 1 is depicted.

[0046] Figures 2A to 2L Shown are tumor growth curves over time in a series of esophageal patient-derived xenograft (PDX) models (expressed as mean ± SEM).

[0047] FIG. 3A to FIG. 3F Shown are tumor growth curves over time in a series of gastric PDX models (expressed as mean ± SEM).

[0048] Figure 4 Relative EGFR and c-Met H scores and antitumor activity of ivanovumab in a series of esophageal PDX models are shown.

[0049] Figure 5 Relative EGFR and c-Met H scores and antitumor activity of ivanovumab in a series of gastric PDX models are shown.

[0050] Figure 6 The overall response of gastric cancer patients in the response-evaluable population is shown.

[0051] Figure 7 The overall response of gastric cancer patients in all treated groups is shown.

[0052] Figure 8 Shown are the overall responses of esophageal cancer patients in the response-evaluable population.

[0053] Fig. 9 The overall response of patients with esophageal cancer in all treated groups is shown.

[0054] Fig.10 Overall responses for esophageal cancer in patients treated with 1750 mg of evitumomab in the response-evaluable population are shown. DETAILED DESCRIPTION

[0055] Receptor tyrosine kinases (RTKs) are involved in the regulation of many processes in mammalian development, cellular function, and tissue homeostasis. Dysregulation of RTKs is associated with the development of many human cancers, and various RTKs are targets of approved and experimental anticancer therapies.

[0056] Epidermal growth factor receptor (EGFR), an RTK in the HER family, is normally expressed in tissues of epithelial, mesenchymal, and neuronal origin. Binding of any of its seven ligands, including EGF, induces a variety of cellular responses, including differentiation, proliferation, migration, and survival (Olayioye 2000). Mesenchymal-epithelial transition factor (cMet or MET) receptor is also an RTK expressed in normal epithelial cells (Prat 1991), where it plays a role 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).

[0057] Overexpression and mutation of EGFR and cMet receptors are associated with tumorigenesis 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% to 70% and 45% to 70% of esophageal cancer (EC) patients express EGFR or cMet, respectively (Hanawa 2006; Gibault 2005). Expression of EGFR or cMet has been considered a poor prognostic factor in GC (Aydin 2014; Gao 2013; Galizia 2007; Atmaca 2012; Fuse 2016) and EC (Wang 2007; Brand 2011; Ozawa 2015).

[0058] Although a number of agents targeting EGFR, including anti-EGFR antibodies and EGFR tyrosine kinase inhibitors (TKIs), have been used as standard of care for many cancers, including colorectal cancer, non-small cell lung cancer (NSCLC), and head and neck cancer, no EGFR-directed therapies are available for gastric cancer or EC. Previous studies have failed to show the efficacy of cetuximab and panitumumab (anti-EGFR antibodies) for the treatment of GC, or the efficacy of gefitinib (EGFR tyrosine kinase inhibitor) for the treatment of EC in non-biomarker selected populations (Lordick 2013; Waddell 2013; Dutton 2014). A recent study evaluating nimotuzumab, an anti-EGFR antibody, in combination with irinotecan in GC patients with EGFR expression has also been unsuccessful (Satoh 2015). There is less clinical experience with cMet-targeted therapies. Studies evaluating the efficacy of rilotumumab or onatumumab, anti-cMet antibodies, in GC have failed to show clinical benefit.

[0059] The present disclosure provides methods and compositions that can be used to treat gastric or esophageal cancer by targeting both EGFR and cMet.

[0060] definition

[0061] It should be understood that the terminology used herein is only for describing specific embodiments and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs.

[0062] Although any methods and materials similar or equivalent to those described herein can be used in the practice of testing the present invention, exemplary materials and methods are described herein.In describing and claiming the present invention, the following terminology will be used.

[0063] When a list is provided, it is understood that each individual element in the list and each combination of the list is a separate embodiment unless otherwise indicated. For example, a list of embodiments presented as "A, B, or C" will be understood to include embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0064] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and so forth.

[0065] The connection term "and / or" between multiple listed elements is understood to cover both single options and combined options. For example, where two elements are connected by "and / or", the first option refers to the application of the first element without the second element. The second option refers to the application of the second element without the first element. The third option refers to the application of the first element and the second element together. Any of these options is understood to fall within the meaning and therefore meets the requirements of the term "and / or" as used herein. The parallel applicability of more than one option is also understood to fall within the meaning and therefore meets the requirements of the term "and / or".

[0066] The transitional terms "comprising," "consisting essentially of," and "consisting of" are intended to suggest their recognized meanings in patent parlance; that is, (i) "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) "consisting of" excludes any element, step, or ingredient not specified in the claim; and (iii) "consisting essentially of" limits the scope of the claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristics of the claimed invention." Embodiments described with the phrase "comprising" (or its equivalent) are also provided, as are those embodiments described independently with "consisting of" and "consisting essentially of."

[0067] "Co-administration," "administered together with," "administered in combination with," "in combination with," and the like encompass administration of selected therapeutics or drugs to a single patient, and are intended to include treatment regimens in which these therapeutics or drugs are administered by the same or different routes of administration or at the same or different times.

[0068] "Treating" a disease or disorder such as cancer means achieving one or more of the following: reducing the severity and / or reducing the duration of the disorder, inhibiting the progression of symptoms characteristic of the disorder being treated, limiting or preventing the recurrence of the disorder in a subject previously suffering from the disorder, or limiting or preventing the recurrence of symptoms in a subject previously experiencing symptoms of the disorder.

[0069] "Preventing" a disease or disorder means preventing the disorder from occurring in a subject.

[0070] "Response," "responsiveness," or "likely to respond" refers to any type of improvement or positive response, such as alleviation or amelioration of one or more symptoms, reduction in extent of disease, stabilization of the disease state (i.e., not worsening), prevention of spread of disease, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.

[0071] A "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic outcome at the required dosage and time period. The therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improvement in the patient's health status, reduction or shrinkage of the size of a tumor, arrest or slowing of tumor growth, and / or the absence of metastasis of cancer cells to other parts of the body.

[0072] "Refractory" refers to a disease that does not respond to treatment. A refractory disease can be resistant to treatment before or at the start of treatment, or a refractory disease can become resistant during treatment.

[0073] "Relapse" refers to the reappearance of a disease or signs and symptoms of a disease after a period of improvement following previous treatment with a therapeutic agent.

[0074] "Subject" includes any human or non-human animal. "Non-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.

[0075] "About" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular assay, result, or embodiment, unless expressly stated otherwise in the embodiment or elsewhere in the specification, "about" means within one standard deviation or up to a range of 5% (whichever is greater) according to common practice in the art.

[0076] "Cancer" refers to an abnormal growth of cells that tend to multiply in an uncontrolled manner and, in some cases, metastasize (spread) to other areas of the patient's body.

[0077] "Cancer expressing EGFR or c-Met or MET" refers to a cancer with detectable EGFR or c-Met expression or with EGFR or c-Met mutation or amplification. EGFR or c-Met expression, amplification and mutation status can be detected using known methods, such as sequencing, fluorescent in situ hybridization, immunohistochemistry, flow cytometry or Western blot.

[0078] "Epidermal growth factor receptor" or "EGFR" refers to human EGFR (also known as HER1 or ErbBl (Ullrich et al., Nature 309:418-425, 1984)) having the amino acid sequence set forth in GenBank Accession No. NP_005219, and naturally occurring variants thereof.

[0079] 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 No. NP_001120972 and its natural variants.

[0080] "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 generally a VH / VL pair, and the bispecific anti-EGFR / c-Met antibody is monovalent in binding to EGFR and c-Met.

[0081] "Specific binding" or "specifically binds" or "binding" refers to the binding of an antibody to an antigen or an epitope within an antigen with a higher affinity than for other antigens. Typically, an antibody binds to an antigen or an epitope within an antigen with an equilibrium dissociation constant (K D ) is about 5x10 -8 M or lower, such as about 1x10 -9 M or lower, about 1x10 -10 M or lower, about 1x10-11 M or lower, or about 1x10 -12 M or lower, usually K D Compared with its K binding to non-specific antigens (such as BSA, casein) D The dissociation constant can be measured using known protocols. However, antibodies that bind to an antigen or an epitope within an antigen may have cross-reactivity to other related antigens, for example, to the same antigen from other species (homologous) (such as humans or monkeys, for example, cynomolgus (Macacafascicularis) (cynomolgus, cyno) or chimpanzee (Pan troglodytes) (chimpanzee, chimp). Monospecific antibodies bind to one antigen or one epitope, while bispecific antibodies bind to two different antigens or two different epitopes.

[0082] "Antibody" refers to and includes immunoglobulin molecules in a broad sense, including monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific antibodies, trispecific antibodies, tetraspecific antibodies, etc.), dimers, tetramers or multimers, single-chain antibodies, domain antibodies, and any other modified configurations of immunoglobulin molecules containing antigen-binding sites with desired specificity. "Full-length antibodies" are composed of two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds, and their multimers (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 the VL region can be further subdivided into hypervariable regions, which are called complementarity determining regions (CDRs) and are interspersed with framework regions (FRs). Each VH and VL is composed of three CDR and four FR segments, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0083] "Complementarity determining region" (CDR) is the region of an antibody that binds an antigen. CDRs can be defined using various delineations, such as 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 various delineations and variable region numbers is described (see, e.g., Lefranc et al., (2003) Dev Comp Immunol 27:55-77; Honegger and Pluckthun (2001), J Mol Biol 309:657-70; International ImMunoGeneTics (IMGT) database; web resource http: / / imgt_org). Available programs (such as abYsis of UCL Business PLC) can be used to delineate CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms "CDR", "HCDR1", "HCDR2", "HCDR3", "LCDR1", "LCDR2" and "LCDR3" include CDRs defined by any of the above methods (Kabat, Chothia, IMGT or AbM).

[0084] Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG, and IgM, based on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subclassified into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chains of any vertebrate species can be assigned to one of two distinct types, kappa and lambda, based on the amino acid sequence of their constant domains.

[0085] "Antigen binding fragment" refers to the part of an immunoglobulin molecule that binds to an antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and contain VH, VL, VH and VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAbs) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camel-humped VH domains, minimal recognition units consisting of amino acid residues that mimic antibody CDRs such as FR3-CDR3-FR4 portions, HCDR1, HCDR2 and / or HCDR3, and LCDR1, LCDR2 and / or LCDR3. The VH and VL domains can be linked together via synthetic linkers to form various types of single-chain antibody designs, in which the VH and VL domains are expressed by separate single-chain antibody constructs, and 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; for example, as described in International Patent Publication Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804, and WO1992 / 01047.

[0086] "Monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., the individual antibodies comprising the population are identical, except for possible well-known changes, such as removal of the C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation. Monoclonal antibodies generally bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monospecific or multispecific, such as bispecific, monovalent, bivalent or multivalent.

[0087] "Recombinant" refers to DNA, antibodies and other proteins that are prepared, expressed, formed or isolated by recombinant means when fragments from different sources are joined to produce a recombinant DNA, antibody or protein.

[0088] "Bispecific" refers to an antibody that specifically binds to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may have cross-reactivity to other related antigens, for example, to the same antigen from other species (homologous) such as humans or monkeys, e.g., cynomolgus (cynomolgus, cyno) or chimpanzees (Pantroglodytes), or may bind to epitopes shared between two or more different antigens.

[0089] An "antagonist" or "inhibitor" refers to a molecule that, when bound to a cellular protein, inhibits at least one reaction or activity induced by the protein's natural ligand. A molecule is an antagonist when the at least one reaction or activity is inhibited by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one reaction or activity inhibited in the absence of the antagonist (e.g., a negative control), or when the inhibition is statistically significant compared to the inhibition in the absence of the antagonist.

[0090] "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.

[0091] As used in this application, "low fucose" or "low fucose content" means that the fucose content of the antibody is about 1%-15%.

[0092] 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%.

[0093] Methods of the present disclosure

[0094] One aspect of the present disclosure provides a method of treating gastric cancer or esophageal 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.

[0095] In some embodiments, 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.

[0096] Gastric cancer as referred to herein also includes esophagogastric junction (GEJ) cancer. In some embodiments, gastric cancer is adenocarcinoma. In some embodiments, gastric cancer is advanced or metastatic cancer. For example, gastric cancer may have metastasized to the esophagus, small intestine, lymph nodes, organs, bones, or a combination thereof.

[0097] In some embodiments, the present disclosure provides a method of treating esophageal 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.

[0098] 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 an advanced or metastatic cancer. For example, the esophageal cancer may have metastasized to the lungs, small intestine, lymph nodes, organs, bones, or a combination thereof.

[0099] In some embodiments, the subject has received prior treatment. Prior treatment may include chemotherapy, targeted therapy, immunotherapy, surgery, radiotherapy, chemoradiotherapy, or a combination thereof.

[0100] In some embodiments, the chemotherapy is a fluoropyrimidine-based chemotherapy, such as 5-fluorouracil or capecitabine.

[0101] In some embodiments, the chemotherapy is a platinum-based chemotherapy. Exemplary platinum-based chemotherapy include, but are not limited to, cisplatin, oxaliplatin, carboplatin, or nedaplatin.

[0102] Additional examples of chemotherapy may include taxanes (eg, paclitaxel, docetaxel), topoisomerase inhibitors (eg, irinotecan, camptothecin), or combinations thereof.

