Method and use of treating gastric cancer by combining anti-HER2 antibodies and chemotherapy agents

Abstract

Combination therapy with trastuzumab, a second anti-HER2 antibody, and a chemotherapy agent (XELOX) extends the progression-free survival (PFS) and / or overall survival (OS) of patients compared to the existing first-line treatment regimen for HER2-positive advanced gastric cancer.

Description

Technology Field

[0001] Cross-reference of related applications

[0002] This application claims priority to Chinese patent application No. CN202311527171.5 filed on November 16, 2023, the contents of which are incorporated herein by reference in their entirety.

[0003] Technology field

[0004] The present invention relates to a method and use for treating cancer by combining drugs. In particular, it relates to a method and use for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma by combining an anti-HER2 antibody, trastuzumab, and a chemotherapy agent. Background Technology

[0005] Gastric cancer is a common malignant tumor; according to WHO statistics, it caused 754,000 deaths in 2015, ranking fourth among causes of death from malignant tumors worldwide. In China, gastric cancer is the second most common malignant tumor with the second-highest annual number of new cases and is also the most prevalent gastrointestinal malignancy, making it a region with a high incidence rate globally. Gastric cancer can be classified into adenocarcinoma, adenosquamous cell carcinoma, squamous cell carcinoma, and carcinoid tumors, with the majority being gastric adenocarcinoma. Clinically, early symptoms of gastric cancer are often unclear. Although the rapid advancement of gastrointestinal endoscopy has significantly improved the rate of early diagnosis, the overall prognosis for gastric cancer remains poor, particularly for locally advanced and metastatic gastric cancer. While surgical resection offers the greatest treatment opportunity for gastric cancer patients, postoperative recurrence and metastasis are also major causes of death in these patients.

[0006] The HER2 (human epidermal growth factor receptor 2) gene is an oncogene located on the long arm of human chromosome 17 (17q21-q22) and encodes a transmembrane glycoprotein receptor. HER2 is a receptor tyrosine kinase bound to the surface of a cell membrane, involved in signaling pathways that induce cell growth and differentiation, and is encoded by the oncogene HER2 / neu. In academia, HER2 is generally considered an orphan receptor, and ligands of the epidermal growth factor family cannot activate HER2; however, when a ligand binds to the ErbB receptor, it can form a dimer, and HER2 can bind to other members of the ErbB (tyrosine kinase receptor) family to form a heterodimer.

[0007] HER2-positive gastric cancer is a distinct disease subtype that requires different diagnostic and treatment strategies and methods compared to HER2-negative gastric cancer. Globally, the reported HER2 overexpression positivity rate in gastric cancer ranges from 7.3% to 20.2%, while the HER2 positivity rate among gastric cancer patients in China is 12% to 13%. Currently, there is no consensus on the value of HER2 in determining the prognosis of gastric cancer, as evaluation criteria used in various studies differ.

[0008] Patients with HER2-positive advanced gastric cancer may benefit from trastuzumab treatment. Based on previous nonclinical results and the established clinical benefits of trastuzumab in combination with chemotherapy for HER2-positive metastatic breast cancer and breast cancer adjuvant therapy, a randomized Phase 3 clinical trial (ToGA) was conducted to evaluate the efficacy and safety of adding trastuzumab to a fluorouracil-based drug (capecitabine or 5-FU) + cisplatin (FP) combination therapy in patients with HER2-positive advanced gastric cancer. 594 patients from 24 countries were enrolled in the study. Patients were randomized in a 1:1 ratio to receive either FP therapy or FP + trastuzumab (TFP) treatment. The primary endpoint was overall survival (OS). As a result, it was confirmed that TFP treatment was superior to FP monotherapy; in the intended target (ITT) group, the median overall survival for patients in the TFP group was 13.8 months, compared to 11.1 months for the FP treatment group (hazard ratio = 0.74; 95% CI: 0.60, 0.91). The median progression-free survival for patients in the TFP group was 6.7 months, compared to 5.5 months for the FP treatment group (hazard ratio = 0.71; 95% CI: 0.59, 0.85).

[0009] In China, combination therapy using both fluorouracil and platinum-based drugs is generally recommended for the selection of chemotherapy agents in patients with advanced gastric cancer. Considering superior patient tolerability and actual clinical application in China, the CSCO Gastric Cancer Guidelines further recommend oxaliplatin among platinum-based drugs. The efficacy of the capecitabine + oxaliplatin (XELOX) regimen has also been demonstrated through relevant clinical trials and received a Grade I recommendation in the Chinese CSCO Gastric Cancer Guidelines. At the same time, current European ESMO guidelines and U.S. NCCN guidelines also prioritize the combination of trastuzumab and chemotherapy (fluorouracil and platinum-based drugs) as the first-line treatment for HER2-positive advanced gastric cancer. Immunotherapy has become an important area of ​​exploration for combination therapy in HER2-positive advanced gastric cancer.