[0103] In some embodiments, the targeted therapy is an anti-HER2 therapy or an 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.

[0104] In some embodiments, the prior treatment includes immunotherapy, such as a checkpoint inhibitor. In some embodiments, the immunotherapy includes a PD-(L)1 axis inhibitor or a CTLA-4 inhibitor. Non-limiting examples of PD-(L)1 axis inhibitors include atezolizumab, nivolumab, pembrolizumab, camrelizumab, and tislelizumab. Non-limiting examples of CTLA-4 inhibitors include ipilimumab.

[0105] In some embodiments, the prior treatment comprises anti-VEGF / VEGFR therapy. Non-limiting examples of anti-VEGF / VEGFR therapy include bevacizumab and ramucirumab.

[0106] In some embodiments, prior treatment included a fluoropyrimidine and cisplatin.

[0107] In some embodiments, prior treatment included oxaliplatin and trastuzumab.

[0108] In some embodiments, prior treatment included ramucirumab and paclitaxel.

[0109] In some embodiments, prior treatment included fluorouracil and irinotecan.

[0110] In some embodiments, prior treatment included fluorouracil and cisplatin.

[0111] In some embodiments, the subject is treatment naive.

[0112] In some embodiments, one or more cells of gastric cancer or esophageal cancer express EGFR and / or cMet. EGFR or c-Met expression can be detected using known methods, such as fluorescent in situ hybridization, immunohistochemistry (IHC), flow cytometry, or Western blot.

[0113] In some embodiments, the expression of EGFR and / or cMet is detected using immunohistochemistry (IHC), which measures the level of EGFR and / or cMet protein on the cell surface. As a non-limiting example, the alpha membrane staining intensity score (0, 1+, 2+, or 3+) of each cell can be determined in a fixed field of view. Tumor samples can be fixed in formalin-fixed paraffin-embedded (FFPE).

[0114] In some embodiments, a subject receiving the bispecific anti-EGFR / c-Met antibody has a staining intensity score of 1+ or above based on EGFR and / or cMet expression in a tumor sample obtained from the subject as determined by IHC assay.

[0115] In some embodiments, the subject receiving the bispecific anti-EGFR / c-Met antibody has a staining intensity score of 2+ or above based on EGFR and / or cMet expression in a tumor sample obtained from the subject as determined by IHC assay.

[0116] In some embodiments, the subject receiving the bispecific anti-EGFR / c-Met antibody has a staining intensity score of 3+ based on EGFR and / or cMet expression in a tumor sample obtained from the subject as determined by IHC assay.

[0117] In some embodiments, an H score (or tissue score) can be assigned to a tumor sample as a semi-quantitative method for analyzing immunohistochemical results (Hirsch FR et al., J Clin Oncol 21: 3798-3807, 2003; John T et al., Oncogene 28: S14-S23, 2009, the entire text is incorporated herein by reference). In some embodiments, the H score can be based on the main 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 the following exemplary formula can be used to assign the H score: [1×(% cell 1+)+2×(% cell 2+)+3×(% cell 3+)]. In a given tumor sample, the final calculated H score (ranging from 0 to 300) can give a higher relative weight to high-intensity membrane staining. In some embodiments, based on a specific discrimination threshold, a tumor sample can be considered positive or negative.

[0118] In some embodiments, a "combined H-score" can be generated by adding an H-score calculated from analysis of one biomarker (e.g., EGFR expression) to an H-score calculated from analysis of a second biomarker (e.g., MET expression). Thus, the combined H-score can have a range of 0 to 600.

[0119] Application

[0120] The bispecific anti-EGFR / c-Met antibodies can be administered in a pharmaceutically acceptable carrier. "Carrier" refers to a diluent, adjuvant, excipient or vehicle with which the antibodies of the present invention are administered. Such vehicles can be liquids, such as water and oils, including those derived from petroleum, animals, plants or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. For example, 0.4% saline and 0.3% glycine can be used to formulate bispecific anti-EGFR / c-Met antibodies. These solutions are sterile and generally free of particulate matter. They can be sterilized by conventional, well-known sterilization techniques (e.g., filtration). For parenteral administration, the carrier may include sterile water, and other excipients may be added to increase solubility or preservatives. Injectable suspensions or solutions can also be prepared using water-based carriers together with suitable additives. For subcutaneous administration, recombinant human hyaluronidase, such as rHuPH20 (CAS Reg. No. 757971-58-7), can be used. Suitable vehicles and formulations including other human proteins (e.g., human serum albumin) are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp. 691-1092 (see especially pp. 958-989).

[0121] The administration mode can be any suitable route for delivering the bispecific anti-EGFR-c-Met antibody to the host, such as parenteral administration, for example, intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, transmucosal (oral, intranasal, vaginal, rectal), using tablets, capsules, solutions, powders, gels, granules; and contained in syringes, implants, osmotic pumps, boxes, mini pumps; or other means well known in the art as understood by the skilled person. Site-specific administration can be achieved, for example, by the following means: intratumoral, parenteral, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracavitary, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intracardiac, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intravesical, intralesional, vaginal, rectal, oral, sublingual, intranasal or transdermal delivery.

[0122] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously. Exemplary intravenous formulations are disclosed in U.S. Patent Application Publication No. US2022 / 0064307 A1.

[0123] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to a 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. Exemplary subcutaneous formulations are disclosed in U.S. Patent Application Publication No. US 2022 / 0395573A1.

[0124] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 140 mg to about 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 350 mg to about 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 350 mg to about 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 350 mg to about 3340 mg.

[0125] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1010mg, about 1020mg, about 1030mg, about 1040mg, about 1050mg, about 1060mg, about 1070mg, about 1080mg, about 1090mg, about 1100mg, about 1110mg, about 1120mg, about 1130mg, about 1140mg, about 1150mg, about 1160mg, about 1170mg, about 1180mg, about 1190mg , about 1200mg, about 1210mg, about 1220mg, about 1230mg, about 1240mg, about 1250mg, about 1260mg, about 1270mg, about 1280mg, about 1290mg, about 1300mg, about 1310mg, about 1320mg, about 1330mg, about 1340mg, about 1350mg, about 1360mg, about 1370mg, about 1380mg, about 1390mg, about 1400mg, about 1410mg, about 1420mg, about 1430mg, about 1440mg, about 1450mg, about 1460mg, about 1470mg, about 1480mg, about 1490mg, about 1500mg,About 1510mg, about 1520mg, about 1530mg, about 1540mg, about 1550mg, about 1560mg, about 1570mg, about 1580mg, about 1590mg, about 1600mg, about 1610mg, 1620mg, about 1630mg, about 1640mg, about 1650mg, about 1660mg, about 1670mg, about 1680mg, about 1690mg, about 1700mg, about 1710mg, about 1720mg, about 1730mg, about 1740mg, about 1750mg, about 1760mg, about 1770mg, about 1780mg, about 1790mg, about 1800mg, about 1810mg, about 1820mg, about 1830mg, about 1840mg, about 1850mg, about 1860mg, about 1870mg, about 1880mg, 1890mg, about 1900mg, about 1910mg, about 1920mg, about 1930mg, about 1940mg, about 19 50mg, about 1960mg, about 1970mg, about 1980mg, about 1990mg, about 2000mg, about 2010mg, about 2020mg, about 2030mg, about 2040mg, about 2050mg, about 2060mg, about 2070mg, about 2080mg, about 2090mg, about 2100mg, about 2110mg, about 2120mg, about 2130mg, about 2140mg, about 2150mg, about 2160mg, about 217 0 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.

[0126] 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.

[0127] In some embodiments, if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. In some embodiments, even if the subject has a body weight of greater than or equal to 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg.

[0128] In some embodiments, if the subject has a body weight greater than or equal to 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

[0129] 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 about 1050 mg once a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered about 1400 mg once a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered about 1600 mg once a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered about 1750 mg once a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered about 2100 mg once a week.

[0130] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered biweekly. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered about 1050 mg every two weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered about 1400 mg once every two weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered about 1600 mg once every two weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered about 1750 mg once every two weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered about 2100 mg once every two weeks.

[0131] In some embodiments, if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1575 mg. In some embodiments, if the subject has a body weight of greater than or equal to 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg.

[0132] In some embodiments, if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1600 mg. In some embodiments, if the subject has a body weight of greater than or equal to 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered weekly for the first 4 weeks and once every 2 weeks thereafter.

[0133] In some embodiments, if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg. In some embodiments, if the subject has a body weight of greater than or equal to 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered weekly for the first 3 weeks and once every 3 weeks thereafter.

[0134] 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.

[0135] 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.

[0136] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week for four weeks and once every two weeks thereafter.

[0137] 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 can be divided into two days, i.e., day 1 (350 mg) and day 2 (700 mg if body weight <80 kg, or 1,050 mg if body weight ≥80 kg).

[0138] 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, an antihistamine, an antipyretic, an H2-antagonist, an antiemetic, an opiate, or any combination thereof.

[0139] In some embodiments, the at least one additional therapeutic agent is administered prior to one or more therapeutic doses.

[0140] In some embodiments, the glucocorticoid is dexamethasone, beclomethasone, betamethasone, budesonide, cortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone or triamcinolone. In some embodiments, the glucocorticoid is dexamethasone or methylprednisolone. For example, the glucocorticoid is dexamethasone (10 mg) or methylprednisolone (40 mg).

[0141] Glucocorticoids (e.g., dexamethasone, methylprednisolone) can be administered intravenously (IV) approximately 45 minutes to 60 minutes prior to administration of the bispecific anti-EGFR / c-Met antibody. Alternatively, glucocorticoids (e.g., dexamethasone, methylprednisolone) can be administered orally 60 minutes to 90 minutes prior to administration of the bispecific anti-EGFR / c-Met antibody.

[0142] 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 mg to 50 mg) or an equivalent.

[0143] In some embodiments, the antihistamine is administered orally about 30 to 60 minutes prior to administration of the bispecific anti-EGFR / c-Met antibody. In some embodiments, the antihistamine is administered intravenously about 15 minutes to 30 minutes prior to administration of the bispecific anti-EGFR / c-Met antibody.

[0144] 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.

[0145] In some embodiments, the antipyretic drug is administered intravenously about 15 minutes to 30 minutes prior to administration of the bispecific anti-EGFR / c-Met antibody orally about 30 minutes to 60 minutes prior to administration of the bispecific anti-EGFR / c-Met antibody.

[0146] 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.

[0147] In some embodiments, the H2-antagonist drug is administered intravenously about 15 minutes to 30 minutes prior to administration of the bispecific anti-EGFR / c-Met antibody, or orally about 60 minutes prior to administration of the bispecific anti-EGFR / c-Met antibody.

[0148] 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.

[0149] In some embodiments, the antiemetic is administered intravenously approximately 15 minutes to 30 minutes prior to administration of the bispecific anti-EGFR / c-Met antibody, or orally approximately 15 minutes to 30 minutes prior to administration of the bispecific anti-EGFR / c-Met antibody.

[0150] In some embodiments, at least one additional therapeutic agent described herein is administered after one or more therapeutic doses. If clinically indicated, the at least one additional therapeutic agent may be administered up to 48 hours after the one or more therapeutic doses.

[0151] As a non-limiting example, if necessary, a glucocorticoid (e.g., dexamethasone (10 mg)), an antihistamine (e.g., diphenhydramine (25 mg to 50 mg)), an antipyretic (e.g., acetaminophen (650 mg to 1,000 mg)), and / or an opiate (e.g., meperidine (25 mg to 100 mg)) may be administered intravenously or orally after administration of one or more therapeutic doses of the bispecific anti-EGFR / c-Met antibody. In addition, if necessary, an antiemetic may be administered to the subject intravenously (e.g., ondansetron (8 mg to 16 mg)) or orally (e.g., ondansetron (8 mg)) after administration of one or more therapeutic doses.

[0152] Generation of bispecific anti-EGFR / c-Met antibodies

[0153] An exemplary bispecific anti-EGFR / c-Met antibody that can be used in the methods of the present disclosure is entuzumab. entuzumab is an IgG1 anti-EGFR / c-Met bispecific antibody described in U.S. Pat. No. 9,593,164, which is incorporated herein by reference in its entirety.

[0154] Avantamab is a low-fucose, fully human immunoglobulin G1 (IgG1)-based bispecific antibody for EGFR and MET receptors, which shows preclinical activity against tumors with overexpressed wild-type EGFR and MET pathway activation. Unlike EGFR TKIs that bind to the intracellular part of EGFR, Avantamab targets the extracellular domains of both EGFR and MET. Avantamab may have at least 3 potential mechanisms of action, including 1) inhibition of ligand-dependent signal transduction, 2) downregulation of EGFR and MET expression levels, and 3) initiation of antibody-dependent cellular cytotoxicity (ADCC). Avantamab with low levels of fucosylation was produced, which was converted into enhanced ADCC activity. The human FcγIIIa receptor, which is critical for ADCC, binds more tightly to low-fucose antibodies, and thus mediates more powerful and effective ADCC killing of target cancer cells (Satoh, 2006). It was hypothesized that by targeting the extracellular domains of EGFR and MET, evitumomab could inhibit the receptor in patients that display primary resistance to EGFR TKI (exon 20 insertions) or have acquired EGFR resistance mutations (T790M or C797S) or secondary activation of the MET pathway (MET amplification).

[0155] Evantumab is characterized by the following amino acid sequence:

[0156] EGFR binding arm

[0157] >SEQ ID NO: 1 (HCDR1, EGFR binding arm)

[0158] TYGMH

[0159] >SEQ ID NO:2 (HCDR2, EGFR binding arm)

[0160] VIWDDGSYKYYGDSVKG

[0161] >SEQ ID NO:3 (HCDR3, EGFR binding arm)

[0162] DGITMVRGVMKDYFDY

[0163] >SEQ ID NO:4 (LCDR1, EGFR binding arm)

[0164] RASQDISSALV

[0165] >SEQ ID NO:5 (LCDR2, EGFR binding arm)

[0166] DASSLES

[0167] >SEQ ID NO:6 (LCDR3, EGFR binding arm)

[0168] QQFNSYPLT

[0169] >SEQ ID NO:7 (HCDR1, c-Met binding arm)

[0170] SYGIS

[0171] >SEQ ID NO:8 (HCDR2, c-Met binding arm)

[0172] WISAYNGYTNYAQKLQG

[0173] >SEQ ID NO:9 (HCDR3, c-Met binding arm)

[0174] DLRGTNYFDY

[0175] >SEQ ID NO: 10 (LCDR1, c-Met binding arm)

[0176] RASQGISNWLA

[0177] >SEQ ID NO: 11 (LCDR2, c-Met binding arm)

[0178] AASSLS

[0179] >SEQ ID NO: 12 (LCDR3, c-Met binding arm)

[0180] QQANSFPIT

[0181] >SEQ ID NO: 13 (VH, EGFR binding arm)

[0182] QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS

[0183] >SEQ ID NO: 14 (VL, EGFR binding arm)

[0184] AIQLTQSPSSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK

[0185] >SEQ ID NO:15 (VH, c-Met binding arm)

[0186] QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS

[0187] >SEQ ID NO:16 (VL, c-Met binding arm) DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK

[0188] >SEQ ID NO:17 HC1

[0189] QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0190] >SEQ ID NO:18 LC1

[0191] AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0192] >SEQ ID NO:19 HC2

[0193] QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0194] >SEQ ID NO:20LC2

[0195] DIQMTQSPSSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0196] 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 a heavy chain complementary determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementary determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and the second domain comprises a HCDR1 of SEQ ID NO: 7, a HCDR2 of SEQ ID NO: 8, a HCDR3 of SEQ ID NO: 9, a LCDR1 of SEQ ID NO: 10, a LCDR2 of SEQ ID NO: 11, and a LCDR3 of SEQ ID NO: 12.

[0197] 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.

[0198] In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0199] 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.

[0200] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises one or more Fc silent mutations.

[0201] In one embodiment, the one or more Fc silent mutations reduce affinity for an Fc gamma receptor.

[0202] In one embodiment, the one or more Fc silent mutations include V234A / G237A / P238S / H268A / V309L / A330S / P331S.

[0203] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of between about 1% and about 15%. Antibodies with reduced fucose content can be made using different methods reported for successful expression of relatively highly defucosylated antibodies with bibranched complex-type Fc oligosaccharides, such as controlling culture osmotic pressure (Konno et al., Cytotechnology 64(:249-65, 2012), using a variant CHO cell line Lec13 as a host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), using a variant CHO cell line EB66 as a host cell line (Olivier et al., MAbs; 2(4), 2010; Epub ahead of print; PMID: 20562582), using a rat hybridoma cell line YB2 / 0 as a host cell line (Shinkawa et al., J Biol Chem 277:26733-26740, 2002), using a variant CHO cell line EB66 as a host cell line (Olivier et al., MAbs; 2(4), 2010; Epub ahead of print; PMID: 20562582), using a rat hybridoma cell line YB2 / 0 as a host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introduction of small interfering RNA specific for 1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expression of β-1,4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II or potent α-mannosidase I inhibitor kifnoside (Ferrara et al., J Biol Chem 281:5032-5036, 2006, Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Xhou et al., Biotechnol Bioeng 99:652-65, 2008). Generally, reducing the fucose content in the glycans of antibodies enhances antibody-mediated cellular cytotoxicity (ADCC).

[0204] Other bispecific anti-EGFR / c-Met antibodies can also be used in the methods of the present disclosure, provided that they exhibit similar properties when compared to ervantumab, as described in U.S. Pat. No. 9,593, 164. Bispecific anti-EGFR / c-Met antibodies useful 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 antibodies for characteristics as described in U.S. Pat. No. 9,593,164.

[0205] The bispecific anti-EGFR / c-Met antibodies used in the methods of the present disclosure can be produced, for example, using Fab arm exchange (or half-molecule exchange) between two monospecific bivalent antibodies by introducing substitutions at the heavy chain CH3 junction in each half molecule to promote the formation of heterodimers of two antibody half molecules with different specificities in a cell-free environment in vitro or using co-expression. The Fab arm exchange reaction is the result of a disulfide bond isomerization reaction and CH3 domain dissociation-association. The heavy chain disulfide bonds in the hinge region of the parent monospecific antibodies are reduced. The resulting free cysteine ​​of one of the parent monospecific antibodies forms an inter-heavy chain disulfide bond with a cysteine ​​residue of a second parent monospecific antibody molecule, while the CH3 domain of the parent antibody is released and reformed by dissociation-association. The CH3 domain of the Fab arm can be engineered to promote heterodimerization rather than homodimerization. The resulting product is a bispecific antibody with two Fab arms or half molecules that each bind to a different epitope (i.e., an epitope on EGFR and an epitope on c-Met). For example, the bispecific antibodies of the present invention can be produced using the technology described in International Patent Publication No. WO2011 / 131746. In the case of an IgG1 antibody, a mutation F405L in one heavy chain and K409R in another heavy chain can be used. For an IgG2 antibody, wild-type IgG2 and IgG2 antibodies with F405L and R409K substitutions can be used. For an IgG4 antibody, wild-type IgG4 and IgG4 antibodies with F405L and R409K substitutions can be used. In order to produce a 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 reducing conditions sufficient to allow disulfide isomerization of the cysteine ​​in the hinge region; thereby generating a bispecific antibody by exchanging Fab arms. The incubation conditions are ideally restored 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, the following conditions can be used: in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol, at a pH of 5-8, such as pH 7.0 or pH 7.4, at a temperature of at least 20° C., incubated for at least 90 minutes.

[0206] Bispecific anti-EGFR / c-Met antibodies for use in the methods of the present disclosure can also be generated using designs such as knob-in-hole or knobs-into-holes (Genentech), CrossMAbs (Roche) and electrostatic matching (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), SEEDbody (EMDSerono) and Biclonic (Merus).

[0207] In the "knob-in-hole" strategy (see, e.g., International Publication No. WO 2006 / 028936), selected amino acids that form the junction of the CH3 domains in human IgG can be mutated at positions that affect the interaction of the CH3 domains, thereby promoting heterodimer formation. Amino acids with small side chains (knobs) are introduced into the heavy chain of an antibody that specifically binds to a first antigen, and amino acids with large side chains (knobs) are introduced into the heavy chain of an antibody that specifically binds to a second antigen. After the two antibodies are co-expressed, heterodimers are formed due to the preferential interaction of the heavy chain with the "knob" with the heavy chain with the "knob". Exemplary CH3 substitution pairs that form a knob and hole (represented as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain) are: T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V.

[0208] In addition to utilizing a "knob-in-hole" strategy to facilitate Fab wall exchange, CrossMAb technology also utilizes CH1 / CL domain exchange in one half-arm to ensure correct light chain pairing of the resulting bispecific antibody (see, e.g., U.S. Pat. No. 8,242,247).

[0209] Other exchange strategies can be used to generate full-length bispecific antibodies of the invention as follows: in one or both arms of the bispecific antibody, variable domains or constant domains, or both domains, are exchanged between the heavy chain and the light chain or within the heavy chain. These exchanges include, for example, VH-CH1 and VL-CL, VH and VL, CH3 and CL, and CH3 and CH1, as described in International Patent Publications WO2009 / 080254, WO2009 / 080251, WO2009 / 018386, and WO2009 / 080252.

[0210] Other strategies may also be used, such as using electrostatic interactions to promote heavy chain heterodimerization by replacing positively charged residues on one CH3 surface and replacing negatively charged residues on the second CH3 surface, as described in US Patent Publication No. US2010 / 0015133; US Patent Publication No. US2009 / 0182127, US Patent Publication No. US2010 / 028637, or US Patent Publication No. US2011 / 0123532. In other strategies, heterodimerization may be promoted by the following substitutions (expressed as modified positions in the first CH3 domain of the first heavy chain / modified positions in the second CH3 domain of the second heavy chain): 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, as described in U.S. Patent Publication No. US2012 / 0149876 or U.S. Patent Publication No. US2013 / 0195849.

[0211] SEEDbody technology can be used to generate bispecific antibodies of the invention. SEEDbody has selected IgG residues substituted with IgA residues in its constant domain to promote heterodimerization, as described in US Pat. No. US20070287170.

[0212] Mutations are generally made using standard methods, from the DNA level to the molecular level, such as the constant domains of antibodies.

[0213] Exemplary embodiments

[0214] 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) / hepatocyte growth factor receptor (c-Met) antibody.

[0215] 2. The method according to embodiment 1, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a heavy chain complementary determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementary determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds to c-Met comprises a HCDR1 of SEQ ID NO: 7, a HCDR2 of SEQ ID NO: 8, a HCDR3 of SEQ ID NO: 9, a LCDR1 of SEQ ID NO: 10, a LCDR2 of SEQ ID NO: 11, and a LCDR3 of SEQ ID NO: 12.

[0216] 3. A method according to embodiment 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 a VH of SEQ ID NO:15 and a VL of SEQ ID NO:16.

[0217] 4. The method according to embodiment 2 or 3, wherein the bispecific anti-EGFR / c-Met antibody is of IgG1 isotype.

[0218] 5. A method according to any one of embodiments 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.

[0219] 6. The method according to any one of embodiments 1 to 5, wherein the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0220] 7. The method according to any one of embodiments 1 to 6, wherein the bispecific anti-EGFR / c-Met antibody is administered to the subject intravenously or subcutaneously.

[0221] 8. The method of embodiment 7, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 350 mg to about 2000 mg.

[0222] 9. The method of embodiment 8, wherein the bispecific anti-EGFR / c-Met antibody is administered at 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.

[0223] 10. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg.

[0224] 11. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

[0225] 12. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1600 mg.

[0226] 13. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1750 mg.

[0227] 14. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg.

[0228] 15. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg.

[0229] 16. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg.

[0230] 17. The method according to embodiment 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg.

[0231] 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 once every 2 weeks thereafter.

[0232] 19. The method according to embodiment 16 or 17, wherein the bispecific anti-EGFR / c-Met antibody is administered weekly for the first 3 weeks and once every 3 weeks thereafter.

[0233] 20. The method of any one of embodiments 10 to 19, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0234] 21. The method of embodiment 18, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

[0235] 22. The method of any one of embodiments 1 to 6, wherein the bispecific anti-EGFR / c-Met antibody is administered to the subject subcutaneously or intradermally.

[0236] 23. The method of embodiment 22, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

[0237] 24. The method according to any one of embodiments 1 to 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.

[0238] 25. The method of embodiment 24, wherein the bispecific anti-EGFR / c-Met antibody is administered once a week for four weeks and once every two weeks thereafter.

[0239] 26. The method of embodiment 25, wherein the first dose of the bispecific anti-EGFR / c-Met antibody is administered within two days.

[0240] 27. A method according to any one of embodiments 1 to 26, wherein one or more cells of the gastric cancer express EGFR and / or cMet.

[0241] 28. A method according to any one of embodiments 1 to 27, wherein the subject has received previous treatment.

[0242] 29. The method of embodiment 28, wherein the prior treatment comprises chemotherapy, targeted therapy, immunotherapy, surgery, radiotherapy, chemoradiotherapy, or a combination thereof.

[0243] 30. The method of embodiment 29, wherein the chemotherapy comprises fluoropyrimidine-based chemotherapy, platinum-based chemotherapy, paclitaxel, irinotecan, or a combination thereof.

[0244] 31. The method of embodiment 30, wherein the fluoropyrimidine is 5-fluorouracil or capecitabine.

[0245] 32. The method of embodiment 30, wherein the platinum-based chemotherapy is cisplatin, oxaliplatin, carboplatin, or nedaplatin.

[0246] 33. A method according to embodiment 29, wherein the targeted therapy comprises anti-HER2 therapy or anti-VEGF / VEGFR therapy.

[0247] 34. The method of embodiment 33, wherein the anti-HER2 therapy comprises trastuzumab.

[0248] 35. The method of embodiment 34, wherein the anti-VEGF / VEGFR therapy comprises bevacizumab or ramucirumab.

[0249] 36. A method according to any one of embodiments 1 to 27, wherein the subject has not received treatment.

[0250] 37. The method of any one of embodiments 1 to 36, wherein the method further comprises administering to the subject at least one additional therapeutic agent.

[0251] 38. A method according to embodiment 37, wherein the additional therapeutic agent comprises a glucocorticoid, an antihistamine, an antipyretic, an H2-antagonist, an antiemetic, an opiate, or any combination thereof.

[0252] 39. A method according to any one of embodiments 1 to 38, wherein the gastric cancer is an advanced or metastatic cancer.

[0253] 40. A method according to any one of embodiments 1 to 39, wherein the subject is a human.

[0254] 41. A method of 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.