[0010] The first objective of the present invention is to provide a combination use of trastuzumab, a second antibody, and a chemotherapy agent in the manufacture of a drug for treating HER2-positive gastric cancer.

[0011] The second objective of the present invention is to provide a kit for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0012] The present invention also provides a method for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma by combining trastuzumab with a second antibody and a chemotherapy agent.

[0013] According to one aspect of the present invention, the present invention provides a method for treating cancer, particularly HER2-positive gastric cancer, by combining trastuzumab, a second antibody, and a chemotherapy agent, wherein the second antibody is an anti-HER2 antibody (also referred to as a second anti-HER2 antibody) or an antigen-binding fragment thereof, and the second antibody has a binding epitope different from that of trastuzumab, and preferably the second antibody comprises a heavy chain and a light chain;

[0014] The above heavy chain includes a heavy chain variable region, and the heavy chain variable region includes HCDR1 (heavy chain complementarity determining region 1) described as SEQ ID NO:1, HCDR2 (heavy chain complementarity determining region 2) described as SEQ ID NO:2, and HCDR3 (heavy chain complementarity determining region 3) described as SEQ ID NO:3; and

[0015] The above light chain includes a light chain variable region, and the light chain variable region includes LCDR1 (light chain complementarity determining region 1) described as SEQ ID NO:6, LCDR2 (light chain complementarity determining region 2) described as SEQ ID NO:7, and LCDR3 (light chain complementarity determining region 3) described as SEQ ID NO:8.

[0016] In a preferred embodiment of the present invention, the heavy chain variable region of the second antibody comprises or is composed of the amino acid sequence described as SEQ ID NO:4, and the light chain variable region of the second antibody comprises or is composed of the amino acid sequence described as SEQ ID NO:9.

[0017] In a preferred embodiment of the present invention, the heavy chain of the second antibody comprises or is composed of the amino acid sequence described as SEQ ID NO:5, and the light chain of the second antibody comprises or is composed of the amino acid sequence described as SEQ ID NO:10.

[0018] As chemotherapy agents used in combination with two types of antibodies, various chemotherapy agents currently applied in clinical practice or recommended in guidelines may be selected, and preferred chemotherapy agents are fluorouracil-based drugs and platinum-based drugs used alone or in combination. Preferred fluorouracil-based drugs are selected from 5-fluorouracil and capecitabine, and platinum-based drugs are selected from cisplatin and oxaliplatin. More preferably, the chemotherapy agents are capecitabine and oxaliplatin, and in the most preferred treatment regimen, trastuzumab is used in combination with a second antibody and a capecitabine + oxaliplatin chemotherapy agent (XELOX).

[0019] The use according to the present invention is primarily for treating HER2-positive gastric cancer, particularly HER2-positive advanced gastric cancer, and is more recommended for the treatment of unresectable advanced or metastatic HER2-positive gastric cancer, including gastroesophageal junction adenocarcinoma having diagnostic criteria and clinical symptoms generally identical or similar to gastric cancer. In a preferred embodiment of the present invention, the method and use of the present invention are applied to a patient who has not received treatment and has been diagnosed with unresectable advanced or metastatic gastric cancer, i.e., for the primary treatment of said cancer.

[0020] Regarding the mode of administration and drug dosage, the dosages of the trastuzumab, the second antibody, or its conjugated fragment are as follows: namely: administered intravenously every 3 weeks, wherein the trastuzumab is administered at an initial loading dose of 8 mg / kg, followed by 6 mg / kg every 3 weeks, and the second antibody is administered at a dose of 25 mg / kg or 15 mg / kg; wherein the chemotherapeutic agent is a combination of capecitabine and oxaliplatin (XELOX regimen), and the dose of oxaliplatin is 130 mg / m² 2 Administered by intravenous infusion at this dose, once every 3 weeks; capecitabine is 1000 mg / m² 2 It is administered orally at a given dose, twice a day, with 3 weeks constituting one administration cycle.

[0021] Based on the above combination therapy, an immune checkpoint inhibitor, e.g., an anti-PD-1 antibody and / or an anti-PD-L1 antibody, may be additionally administered as needed, preferably an anti-PD-1 antibody.

[0022] According to another aspect of the present invention, the combination therapy regimen of the present invention may involve administering each drug to a patient individually according to the regimen, or may be manufactured in the form of a drug package or kit to facilitate convenience of administration. Accordingly, the present invention provides a kit for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, wherein the kit comprises the following composition, namely:

[0023] Trastuzumab;

[0024] Second antibody - The second antibody is a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of the trastuzumab, and comprises a heavy chain and a light chain, and

[0025] The above heavy chain includes a heavy chain variable region, and the heavy chain variable region includes HCDR1 listed in SEQ ID NO:1, HCDR2 listed in SEQ ID NO:2, and HCDR3 listed in SEQ ID NO:3; and

[0026] The above light chain includes a light chain variable region, and the light chain variable region includes LCDR1 listed in SEQ ID NO:6, LCDR2 listed in SEQ ID NO:7, and LCDR3 listed in SEQ ID NO:8 - ; and

[0027] Includes chemotherapy agents.