[0255] 42. The method of embodiment 41, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a heavy chain complementary determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementary determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds to c-Met comprises a HCDR1 of SEQ ID NO: 7, a HCDR2 of SEQ ID NO: 8, a HCDR3 of SEQ ID NO: 9, a LCDR1 of SEQ ID NO: 10, a LCDR2 of SEQ ID NO: 11, and a LCDR3 of SEQ ID NO: 12.

[0256] 43. A method according to embodiment 42, 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.

[0257] 44. The method according to embodiment 42 or 43, wherein the bispecific anti-EGFR / c-Met antibody is of IgG1 isotype.

[0258] 45. A method according to any one of embodiments 41 to 44, 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.

[0259] 46. ​​The method of any one of embodiments 41 to 45, wherein the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure having a fucose content of between about 1% and about 15%.

[0260] 47. The method of any one of embodiments 41 to 46, wherein the bispecific anti-EGFR / c-Met antibody is administered to the subject intravenously or subcutaneously.

[0261] 48. The method of embodiment 47, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 350 mg to about 2000 mg.

[0262] 49. The method of embodiment 48, wherein the bispecific anti-EGFR / c-Met antibody is administered at 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.

[0263] 50. The method of embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg.

[0264] 51. The method of embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

[0265] 52. The method of embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1600 mg.

[0266] 53. The method of embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1750 mg.

[0267] 54. The method of embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg.

[0268] 55. The method of embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg.

[0269] 56. The method of embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg.

[0270] 57. The method of embodiment 49, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg.

[0271] 58. The method of any one of embodiments 50 to 55, wherein the bispecific anti-EGFR / c-Met antibody is administered weekly for the first 4 weeks and once every 2 weeks thereafter.

[0272] 59. The method of embodiment 56 or 57, wherein the bispecific anti-EGFR / c-Met antibody is administered weekly for the first 3 weeks and once every 3 weeks thereafter.

[0273] 60. The method of embodiment 58, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

[0274] 61. A method according to embodiment 59, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0275] 62. A method according to any one of embodiments 50 to 59, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0276] 63. The method of any one of embodiments 41 to 57, wherein the bispecific anti-EGFR / c-Met antibody is administered to the subject subcutaneously or intradermally.

[0277] 64. A 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 the subject.

[0278] 65. The method of any one of embodiments 41 to 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.

[0279] 66. A method according to embodiment 65, wherein the bispecific anti-EGFR / c-Met antibody is administered once a week for four weeks and once every two weeks thereafter.

[0280] 67. The method of embodiment 66, wherein the first dose of the bispecific anti-EGFR / c-Met antibody is administered within two days.

[0281] 68. A method according to any one of embodiments 41 to 67, wherein one or more cells of the esophageal cancer express EGFR and / or cMet.

[0282] 69. A method according to any one of embodiments 41 to 68, wherein the subject has received prior treatment.

[0283] 70. The method of embodiment 69, wherein the prior treatment comprises chemotherapy, targeted therapy, immunotherapy, surgery, radiotherapy, chemoradiotherapy, or a combination thereof.

[0284] 71. The method of embodiment 70, wherein the chemotherapy comprises fluoropyrimidine-based chemotherapy, platinum-based chemotherapy, paclitaxel, irinotecan, or a combination thereof.

[0285] 72. The method of embodiment 71, wherein the fluoropyrimidine is 5-fluorouracil or capecitabine.

[0286] 73. The method of embodiment 71, wherein the platinum-based chemotherapy is cisplatin, oxaliplatin, carboplatin, or nedaplatin.

[0287] 74. A method according to embodiment 70, wherein the targeted therapy comprises anti-HER2 therapy or anti-VEGF / VEGFR therapy.

[0288] 75. The method of embodiment 74, wherein the anti-HER2 therapy comprises trastuzumab.

[0289] 76. The method of embodiment 74, wherein the anti-VEGF / VEGFR therapy comprises bevacizumab or ramucirumab.

[0290] 77. The method of any one of embodiments 41 to 68, wherein the subject is treatment naive.

[0291] 78. The method of any one of embodiments 41 to 77, wherein the method further comprises administering to the subject at least one additional therapeutic agent.

[0292] 79. The method of embodiment 78, wherein the additional therapeutic agent is a glucocorticoid, an antihistamine, an antipyretic, an H2-antagonist, an antiemetic, an opiate, or any combination thereof.

[0293] 80. The method of any one of embodiments 41 to 79, wherein the esophageal cancer is an advanced or metastatic cancer.

[0294] 81. The method of any one of embodiments 41 to 80, wherein the subject is human.

[0295] Example

[0296] The following examples are provided to further describe some of the embodiments disclosed herein. These examples are intended to illustrate, but not to limit, the embodiments disclosed herein.

[0297] Example 1. Evanta in Subjects with Previously Treated Advanced or Metastatic Gastric or Esophageal Cancer Phase 2, open-label study of a monoclonal antibody

[0298] Study Rationale

[0299] Gastric cancer (GC) and esophageal cancer (EC) are known to express EGFR and cMet, and expression of these proteins is associated with poor prognosis. Although many agents targeting EGFR are part of the standard of care for many tumor types, no anti-EGFR or anti-cMet therapies have been approved for GC or EC. As a bispecific diabody capable of engaging the extracellular domains of the EGFR receptor and the cMet receptor, entuzumab has a unique mechanism of action, which suggests that it has the potential to control GC and EC patients with EGFR expression and / or cMet expression. In vitro and in vivo preclinical activity of entuzumab against tumors has been demonstrated using GC and EC models with EGFR or cMet amplification (Vijayaraghavan 2020). In addition, clinical experience with entuzumab in NSCLC has shown clinical benefits against a broad spectrum of EGFR and cMet aberrations, including EGFR protein overexpression and cMet amplification.

[0300] This study was designed to evaluate the clinical activity of evitumab as monotherapy in patients with GC (including GEJ cancer) and EC who had received at least 2 prior (GC / GEJ participants) or 1 prior (EC participants) standard of care. The Phase 2a cohort was designed to initially investigate the antitumor activity of evitumab in participants with documented expression of EGFR, cMet, or both as assessed by immunohistochemistry (IHC). Approximately 30 participants with any expression level of EGFR, cMet, or both proteins were recruited to each of the Phase 2a cohorts. However, based on prior experience studying anti-EGFR and anti-cMet antibodies in gastroesophageal cancer, at least 20 participants with expression IHC 2+ or higher (defined as participants expressing EGFR IHC 2+ or higher and / or cMet IHC 2+ or higher) were recruited. Additional recruitment in the Phase 2a cohort was allowed to achieve this minimum enrollment requirement. In addition, at least 10 participants expressing any level of cMet protein will be enrolled in each of the Phase 2a cohorts to better characterize the contribution of cMet in the activity of entuzumab. If activity is shown in the Phase 2a cohort, an expansion cohort of the Phase 2a cohort investigating participants without EGFR and cMet expression will be open for enrollment. The Phase 2b cohort is based on the Phase 2a data to investigate the clinical activity of entuzumab in selected patient populations.

[0301] Table 1: Activity Plan for Research Procedures / Assessment

[0302]

[0303] Abbreviations: AE = adverse event; C = cycle; ctDNA = circulating tumor DNA; CT = computed tomography; cMet = tyrosine-protein kinase mesenchymal-epithelial transition; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; EoT = end of treatment; FU = follow-up; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; h = hour; ICF = informed consent; IHC = immunohistochemistry; IV = intravenous; MRI = magnetic resonance imaging; Q12W = every 12 weeks; wk = week

[0304] Benefit-Risk Assessment

[0305] Risks of participating in research

[0306] The safety and tolerability of ervantumab monotherapy was shown in the Phase 1 study 61186372EDI1001 in patients with NSCLC. ervantumab was generally well tolerated without any dose-limiting toxicities (DLTs). However, given that the available clinical data were limited to participants with NSCLC, unforeseen safety risks associated with the study treatment are possible in participants with GC or EC. The study protocol included the following elements to mitigate the risks to study participants:

[0307] Participants were closely monitored for safety throughout the study according to the planned assessments outlined in the activity schedule (Table 1) (see the Safety Assessments section).

[0308] Provide guidance on dose modifications to manage toxicities that occur during the study (see the “Guidelines for Dose Delays” section and the “Guidelines for Dose Modifications” section), including specific guidance on infusion-related reactions (IRRs), rash, interstitial lung disease (ILD), abnormal liver tests, or paronychia.

[0309] Based on the above data, ivanovumab was generally safe and well tolerated.

[0310] Benefits of participating in research

[0311] Although many agents targeting EGFR have been approved and are part of the standard of care for many tumor types, no anti-EGFR or anti-cMet therapies have been approved for GC or EC. Evantumab has shown significant activity as a monotherapy for the treatment of NSCLC, receiving breakthrough therapy designation from the U.S. FDA and the China Center for Drug Evaluation based on an overall response rate of 41% in subjects with EGFR exon 20 insertion disease after prior treatment with platinum-based chemotherapy. Consistent with the unique mechanism of action of Evantumab, activity was observed in subjects with different EGFR mutations and in subjects with MET amplification and EGFR overexpression.

[0312] It is expected that this therapeutic targeted approach using ivanovumab as a single agent in participants with advanced GC (including GEJ cancer) or EC may provide benefit to these participants.

[0313] Benefit-Risk Assessment of Participating in Research

[0314] Considering the measures taken to minimize risks to participants in this study (see the “Risks of Study Participation” section), the potential risks of ivanovumab are justified by the anticipated benefits that participants with advanced GC or EC may derive (see the “Benefits of Study Participation” section).

[0315] Table 2. Objectives and endpoints

[0316]

[0317] hypothesis

[0318] It is anticipated that ivanovumab will show antitumor activity in participants with GC or EC expressing any level of EGFR, cMET, or both proteins.

[0319] Study Design

[0320] Overall Design

[0321] This is an open-label, multicenter, 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. Japanese participants with gastric / GEJ or EC expressing varying degrees of EGFR, cMet, or both as determined by local or central IHC will be recruited to the GC cohort or EC cohort. If activity is shown in the Phase 2a cohort, a Phase 2a expansion cohort in participants without EGFR and cMet expression may be open for enrollment. If activity is observed in the Phase 2a cohort, a corresponding Phase 2b GC or EC expansion cohort may be initiated to evaluate the antitumor activity of entuzumab in selected GC and EC participants based on prospective assessment of IHC during Phase 2a. Figure 1 ).

[0322] If the efficacy observed in both Phase 2a cohorts requires full enrollment in their respective Phase 2b cohorts, a maximum of approximately 282 participants will be recruited in the combined Phase 2a and Phase 2b populations. Approximately 30 participants who can be evaluated for response will be recruited in each of the Phase 2a GC and EC groups. However, based on previous experience studying anti-EGFR and anti-cMet antibodies in gastroesophageal cancer, at least 20 participants expressing IHC 2+ or higher (defined as participants expressing EGFR IHC 2+ or higher or cMet IHC 2+ or higher) were recruited. In addition, at least 10 participants expressing any level of cMet protein (IHC1+ or above) were recruited to each Phase 2a cohort to better characterize the contribution of cMet in the activity of entuzumab. If these criteria are not met in the initial 30 evaluable subjects, additional recruitment in the Phase 2a cohort may be allowed to reach the minimum enrollment number. If activity is shown in the Phase 2a cohort, the Phase 2a expansion cohort of up to 11 participants without any EGFR and cMet expression will be open for enrollment. The Phase 2b GC expansion or EC expansion cohort will evaluate the antitumor activity of entuzumab in GC and EC patients using biomarker selection based on the Phase 2a results. If activated, approximately 100 participants will be enrolled in each of the Phase 2b cohorts.

[0323] The study consists of a screening phase (the “Screening Phase (Prescreening and Full Screening)” section), a treatment phase (the “Treatment Phase” section), and a follow-up phase (the “Follow-up Phase (Phase 2b only)” section).

[0324] Screening stage (pre-screening and full screening)

[0325] During the comprehensive screening period, participants were evaluated for eligibility to join the study. Participants completed all screening procedures within 28 days of C1D1. Pre-treatment biopsies were collected for all participants in Phase 2a and Phase 2b. If central tumor IHC results were not reported within the 28-day screening period, the screening period could be extended by 14 days. However, all other assessments still met the timing criteria relative to C1D1 or were repeated.

[0326] An optional pre-screening period is provided to facilitate molecular characterization of archived tumor biopsy samples. Participants may submit archived samples prior to completion of a previous therapy.

[0327] Treatment phase

[0328] The treatment phase of the participants starts at C1D1 and continues with a 28-day cycle until the end of treatment (EOT) visit, i.e. about 30 days after the suspension of study treatment. This study is conducted in an outpatient setting. However, in Phase 2a (including Phase 2a expansion group), in-hospital observation is allowed from C1D1 until C1D8 for close monitoring. Study treatment continues until there is documented clinical or radiological (RECIST 1.1 version) disease progression, or until the participant meets another criterion for suspension of study treatment.

[0329] Disease assessments were performed as close to treatment initiation as possible (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, and then every 12 weeks (+1 week) until objective radiographic disease progression or withdrawal of consent.

[0330] At each study visit during the treatment phase, participants were evaluated for safety, including physical examinations and evaluation of adverse events (AEs), vital signs, concomitant medication use, and clinical laboratory parameters. At selected visits, blood samples were also drawn from participants for evaluation of PK and immunogenicity parameters and for biomarker evaluation. Biopsies, circulating tumor DNA (ctDNA), and biomarkers were collected from all participants in Phase 2a on C2D15 (+1 week) and post-treatment according to the active schedule section.

[0331] Follow-up phase (only applicable to Phase 2b)

[0332] During the follow-up phase, participants who discontinued study treatment were followed for subsequent therapy, disease status (applicable only if the participant discontinued treatment for reasons other than progressive disease, to confirm the date of disease progression), and survival. This phase began with assessments at the EOT visits every 12 weeks (±14 days) after the last dose of study treatment or disease progression, whichever occurred first, and continued until the end of the study, death, loss to follow-up, or withdrawal of consent to participate in the study, whichever occurred first.

[0333] Figure 1 A diagram of the study design is provided in .

[0334] Rationality of dosage

[0335] In a Phase 1 study (Study 61186372EDI1001), ervantumab was generally well tolerated, with doses up to 1750 mg tolerated, no dose-limiting toxicities reported during dose escalation and no maximum tolerated dose identified in lung cancer participants. Based on all 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 in 28-day cycles: once weekly in Cycle 1 (split doses from Day 1 to Day 2), then every 2 weeks in subsequent cycles. In lung cancer participants, the recommended Phase 2 dose achieved complete soluble target saturation of EGFR and cMet throughout dosing. The observed safety profile of ervantumab was consistent with EGFR and cMet inhibition, and most treatment-emergent adverse events (TEAEs) were grade 1 to 2 in severity. Therefore, it was considered appropriate to administer the same dosing regimen to GC or EC participants.

[0336] Study population

[0337] Screening of eligible participants was performed within 28 days prior to administration of study treatment.

[0338] The inclusion and exclusion criteria for recruiting participants in this study are described below.

[0339] Inclusion criteria

[0340] Each potential participant met all of the following study recruitment criteria:

[0341] 1. Participants must be ≥ 20 years old (or the legal age of consent in the jurisdiction where the research is conducted).

[0342] 2. Participant tumors express EGFR, cMet, or both as determined by local or central IHC assay (IHC 1+ or above). If eligibility is determined using local IHC testing, submit a copy of the de-identified pathology report for IHC analysis during the screening period. Phase 2a expansion cohort: Participant tumors lack expression of EGFR and MET as determined by local or central IHC assessment. If eligibility is determined using local IHC testing, submit a copy of the de-identified pathology report for IHC analysis during the screening period.

[0343] 3. Participants have histologically or cytologically confirmed gastric cancer (including GEJ) or EC that is locally advanced, unresectable or metastatic and are not eligible for radical treatment.

[0344] Gastric or GEJ cancer only: Participants were refractory to at least 2 prior standard-of-care systemic therapies or were ineligible. Prior therapies included fluoropyrimidine-based and platinum-based chemotherapy. Participants with known HER2 expression had received HER2-targeted therapy as part of prior therapy. In the case of progression within 24 weeks of prior adjuvant or neoadjuvant chemotherapy, that therapy was considered 1 prior systemic therapy for the purpose of meeting eligibility criteria.

[0345] Esophageal cancer only: (a) Participants were refractory or intolerant to at least 1 prior systemic therapy. Prior therapy included fluoropyrimidine-based and platinum-based chemotherapy (including chemoradiotherapy given as a stage IV setting). (b) For the purpose of meeting eligibility criteria, participants who received chemotherapy (including neoadjuvant / adjuvant therapy and chemoradiotherapy) concurrently with radical resection (including participants who received chemoradiotherapy followed by salvage surgery in the presence of residual tumor) were considered to have received 1 prior systemic therapy with recurrence confirmed by imaging within 24 weeks of the last dose of chemotherapy. If a prior combination therapy was discontinued due to an AE and then one of the agents was continued, this was considered "prior 1" rather than "prior 2". A change in dosage form (IV administration, oral administration) or dose reduction without progression was considered "prior 1" rather than "prior 2".

[0346] 4. Participants have measurable disease according to RECIST version 1.1. If only one measurable lesion is present, the baseline tumor assessment scan may be used for the screening biopsy if it is performed ≥7 days after the biopsy.

[0347] 5. The participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Eastern Cooperative Oncology Group (ECOG) performance status).

[0348] 6. Participants have the following adequate organ and bone marrow function, no history of red blood cell transfusion and platelet transfusion within 7 days before the date of laboratory testing.

[0349] a. Hemoglobin ≥ 8 g / dL

[0350] b. Absolute neutrophil count ≥ 1500 / mm 3 , do not use granulocyte colony stimulating factor (G-CSF) within 10 days before the test date.

[0351] c. Platelet count ≥ 75,000 / mm 3

[0352] d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN). If liver metastasis is present, ≤ 5 × ULN

[0353] e. Total bilirubin ≤ 1.5 × ULN (Participants with Gilbert's syndrome can be enrolled if direct bilirubin is within normal limits)

[0354] f. Glomerular filtration rate ≥ 40 mL / min calculated or measured using the Modification of Diet in Renal Disease (MDRD) equation (eGFR refers to the MDRD formula)

[0355] 7. Participants have tumor lesions suitable for biopsy and agree to undergo mandatory biopsy as defined in the protocol.

[0356] Exclusion criteria

[0357] Any potential participant who met any of the following criteria was excluded from participating in the study.

[0358] 1. The participant suffers from an uncontrolled disease, including but not limited to the following:

[0359] a. Diabetes

[0360] b. Persistent or active bacterial infection (including infections requiring treatment with antimicrobial therapy [requiring participants to complete antibiotics 1 week prior to enrollment]), symptomatic viral infection, or any other clinically significant infection

[0361] c. Active bleeding

[0362] d. Mental illness / social conditions that would limit compliance with research requirements

[0363] 2. Participants have received prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or 4 half-lives (whichever is longer), or have received radiation therapy within 4 weeks prior to the first administration of study treatment. For agents with long half-lives, the maximum required time from the last dose is 28 days. Toxicity from prior anticancer therapy should have resolved to baseline levels or Grade 1 or less (except for alopecia or post-radiation skin changes [any grade], Grade 2 peripheral neuropathy, and Grade 2 hypothyroidism stable on hormone replacement).

[0364] 3. Participants have untreated brain metastases (participants with definitive, locally treated metastases are eligible who are clinically stable, asymptomatic, and on corticosteroid therapy for at least 2 weeks prior to the first dose of study treatment), leptomeningeal disease that has not been definitively treated with surgery or radiation, or a history of spinal cord compression. If brain metastases are diagnosed on screening imaging, participants may be rescreened for eligibility after definitive treatment.

[0365] 4. Participants have a history of (non-infectious) ILD / pneumonitis requiring steroids, or have current ILD / pneumonitis, or in which suspected ILD / pneumonitis cannot be ruled out by imaging at screening. Participants with esophageal cancer with a history of completely resolved radiographic pneumonitis (defined as radiographically stable without any treatment in the 3 months prior to enrollment) may be enrolled.

[0366] 5. The participant has an active malignancy other than the disease being treated in the study (i.e., has progressed or required a change in treatment within the last 12 months). Only the following exceptions are allowed:

[0367] a. Non-muscle invasive bladder cancer considered completely cured and treated within the last 24 months.

[0368] b. Skin cancer (non-melanoma or melanoma) treated within the last 24 months and considered completely cured.

[0369] c. Non-invasive cervical cancer considered completely cured and treated within the last 24 months.

[0370] d. Localized prostate cancer (N0M0):

[0371] Gleason score 6, treated or untreated and under surveillance within the last 24 months,

[0372] Gleason score 3+4, who have been treated for more than 6 months prior to full study screening and are considered to have a very low risk of recurrence,

[0373] or a history of localized prostate cancer and receiving androgen deprivation therapy and considered to be at very low risk of recurrence.

[0374] e.Breast cancer:

[0375] Adequately treated lobular carcinoma in situ or ductal carcinoma in situ,

[0376] or history of localized breast cancer and receiving anti-hormonal agents and considered to be at very low risk of recurrence.

[0377] f. Malignant tumors that are considered to be curable and have a very low risk of recurrence.

[0378] g. Phase 2a participants only: Participants with a second malignancy may be enrolled if they are deemed not to require any systemic therapy for at least 6 months after enrollment.

[0379] 6. Participants have a history of clinically significant cardiovascular disease, including but not limited to:

[0380] a. Deep vein thrombosis or pulmonary embolism diagnosed within 4 weeks before the first dose of study treatment or within 6 months before the first dose of study treatment: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary artery / peripheral artery bypass graft surgery, or any acute coronary syndrome. Clinically insignificant thrombosis, such as non-occlusive catheter-related clots, is not excluded.

[0381] b. Prolonged QTcF interval >480 milliseconds or clinically significant arrhythmia or electrophysiological disease (e.g., placement of an implantable cardioverter-defibrillator or atrial fibrillation with uncontrolled heart rate). Clinically stable participants with a pacemaker are eligible.

[0382] c. Uncontrolled (persistent) hypertension: systolic blood pressure >180 mm Hg; diastolic blood pressure >100 mm Hg.

[0383] d. Congestive heart failure, defined as New York Heart Association (NYHA) class III-IV or hospitalization for congestive heart failure (any NYHA class) within 6 months of study entry (New York Heart Association criteria).

[0384] e. Pericarditis / clinically significant pericardial effusion.

[0385] f. Myocarditis.

[0386] 7. Participants are known to be allergic, hypersensitive, or intolerant to the excipients of entuzumab.

[0387] 8. Participants have received study treatment (including investigational vaccines) within 6 weeks prior to enrollment, except for anticancer therapy described in the second exclusion criterion.

[0388] 9. The participant has or is expected to have any of the following:

[0389] a. Invasive surgical procedures into body cavities within 4 weeks prior to C1D1 or without full recovery. Thoracic puncture (if necessary) and percutaneous biopsy of baseline tumor tissue samples may be performed less than 4 weeks prior to C1D1, as long as the participant has adequately recovered from the procedure prior to the first dose of study treatment, based on the clinical judgment of the investigator.

[0390] b. Significant traumatic injury within 3 weeks before the start of C1D1 (unless all wounds are completely healed before Day 1)

[0391] c. Major surgery is planned during administration of the study drug or within 6 months after the last dose of study treatment

[0392] 10. Participants have:

[0393] a. Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg). Participants with a past history of HBV as evidenced by positive hepatitis B core antibody were eligible if they had 1) negative HBsAg and 2) HBV DNA (viral load) below the lower limit of quantification at screening based on local testing. Participants with positive HBsAg due to recent vaccination were eligible if the HBV DNA (viral load) was below the lower limit of quantification based on local testing.

[0394] b. Positive hepatitis C antibodies (anti-HCV [hepatitis C virus]). Participants with a past history of HCV, who had completed antiviral therapy and subsequently had HCV RNA below the limit of quantification by local testing were eligible.

[0395] c. Other clinically active infectious or non-infectious liver diseases 11. Participants are known to be positive for human immunodeficiency virus (HIV) and have any of the following:

[0396] One or more of:

[0397] a. Not receiving highly active antiretroviral therapy (ART)

[0398] b. Changes in ART within 6 months of screening

[0399] c. Receiving ART that may interfere with study treatment

[0400] d. CD4 count <350 at screening

[0401] e. Acquired Immune Deficiency Syndrome (AIDS) - defined as an opportunistic infection within 6 months of screening. Not consenting to start ART and receiving ART for >4 weeks plus HIV viral load <400 copies / mL at the end of the 4-week period (to ensure ART is tolerated and HIV is controlled).

[0402] 12. Participants have received prior therapy targeting EGFR or cMet.

[0403] active

[0404] Participants agreed to use sun protection measures (such as hats, sunglasses, protective clothing, sunscreen), limit prolonged 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 skin protection factor ≥ 15.

[0405] Study Treatment Administered

[0406] Evantumab was supplied for this study at a concentration of 50 mg / mL in 7 mL vials in glass vials containing 350 mg / vial. The IV infusion was prepared on site in 250 mL of diluent.

[0407] The initial dose of ivanovumab was based on the participant's weight at screening: 1,050 mg (if weight <80 kg) or 1,400 mg (if weight ≥80 kg). ivanovumab was administered as an IV infusion in 28-day cycles as follows:

[0408] Cycle 1: Once weekly (first dose divided into day 1 [350 mg] and day 2 [700 mg if body weight < 80 kg, or 1,050 mg if body weight ≥ 80 kg]).

[0409] Cycle 2+: Days 1 and 15 of each cycle.

[0410] Evantumab may be administered as an IV infusion in 28-day cycles at higher doses based on weight: 1750 mg for weight < 80 kg and 2100 mg for weight >= 80 kg, as follows:

[0411] Cycle 1: Once weekly (first dose divided into day 1 [350 mg] and day 2 [1400 mg if body weight < 80 kg, or 1,750 mg if body weight ≥ 80 kg]).

[0412] Cycle 2+: Days 1 and 15 of each cycle.

[0413] Evantumab was administered intravenously using an ascending infusion rate schedule. For all Cycle 1 doses, the product was infused via a peripheral intravenous route; for subsequent dosing beginning with the C2D1 dose, infusion via a central line was permitted.

[0414] Administer ivantazumab according to clinical protocol. Additional guidance is provided below:

[0415] On Day 1 of each cycle, check the results of hematology and chemistry laboratory evaluations prior to administration of study treatment.

[0416] Dilute ivanovumab before infusion

[0417] Do not mix or dilute ivanovumab with other medications.

[0418] • Evantumab is not administered as an IV push or bolus injection.

[0419] Dosage and administration schedule may be adjusted during this study.

[0420] Preparation / Handling / Storage / Responsibility

[0421] Preparation / Handling / Storage

[0422] All study treatments were stored at controlled temperature as directed on the label. Protect entuzumab from light until use.

[0423] Measures to minimize bias: randomization and blinding

[0424] Treatment allocation

[0425] Randomization Procedure: No randomization was used in this study. Participants were assigned to treatments in the order in which they met the criteria for this study.

[0426] Blind

[0427] Because this was an open-label study, blinding procedures were not applicable.

[0428] Dose Delay Instructions

[0429] In cases where treatment deferral is indicated, treatment with ivanovumab may be deferred until toxicity has recovered to a level that allows continuation of treatment. Participants whose treatment is deferred will be assessed at least weekly to ensure adequate supportive care and to assess for improvement in toxicity. For most clinically significant toxicities, dose hold and dose modification may be performed according to the guidelines described below (“Guidelines for Dose Modifications” section).

[0430] The following sections provide additional guidance for preventing, monitoring, and managing toxicities reported with ivanovich.

[0431] Infusion-related reactions

[0432] Infusion-related reactions were commonly observed during treatment with evitumab, primarily at the first exposure to C1D1, and generally within the first 90 minutes of infusion. Most IRRs were Grade 1 or 2. The guidelines described herein relate to the safe administration of evitumab during initial dosing.

[0433] Participants were clinically monitored regularly during the ivanovumab infusion (including assessments before the infusion began). Monitoring included measurements of heart rate, blood pressure, temperature, respiratory rate, and oxygen saturation.

[0434] Pre- and post-infusion medications for ivanovumab

[0435] Pre-infusion medications for ivanovumab

[0436] Required and optional pre-infusion medications for ivanovumab for IRR are summarized in Table 3.

[0437] Table 3. Medication before ivandumab infusion

[0438]

[0439] C = cycle; D = day X; IV = intravenous.

[0440] If the drugs listed in this table are not available locally, similar drugs and dosages may be used as substitutes and administered according to local guidelines.

[0441] b. For participants who are contraindicated from taking their required medications, alternative medications may be explored with their study physician. If the alternative medication is not suitable for the above purposes, the participant does not need to take the corresponding medication.

[0442] c. Starting on C1D8, for participants who experienced an infusion-related reaction on C1D1 or C1D2, if clinically indicated,

[0443] Optional pre-dose steroids may then be administered.

[0444] Medication after ivandumab infusion

[0445] As described in Table 4, optional evitumomab post-infusion medications may be prescribed if clinically indicated and continued for up to 48 hours after infusion.

[0446] Table 4. Medication after ivandumab infusion

[0447]

[0448] IV = intravenous.

[0449] a. Optional drugs may be used prophylactically as clinically indicated. If the drugs listed in this table are not available locally, similar drugs and dosages may be used as substitutes and administered according to local guidelines.

[0450] Prohibited or restricted drugs and treatments

[0451] The following concomitant medications and therapies must not be used during the study.

[0452] Any chemotherapy, systemic anticancer therapy, or experimental therapy (other than investigational therapy). Hormonal therapy as specified in Exclusion 5 is permitted.

[0453] Radiotherapy of lesions before radiographic progression while evaluating tumor response

[0454] · Prohibit the use of live vaccines or live attenuated vaccines

[0455] Because of the potential for hypomagnesemia associated with EGFR inhibitors, avoid concomitant medications that may lower serum magnesium whenever possible.

[0456] Research Assessment and Procedures

[0457] Overview

[0458] The frequency and timing of the measurements applicable to this study are summarized in the “Activity Schedule” section.

[0459] The total blood volume collected for the study was approximately 25 mL (screening), 105 mL (cycle 1), 75 mL (cycle 2), and 30 mL (for each cycle after cycle 3 and EOT).

[0460] Duplicate or unplanned samples may be taken for safety reasons or technical issues with the sample.

[0461] Efficacy and immunogenicity assessment

[0462] Disease assessment

[0463] Disease assessments were performed as described in the activity schedule (Table 1), regardless of any dose modifications. More frequent radiographic assessments were permitted if clinically indicated.

[0464] Computed tomography with IV contrast was performed of the chest (including the supraclavicular region), abdomen, pelvis, and any other disease location (if clinically indicated). Participants who were unable to undergo CT scans with IV contrast (e.g., due to allergies or renal insufficiency) could undergo non-contrast CT of the chest and MRI of the abdomen and pelvis with IV contrast at baseline and during the study. Disease assessment was performed at baseline and throughout the study using the same methodology to characterize each identified and reported lesion to document disease status. Techniques other than CT or MRI may be used based on local standards of care and RECIST version 1.1 guidelines.

[0465] Baseline disease assessments were performed as close to the start of treatment as possible, but no later than 28 days before the first dose. Subsequent assessments were 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 target radiographic disease progression. Each disease assessment was timed relative to the first dose of study treatment administered, regardless of dose modifications, and continued until disease progression occurred. Any other site suspected of new disease was also imaged.

[0466] If a participant achieved a partial response (PR) or complete response (CR), the response was confirmed 4 weeks into the PR or CR rather than the predefined 6 weeks later (but closer to 4 weeks).

[0467] If it is unclear whether progression has occurred, particularly with response to non-target lesions or the appearance of new lesions, continue treatment until the next scheduled assessment (or earlier if clinically indicated) and reassess the participant's status. If a repeat scan confirms progression, the date of the initial scan is declared the date of progression. To achieve "definite progression" on the basis of non-target lesions, there must be an overall significant worsening in the non-target lesions such that the overall tumor burden has increased sufficiently to warrant discontinuation of therapy, even in the presence of stable disease or PR in target lesions. A modest "increase" in the size of 1 or more non-target lesions is generally not sufficient to qualify as definite progression. If worsening of symptoms (based on overall worsening of health status) is recorded as the basis for determining disease progression, the clinical findings used to make that determination are specified. Even after treatment is discontinued due to worsening symptoms, radiographic progression should be recorded before subsequent therapy, if possible. For participants who discontinue study treatment due to toxicity or reasons other than target progressive disease, tumor assessments continue as scheduled until radiographic progressive disease is documented.

[0468] Participants were given a brain MRI scan at screening (if MRI was contraindicated, a CT scan with contrast agent could also be used to determine the presence of brain lesions) to identify any untreated brain metastases (exclusion criterion #3). Regardless of prior history of brain metastases, a brain scan was not required at each subsequent disease assessment and was performed according to local guidelines and practices if clinically indicated.

[0469] If the participant was achieving clinical benefit and treatment was approved after documented disease progression, disease assessments continued as planned, and clinical benefit was reviewed after each disease assessment.

[0470] Safety Assessment

[0471] Follow-up of any clinically significant abnormality at study end / early withdrawal continued until resolved or clinically stable condition achieved.

[0472] The study included the following evaluations of safety and tolerability according to the time points provided in the Schedule of Activities section.

[0473] Physical examination

[0474] The screening physical examination included, at a minimum, the participant's height, weight, and general appearance, as well as examination of the skin, ears, nose, throat, lungs, heart, abdomen, limbs, musculoskeletal system, lymphatic system, and nervous system. On day 1 of each cycle, a directed physical examination of the organs and other body systems involved was performed as indicated, and the participant's weight was obtained using a calibrated scale.

[0475] Vital signs

[0476] Vital sign measurements included the following assessments as indicated in the activity plan (Table 1):

[0477] ·body temperature

[0478] Heart rate

[0479] Respiratory rate

[0480] Oxygen saturation

[0481] ·blood pressure

[0482] Blood pressure and heart rate measurements were assessed in the sitting position using a fully automated device. Manual techniques were used only when automated devices were not available.

[0483] Blood pressure and heart rate measurements were taken after resting for at least 5 minutes in a quiet environment without distractions (e.g., television, mobile phone).

[0484] Electrocardiogram

[0485] A locally performed electrocardiogram (ECG) in triplicate was collected at screening to determine eligibility. During the collection of the ECG, participants were in a quiet environment free from distractions (e.g., television, cell phones). Participants rested in a supine position for at least 5 minutes prior to ECG collection and refrained from talking or moving their arms or legs. If blood sampling or vital sign measurements were scheduled at the same time point as ECG recording, the procedures were performed in the following order: ECG, vital signs, blood draw.

[0486] Obtain three separate ECG tracings as closely consecutively as possible, but approximately 2 minutes apart. Review the ECG (including ECG morphology) for immediate management.

[0487] QTcF was calculated using the Friedrichia formula: QTcF = QT / (RR)^0.33.

[0488] ECOG performance status

[0489] Eastern Cooperative Oncology Group performance status score was assessed during the screening phase to determine eligibility.

[0490] Clinical safety laboratory evaluation

[0491] Clinical laboratory evaluation was performed locally. Clinical laboratory tests were performed as shown in Table 5.

[0492] Table 5. Clinical laboratory evaluation

[0493]

[0494] More frequent clinical laboratory testing may be performed as indicated by the participant's overall clinical condition or abnormalities requiring more frequent monitoring.

[0495] Pharmacokinetics

[0496] Blood samples were used to evaluate the PK of ivanovumab. Serum collected for PK can be additionally used to assess safety or efficacy aspects that address questions that arise during or after the study period. evaluate

[0497] Blood samples were collected for measurement of serum entuzumab for PK analysis. The entuzumab PK profile was based on serum concentration data obtained at time points before and after the first and fifth dose administrations collected from at least 10 participants of each cancer type in Phase 2a. Blood samples for sparse PK were also obtained from all participants before the start of the infusion and after the end of the infusion, and after all other dose administrations for participants in Phase 2a and Phase 2b. Analytical procedures

[0498] Pharmacokinetics: Serum samples were analyzed using a validated, specific, and sensitive enzyme-linked immunosorbent assay (ELISA) method to determine the concentration of entuzumab.

[0499] Additionally, serum PK samples can be stored for future analysis of other co-administered treatments.

[0500] Pharmacokinetic parameters and assessments

[0501] The primary PK endpoints included but were not limited to the maximum serum concentration (C max ), T max 、AUC( t1-t2 )(For example, AUC 第1天至8天 ), AUC tau , plasma / serum concentration immediately before the next study treatment administration (C 谷 ), t 1 / 2 , CL, steady-state distribution volume (V SS Population PK modeling can be performed to assess the potential impact of intrinsic and extrinsic factors on the PK of ervantumab.

[0502] Biomarkers

[0503] Tumor surface levels of EGFR and cMET protein expression are evaluated by centrally performed IHC assays using collected tumor tissue samples to determine patient eligibility, but records of previously performed local IHC results may also be submitted for the purpose of demonstrating eligibility for the study. However, all statistical and biomarker analyses utilize the results of centrally performed IHC assays, which classify patients as 0, 1+, 2+, or 3+ based on the highest staining for EGFR or cMet. Tumor tissue collected at screening may also be analyzed by tumor next-generation sequencing to evaluate molecular alterations and track response to treatment. Tumor samples collected after treatment and progression may also be analyzed by IHC and next-generation sequencing to track response to ivantuzumab. Tissue may also be used to determine biomarkers associated with GC / EC and / or analyzed to confirm ctDNA results.

[0504] Screening blood samples from all participants will be analyzed for ctDNA to evaluate the pre-treatment mutational status of EGFR, cMet, and other key oncogenes to characterize the tumor. Additional blood samples will be collected during the study and may be evaluated for ctDNA to assess changes in the levels or types of genetic alterations observed over time and to monitor for the emergence of potential markers of resistance to ivanovumab.

[0505] Blood samples are also collected at various time points and can be analyzed for circulating factors relevant to disease biology (eg, hepatocyte growth factor).

[0506] Blood samples were also collected from at least 10 participants per cancer type at selected time points to analyze PD markers (e.g., soluble EGFR and cMet) in samples taken before and after exposure to ivanovumab to explore whether complete soluble target saturation was achieved throughout the dosing period.

[0507] To provide a biopsy tissue sample, a formalin-fixed, paraffin-embedded (FFPE) tissue sample is required and evaluated for cancer-related biomarkers (DNA, RNA and / or protein).

[0508] Immunogenicity assessment

[0509] Serum samples were collected for evaluation of the immunogenicity of evitumab (anti-drug antibodies to evitumab). Detection and characterization of antibodies against evitumab were performed using a validated immunoassay method.

[0510] Serum samples are screened for antibodies that bind to entuzumab, and serum titers are determined from positive samples. The ability of the antibodies to neutralize the activity of the study treatment can be further characterized and / or evaluated. All samples collected for immune response analysis are also evaluated for entuzumab serum concentration to ensure appropriate interpretation of the immunogenicity data. Additional immunogenicity analyses may be performed to further characterize any resulting immune responses.

[0511] Statistical considerations

[0512] A general description of the statistical methods used to analyze the efficacy and safety data is outlined below.

[0513] Statistical assumptions

[0514] There are no plans to test any hypotheses in Phase 2a.

[0515] The statistical hypothesis for Phase 2b was that ervantumab monotherapy resulted in an objective response rate (ORR) greater than 15% in patients with GC or EC (selected based on expression of EGFR, cMET, or both) (i.e., H0 ≤ 15% vs. H a >15%). This threshold is based on historical studies of approved 3L GC regimens (11.2% to 13.6%) and the reported efficacy of approved 2LEC regimens (approximately 15%).

[0516] Sample volume determination

[0517] In Phase 2a, approximately 30 response-evaluable participants with tumors expressing EGFR, cMet, or both (as determined by central IHC) will be enrolled into the GC and EC cohorts. By enrolling twenty participants with IHC 2+ / 3+, there is approximately a 90% probability of observing a posterior probability (ORR>22.5%%) ≥40% (similar to an ORR≥20%), assuming an ORR of 30% in the subpopulation. By enrolling 10 participants with IHC 1+, there is an 80% probability of observing a posterior probability (ORR>22.5%%) ≥40%. A maximum of 11 participants may be enrolled in each Phase 2a expansion cohort. Enrollment will be stopped if no response or stable disease of 6 weeks or longer is observed in the first 6 ineffective participants in each of the Phase 2a expansion cohorts. If 2 or more responses are observed in each of the Phase 2a expansion cohorts, additional participants may be enrolled for further characterization.

[0518] In the phase 2b cohort, approximately 100 participants were enrolled in each of the GC and EC expansion cohorts. Eligible participants were determined based on the results of the phase 2a portion. Assuming an overall ORR of 30% with entuzumab, 100 participants in the phase 2b portion provided approximately 90% power to reject the null hypothesis of a 15% ORR using a 2-sided z-test with α = 0.05.

[0519] Analysis set population

[0520] For the purpose of analysis, the following groups were defined:

[0521] (1) All treated groups: all participants who received at least 1 dose of study treatment;

[0522] (2) Evaluable response group: All participants who meet the following criteria:

[0523] Received at least 1 dose of study treatment;

[0524] At least 2 post-baseline efficacy disease assessments, or discontinuation of treatment for any reason, or disease progression / death before the second post-baseline disease assessment;

[0525] (3) Safety group: all participants who received at least one dose of study treatment;

[0526] (4) Pharmacokinetic population: all participants who received at least 1 dose of study treatment and had at least 1 evaluable post-baseline measurement;

[0527] (5) Immunogenicity population: All participants who received at least 1 dose of study treatment and had at least 1 evaluable post-baseline measurement.

[0528] General considerations

[0529] All continuous variables were summarized using the number of participants (n), mean, standard deviation (SD), median, minimum, and maximum values. Discrete variables were summarized using numbers and percentages. Time-to-event variables, including median survival time, were estimated using the Kaplan-Meier product limit method. Analyses were performed separately for each period and group unless otherwise stated.

[0530] The ORR and disease control rate (DCR) were analyzed for the response-evaluable population. Other efficacy analyses were performed on all treated populations. Central IHC data were used for statistical analysis purposes.

[0531] At the end of the Phase 2a portion, the results are reviewed and a determination is made as to which subpopulations are included in the Phase 2b portion.

[0532] Primary End Point

[0533] Objective response rate. Primary estimates:

[0534] Population: Participants with GC or EC expressing EGFR and / or MET

[0535] Variables: Overall response; CR or PR

[0536] Study drug: Evantumab monotherapy

[0537] Intercurrent event: subsequent anticancer therapy. During-treatment policy: responses after this intercurrent event are not included.

[0538] Summary: ORR

[0539] The primary efficacy measure was ORR. Objective response rate was defined as the proportion of participants who achieved CR or PR, as determined by investigator assessment using RECIST version 1.1. Confirmation of investigator-assessed ORR can be performed in Phase 2b by IRC.

[0540] For the phase 2a portion, there was no formal hypothesis testing. ORRs were calculated descriptively for the response-evaluable population.

[0541] For the phase 2b part, the z test with normal approximation was used to compare the ORR with 15%. The multiplicity caused by subpopulation selection at the interim analysis (see the "Interim Analysis" section) was controlled by a closed testing procedure and weighted statistics. The ORR and its 95% confidence interval (CI) were also calculated.

[0542] Secondary End Points

[0543] Disease Control Rate: The disease control rate was defined as the percentage of participants who achieved a complete or partial response or stable disease for at least 6 weeks as defined by RECIST version 1.1. The DCR and its 95% CI were also calculated using the Clopper-Pearson method.

[0544] Duration of response: Duration of response (DoR) is defined as the time from the date of first documented response (CR or PR) to the date of documented progression or death, whichever occurs first. The end time of the response will coincide with the date of progression or death due to any cause for the PFS endpoint. If a participant does not progress after a response, his / her duration of response uses the PFS censoring time. Kaplan-Meier plots and median DoRs with 95% confidence intervals (calculated from Kaplan-Meier estimates) are given. Confirmation of the investigator-assessed DoR can be performed by the IRC in Phase 2b.

[0545] Progression-free survival: Progression-free survival was defined as the time from the first dose until the date of target disease progression or death (from any cause in the absence of disease progression), whichever occurred first, based on investigator assessment using RECIST, version 1.1. Participants who had not progressed or died at the time of the analysis were censored at the latest assessment date based on their last evaluable RECIST, version 1.1 assessment. PFS was analyzed using the same approach as for DoR.

[0546] Overall survival: Overall survival was defined as the time from the date of the first dose to the date of death from any cause. Any participant not known to have died at the time of analysis was censored based on the last recorded date that the participant was known to be alive. OS was analyzed using the same methods as for DoR.

[0547] Other analyses

[0548] Pharmacokinetic analysis

[0549] PK analysis used the PK population. Serum evitumab concentrations for each cancer type and the total population were summarized in tables of mean, SD, median, and range over time (as appropriate). Individual PK parameters were estimated and descriptive statistics were calculated for each cancer type and the total population.

[0550] If a participant's data did not allow accurate assessment of PK (e.g., incomplete administration of study treatment; missing information on dosing and sampling times; insufficient concentration data for PK parameter calculations), the subject was excluded from the PK analysis.

[0551] Pharmacokinetic / pharmacodynamic analysis

[0552] If data allow, the exposure-response relationship between entuzumab exposure and key efficacy and safety parameters can be explored. In addition, exposure-response models can be used to characterize this relationship.

[0553] Immunogenicity analysis

[0554] The incidence of anti-ivacan antibodies was pooled for the immunogenicity groups.

[0555] Serum samples are screened for antibodies that bind to evitumab and the number of confirmed positive samples is reported. Additional analyses may be performed to further characterize the immunogenicity of evitumab.

[0556] Pharmacodynamics and biomarker analysis

[0557] Biomarker analysis uses a biomarker population. Analyses are planned to explore PD and other biomarkers that may indicate the mechanism of action of the drug or predict efficacy and potential resistance mechanisms to ervantumab.

[0558] The association of biomarker positivity with clinical response or time-to-event endpoints was assessed using statistical methods appropriate for each endpoint (e.g., analysis of variance, classification, or survival models). Correlation of baseline biomarker expression levels with clinical response or relevant time-to-event endpoints was performed to identify responsive (or resistant) subgroups.

[0559] Additional biomarkers (DNA, RNA, and / or protein) associated with GC / EC may also be assessed in blood and tissue samples collected during the study to better understand the disease and the mechanisms of response or resistance to evitumomab.

[0560] Interim analysis

[0561] In Phase 2b, an interim futility analysis is planned in each of the GC and EC groups approximately 12 weeks after 50 participants receive the first infusion. The interim futility analysis is based on the best response rate in each subgroup (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 in each subgroup can be terminated due to futility if the posterior probability (ORR>22.5%) is <40%.

[0562] result :

[0563] Participants in the Phase 2a gastric cancer (GC) and esophageal cancer (EC) cohorts received intravenous (IV) infusions of ervantumab at weight-based doses in 28-day cycles. Participants weighing less than (<) 80 kilograms (kg) received an IV infusion of 1,050 milligrams (mg) of ervantumab, and participants weighing greater than or equal to (≥) 80 kg received an IV infusion of 1,400 mg of ervantumab, once a week in cycle 1 and then every 2 weeks in subsequent cycles (on days 1 and 15 of each cycle). Recruitment status is shown in Table 6. Demographic and disease characteristics are shown in Table 7. An overall safety summary of treatment-emergent adverse events (TEAEs) is shown in Table 8. TEAEs of grade 3 or above are shown in Table 9.

[0564] Table 6. Recruitment status

[0565]

[0566] Table 7. Demographic and disease characteristics

[0567]

[0568]

[0569] Table 8. Overall safety summary of TEAEs

[0570]

[0571] Table 9. Related TEAEs of Grade ≥3

[0572]

[0573] The observed incidence of infusion-related reactions (IRRs) was similar to that seen in other studies of ivanovumab monotherapy. The incidence of hypoalbuminemia was slightly higher in the gastric cohort than in the esophageal cohort:

[0574] Gastric (n=29): All grades: 12 (41.4%), ≥ grade 3: 3 (10.3%)

[0575] Esophagus (n=30): All grades: 10 (33.3%), ≥ grade 3: 3 (10.0%)

[0576] Then, evaluate the response to treatment. "All treated " patient population is the patient who receives at least 1 dose of research treatment. "Can evaluate response " patient population is such patient, it (1) receives at least 1 dose of research treatment, (2) meets all qualification criteria of research, and (3) has baseline and at least 1 baseline post-efficacy disease assessment, or has disease progression / death due to disease progression before disease assessment after first baseline. Table 10 shows in the colony that can evaluate response, based on RECIST 1.1 version standard by the summary of the objective response rate of pre-screening IHC scoring (center). Table 11 shows in the colony that all treated, based on RECIST 1.1 version standard by the summary of the objective response rate of pre-screening IHC scoring (center).

[0577] Table 10. Summary of objective response rate by prescreening IHC score (center) based on RECIST version 1.1 criteria - Study Judgment of the respondent (the group that can evaluate the response)

[0578]

[0579]

[0580] Keyword: CI = Confidence Interval

[0581] a For a response to qualify as stable disease, follow-up measurements must meet stable disease criteria at least once within a minimum interval of ≥6 weeks after the first dose of study medication.

[0582] b The exact Clopper-Pearson 95% CI was used.

[0583] c The posterior probability (ORR>22.5%) was calculated based on the beta distribution.

[0584] Note: A response of PR or CR must be confirmed by repeat assessment ≥4 weeks from the initial observation.

[0585] NOTE: IHC score was defined as the highest staining of EGFR or cMet.

[0586] Table 11. Summary of objective response rates by prescreening IHC score (center) based on RECIST version 1.1 criteria - Study (all treated groups)

[0587]

[0588]

[0589] Keyword: CI = Confidence Interval

[0590] aFor a response to qualify as stable disease, follow-up measurements must meet stable disease criteria at least once within a minimum interval of ≥6 weeks after the first dose of study medication.

[0591] b Using exact Clopper-Pearson 95% CI.

[0592] cPosterior probability calculated based on β distribution (ORR>22.5%).

[0593] Note: A response of PR or CR must be confirmed by repeat assessment ≥4 weeks from the initial observation.

[0594] NOTE: IHC score was defined as the highest staining of EGFR or cMet.

[0595] The overall response of gastric cancer patients in the response-evaluable population is shown in Figure 6 The overall response of gastric cancer patients in all treated groups is shown in Figure 7 The overall response of patients with esophageal cancer in the response-evaluable population is shown in Figure 8 The overall response of patients with esophageal cancer in all treated groups is shown in Fig. 9 middle.

[0596] In summary, the safety profile in the gastric cancer / esophageal cancer cohort is consistent with the reported experience of other studies of ervantumab monotherapy. Among the 24 patients who were evaluable for response, the gastric cancer cohort had 1 partial response patient and 5 patients with stable disease (disease control rate (DCR): 25.0%). Among the 28 patients who were evaluable for response, the esophageal cancer cohort had 3 partial responses and 16 patients with stable disease (DCR: 67.9%).

[0597] A higher dose of 1,750 mg of ervantumab was evaluated in 3 patients with esophageal cancer. All 3 participants weighed less than (<) 80 kilograms (kg) and received IV infusions of 1,750 mg of ervantumab once a week in cycle 1 (the first dose was divided into 350 mg and 1400 mg on day 1 and day 2), and then received infusions every 2 weeks in subsequent cycles (on day 1 and day 15 of each cycle). Table 12 shows the demographic data and disease characteristics of patients treated with 1,750 mg of ervantumab. Table 13 shows the overall safety summary of TEAEs in patients treated with 1,750 mg of ervantumab. No TEAEs of grade 3 or higher were observed in the 1,750 mg ervantumab population.

[0598] Table 12. Demographic and disease characteristics

[0599]

[0600]

[0601] Table 13. Overall safety summary of TEAEs .

[0602] Patients treated with 1750 mg of ivantazumab All treated groups (safety analysis set) 3 Subjects who experienced 1 or more of the following events: AE 3(100.0％) Related AE 3(100.0％) SAE 0 Related SAE 0 Fatal AE 0 Fatal related AEs 0 AEs leading to discontinuation of study medication 0 Related AEs leading to study drug discontinuation 0 AEs leading to study treatment discontinuation 2(66.7％) Related AEs leading to study treatment discontinuation 1(33.3％) AEs leading to dose reduction 0 Related AEs leading to dose reductions 0 AEs leading to dose delays 0 Related AEs leading to dose delays 0

[0603] Efficacy was evaluated in 3 patients treated with 1750 mg of ivanovumab. One patient had stable disease, one patient had a partial response, and one patient had progressive disease. Fig.10 The best overall response among response-evaluable patients is shown.

[0604] Example 2. Evaluation of EGFR in a esophageal patient-derived xenograft (PDX) model expressing wild-type EGFR Ventuzumab

[0605] To evaluate the efficacy of ivantuzumab in a series of esophageal PDX models carrying wild-type EGFR (n=12, provided by CrownBio), tumor fragments from tumor-bearing reserve mice were harvested and inoculated into designated experimental mice. Each mouse was subcutaneously inoculated with designated tumor fragments (2 mm to 3 mm in diameter) in the right side for tumor development. Detailed esophageal PDX inoculation information is listed in Table 14.

[0606] Table 14.

[0607] serial number Model ID Cancer Type Mouse strains 1 ES0026 Esophageal cancer BALB / c nude mice 2 ES0110 Esophageal cancer BALB / c nude mice 3 ES0136 Esophageal cancer BALB / c nude mice 4 ES0148 Esophageal cancer BALB / c nude mice 5 ES0176 Esophageal cancer BALB / c nude mice 6 ES0178 Esophageal cancer BALB / c nude mice 7 ES11062 Esophageal cancer NOD / SCID 8 ES11079 Esophageal cancer BALB / c nude mice 9 ES11082 Esophageal cancer NOD / SCID 10 ES2267 Esophageal cancer BALB / c nude mice 11 ES3431 Esophageal cancer BALB / c nude mice 12 ES3862 Esophageal cancer BALB / c nude mice

[0608] After palpable lesions were established, tumor growth was measured twice weekly. Once the mean tumor volume reached approximately 150 mm 3 , the 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 denoted as day 0. In Table 15, treatment was started according to the study design on the same day of randomization.

[0609] Table 15.

[0610] Group N treat Dosage (mg / kg) Route of administration Dosing frequency 1 8 Isotype Control 10 ip BIW 2 8 Evantamab 10 ip BIW

[0611] ip: intraperitoneal; BIW: twice a week (day 0 and day 3 of each week).

[0612] The study endpoint was to compare the tumor growth of each group at the end of treatment with the subsequent tumor growth after drug administration was stopped. Tumor size was measured twice a week in two dimensions using calipers, and tumor volume was expressed in mm3 using the following equation: =0.5×L×W 2 , where V is the tumor volume, L is the tumor length (the longest tumor dimension) and W is the tumor width (the longest tumor dimension perpendicular to L). Tumor growth curves over time (expressed as mean ± SEM) are shown in Figures 2A to 2L middle.

[0613] Tumor growth inhibition (TGI%) is an indicator of antitumor activity and is calculated as TGI%=(1-(T-T0) / (C-C0))×100%, where T and C are the average TV of the treated and control groups, respectively, on the day when the tumor volume (TV) of the control group was terminated according to the study design. Tumor growth inhibition is summarized in Table 16.

[0614] Table 16.

[0615] serial number Model ID <![CDATA[Amivantamab TGI% * > 1 ES3431 112.68％ 2 ES0178 100.40％ 3 ES0110 90.76％ 4 ES11079 94.47％ 5 ES0026 58.57％ 6 ES3862 49.36％ 7 ES11062 45.51％ 8 ES0176 2.97％ 9 ES11082 -26.05％ 10 ES0136 -17.16％ 11 ES2267 35.48％ 12 ES0148 -5.59％

[0616] *: TGI% calculated as follows:

[0617]

[0618] C (i or 0): mean tumor volume of the control group on the indicated study day.

[0619] T(i or 0): mean tumor volume of the treatment group on the indicated study day.

[0620] like Figures 2A to 2L As shown in Table 16, 7 of 12 esophageal PDX tumors responded to ervantumab monotherapy. Among them, ervantumab 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 modest responses in ES0026, ES3862, and ES11062 (TGI% 58.6%, 49.4%, and 45.5%, respectively).

[0621] Example 3. Evaluation of ervantumab alone or in combination with chemotherapy or capmatis in the treatment of gastric PDX tumors Ni's combination

[0622] To evaluate the antitumor activity of evitumab, a panel of gastric PDX models were selected and treated with evitumab alone or in combination with the c-Met inhibitor capmatinib (Selleck), as well as gastric chemotherapy regimens such as 5-FU (Shanghai XudongHaipu Pharm) plus cisplatin (Qilu Pharm) or paclitaxel (Beijing Union Pharm).

[0623] Tumor fragments were harvested from mice bearing reserve tumors and inoculated into BALB / c nude mice. Each mouse was subcutaneously inoculated with designated tumor fragments (2 mm to 3 mm in diameter) in the right flank for tumor development. Detailed gastric PDX information is listed in Table 17.

[0624] Table 17.

[0625] serial number Model ID Cancer Type Mouse strains 1 GA0046 Gastric cancer BALB / c nude mice 2 GA0075 Gastric cancer BALB / c nude mice 3 GA0152 Gastric cancer BALB / c nude mice 4 GA2254 Gastric cancer BALB / c nude mice 5 GA3121 Gastric cancer BALB / c nude mice 6 GA3236 Gastric cancer BALB / c nude mice

[0626] After palpable lesions were established, tumor growth was measured twice weekly. Once the mean tumor volume reached approximately 150 mm 3 , the 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 denoted as day 0. When appropriate, treatment was started on the same day of randomization according to the dosing regimen in Table 18.

[0627] Table 18.

[0628]

[0629] ip: intraperitoneal; iv: intravenous; po: oral administration.

[0630] QW: once a week; BIW: twice a week (day 0 and day 3 of each week); BID: twice a day, with an interval of 12 hours; QD, 5 days / week: once a day from day 0 to day 5 of each week.

[0631] *: GA0046 was treated with groups 1, 2, 7, 8; GA0075 and GA0152 were treated with groups 1-6 (15 mg / kg paclitaxel); GA3121 was treated with groups 1, 2, 5, 6 (10 mg / kg paclitaxel); GA2254 and GA3236 were treated with groups 1-2.

[0632] The study endpoint was to compare the tumor growth of each group at the end of treatment with the subsequent tumor growth after drug administration was stopped. Tumor size was measured twice a week in two dimensions using calipers, and tumor volume was expressed in mm3 using the following equation: =0.5×L×W 2 , where V is the tumor volume, L is the tumor length (the longest tumor dimension) and W is the tumor width (the longest tumor dimension perpendicular to L). Tumor growth curves over time (expressed as mean ± SEM) are shown in FIG. 3A to FIG. 3F middle.

[0633] Tumor growth inhibition (TGI%) is an indicator of antitumor activity and is calculated as TGI%=(1-(T-T0) / (C-C0))×100%, where T and C are the average TV of the treated and control groups, respectively, on the day when the tumor volume (TV) of the control group was terminated according to the study design. Tumor growth inhibition is summarized in Table 19.

[0634] Table 19.

[0635]

[0636]

[0637] *: TGI% calculated as follows:

[0638]

[0639] C (i or 0): mean tumor volume of the control group on the indicated study day.

[0640] T(i or 0): mean tumor volume of the treatment group on the indicated study day.

[0641] like FIG. 3A to FIG. 3F As shown in Table 19, ervantumab monotherapy (10 mg / kg BIW) inhibited tumor growth in 3 out of 6 PDX models, with strong anti-tumor activity observed in GA0046 (TGI% 121.31%) and GA0075 (101.17%).

[0642] In GA0046 ( Figure 3A ), complete tumor regression was observed with ivanovumab single agent. In contrast, the c-Met inhibitor capmatinib (10 mg / kg BID) showed no effect on tumor growth (TGI %: 5.93% on day 28).

[0643] Standard of care chemotherapy regimens were also evaluated in this study. Figure 3B As shown in Figure 2, 5-FU (10 mg / kg QD 5 days / week) plus cisplatin (4 mg / kg QW) or paclitaxel (10 / 15 mg / kg, QW) showed moderate activity in GA0075 at day 28, at 43.35% and 66.09%. Strikingly, the ervantumab combination caused strong and durable tumor growth inhibition in the same model (104.92% and 111.54%, respectively). A similar synergistic effect between ervantumab and paclitaxel was observed in another model, GA0152, with TGI% increasing from 27.29% to 70.13% ( Figure 3E ).

[0644] Example 4. Relationship between receptor expression and in vivo efficacy of ervantamab in esophageal and gastric PDX tumors

[0645] To further investigate the antitumor activity of ervantumab versus receptor levels, immunohistochemistry assays were 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 blocking, primary antibody incubation, secondary antibody incubation, DAB reaction), the stained slides (with EGFR antibody, clone 5B7 from Ventana or SP84 from Abcam, or with c-Met antibody, clone SP44 from Ventana or Abcam) were further scanned into high-resolution pictures with an imaging system (NanoZoomer) for pathologist review and scoring.

[0646] The intensity of EGFR or c-Met membrane staining from each slide was scored at four levels: 0, 1+, 2+, and 3+. Further H scores were 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 tested esophageal and gastric PDX models and the antitumor activity of entuzumab are listed in Tables 20, Figure 4 and Table 21, Figure 5 In esophageal tumors, high EGFR levels appeared to be associated with tumor growth inhibition (TGI%), whereas in gastric tumors, high EGFR and / or cMet levels appeared to be associated with entuzumab TGI%.

[0647] H-Score(0-300)=(%@0)×0+(%@1)×1+(%@2)×2+(%@3)×3

[0648] %@0: percentage of cells with intensity 0 (negative staining).

[0649] %@1: Percentage of cells with intensity 1+ (weak or incomplete membrane staining).

[0650] %@2: percentage of cells with intensity 2+ (weak to moderate complete membrane staining).

[0651] %@3: percentage of cells with intensity 3+ (strong complete membrane staining).

[0652] Table 20.

[0653]

[0654] Table 21.

[0655]

[0656] ***

[0657] The present invention is not limited to the scope of the specific embodiments described herein. In fact, various modifications of the present invention, in addition to those described herein, will become apparent to those skilled in the art based on the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0658] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety, as if physically present in this specification.

Claims

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) / hepatocyte growth factor receptor (c-Met) antibody.

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

12.

3. The method of 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 a VH of SEQ ID NO: 15 and a VL of SEQ ID NO:

16.

4. The method of claim 2 or 3, wherein the bispecific anti-EGFR / c-Met antibody is of IgG1 isotype.

5. The method of 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.

6. The method of any one of claims 1 to 5, wherein the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure having a fucose content of between about 1% and about 15%.

7. The method of any one of claims 1 to 6, wherein the bispecific anti-EGFR / c-Met antibody is administered to the subject intravenously or subcutaneously.

8. The method of claim 7, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 350 mg to about 3400 mg.

9. The method of claim 8, wherein the bispecific anti-EGFR / c-Met antibody is administered at about 350 mg, 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 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 of claim 9, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg.

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

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

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

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

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

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

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

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

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

20. The method of any one of claims 1 to 19, 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.

21. The method of claim 20, wherein the bispecific anti-EGFR / c-Met antibody is administered once a week for four weeks and once every two weeks thereafter.

22. The method of claim 21, wherein the first dose of the bispecific anti-EGFR / c-Met antibody is administered within two days.

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

24. The method of any one of claims 1 to 23, wherein the subject has received prior treatment.

25. The method of claim 24, wherein the prior treatment comprises chemotherapy, targeted therapy, immunotherapy, surgery, radiation therapy, chemoradiotherapy, or a combination thereof.

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

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

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

29. The method of claim 25, wherein the targeted therapy comprises anti-HER2 therapy or anti-VEGF / VEGFR therapy.

30. The method of claim 29, wherein the anti-HER2 therapy comprises trastuzumab.

31. The method of claim 30, wherein the anti-VEGF / VEGFR therapy comprises bevacizumab or ramucirumab.

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

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

34. The method of claim 33, wherein the additional therapeutic agent comprises a glucocorticoid, an antihistamine, an antipyretic, an H2-antagonist, an antiemetic, an opiate, or any combination thereof.

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

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

37. A method of 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.

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

12.

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

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

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

45. The method of claim 44, wherein the bispecific anti-EGFR / c-Met antibody is administered at about 350 mg, 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg, 1550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2100mg, 2200mg, 2240mg, 2300mg, 2400mg, 2500mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, Doses of 3300 mg, 3360 mg or 3400 mg were administered.

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

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

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

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

50. The method of claim 455, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2100 mg.

51. The method of claim 455, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2240 mg.

52. The method of claim 455, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 2400 mg.

53. The method of claim 455, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of 3360 mg.

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

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

56. The method of 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 of claim 56, wherein the bispecific anti-EGFR / c-Met antibody is administered once a week for four weeks and once every two weeks thereafter.

58. The method of claim 57, wherein the first dose of the bispecific anti-EGFR / c-Met antibody is administered within two days.

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

60. The method of any one of claims 37 to 59, wherein the subject has received prior treatment.

61. The method of claim 60, wherein the prior treatment comprises chemotherapy, targeted therapy, immunotherapy, surgery, radiation therapy, chemoradiotherapy, or a combination thereof.

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

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

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

65. The method of claim 61, wherein the targeted therapy comprises anti-HER2 therapy or anti-VEGF / VEGFR therapy.

66. The method of claim 65, wherein the anti-HER2 therapy comprises trastuzumab.

67. The method of claim 65, wherein the anti-VEGF / VEGFR therapy comprises bevacizumab or ramucirumab.

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

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

70. The method of claim 69, wherein the additional therapeutic agent is a glucocorticoid, an antihistamine, an antipyretic, an H2-antagonist, an antiemetic, an opiate, or any combination thereof.

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

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

Images