[0028] In a preferred embodiment of the present invention, the chemotherapy agents are capecitabine and oxaliplatin.

[0029] The kit according to the present invention may further include an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0030] Beneficial effects:

[0031] The present invention provides a method and use of combining an anti-HER2 antibody combination and a chemotherapy agent for the treatment of HER2-positive gastric cancer patients. In particular, the method and use involve treating HER2-positive advanced gastric cancer by combining trastuzumab, a second anti-HER2 antibody, and a chemotherapy agent. According to data from a randomized, double-blind, multi-center, phase 2 clinical trial on the combination therapy of trastuzumab, a second anti-HER2 antibody, and a chemotherapy agent (XELOX) in patients with unresectable advanced or metastatic HER2-positive gastric cancer, the combination therapy of trastuzumab, a second anti-HER2 antibody, and a chemotherapy agent (XELOX) was shown to extend the patients' progression-free survival (PFS) and / or overall survival (OS) compared to first-line treatment regimens for HER2-positive advanced gastric cancer. Brief explanation of the drawing

[0032] FIG. 1 shows the results of a HER2 epitope binding competition analysis of the second anti-HER2 antibody, trastuzumab, and pertuzumab according to the present invention; Here, a is the result of epitope binding competition analysis with sequential injection of HER2-Fc protein, trastuzumab, and pertuzumab; b is the result of an epitope binding competition analysis with sequential injection of HER2-Fc protein, pertuzumab, and trastuzumab; In the diagram, HER2 represents the HER2-Fc protein. Figure 2 shows the results of a study on the effect of combination treatment of the second anti-HER2 antibody according to the present invention and trastuzumab on HER2-mediated endocytosis in gastric cancer cells NCI-N87(a) and SNU216(b). FIG. 3 shows the results of a study on the EGFR cell expression levels induced in gastric cancer cells NCI-N87 by combination treatment with the second anti-HER2 antibody and trastuzumab according to the present invention; Here, a, b, and c are HER2 expression levels over time in NCI-N87 cells; d, e, and f are EGFR expression levels over time in NCI-N87 cells. Figure 4a shows the results of a study on the effect of combination treatment of the second anti-HER2 antibody according to the present invention and trastuzumab on the cell viability of gastric cancer cells NCI-N87. Figure 4b shows the results of a study on the effect of combination treatment of the second anti-HER2 antibody according to the present invention and trastuzumab on apoptosis of gastric cancer cells NCI-N87. Figure 4c shows the results of the combination treatment of the second anti-HER2 antibody and trastuzumab according to the present invention on the tumor volume of a heterologous human gastric cancer NCI-N87 model. Figures 4d and 4e show the results of combination treatment of the second anti-HER2 antibody and trastuzumab according to the present invention on the tumor volume of a human gastric cancer PDX model. Figure 5 shows the Kaplan-Meier curve (RECIST 1.1) for the progression-free survival of subjects in a clinical study according to the present invention. Specific details for implementing the invention

[0033] The present invention will be explained in more detail through the following embodiments, and this should not be interpreted as limiting the present invention.

[0034] I. Definition

[0035] The term “HER receptor” refers to a receptor protein tyrosine kinase belonging to the HER receptor family, including EGFR, HER2, HER3, and HER4 receptors. HER receptors generally comprise a. an extracellular domain—which binds to a HER ligand and / or can dimerize with other HER receptor molecules—; b. a lipophilic transmembrane domain; c. a conserved intracellular tyrosine kinase domain; and d. a carboxy-terminal signaling domain containing several tyrosine residues capable of phosphorylation. HER receptors may be “natural sequence” HER receptors or their “amino acid sequence variants.” Preferably, HER receptors are natural sequence human HER receptors.

[0036] “HER dimer” as in this specification refers to a non-covalent dimer comprising at least two HER receptors. Such a complex may be formed when cells expressing two or more types of HER receptors are exposed to a HER ligand and can be separated by immunoprecipitation and analyzed by SDS-PAGE (e.g., Sliwkowski et al., J. Biol. Chem. 269(20):14661-14665 (1994)). Other proteins, such as cytokine receptor subunits, may bind to said dimer. Preferably, said HER dimer comprises HER2.

[0037] “HER dimer” in this specification means a non-covalent dimer comprising at least two different HER receptors, such as EGFR-HER2, HER2-HER3, or HER2-HER4.

[0038] “HER antibody” refers to an antibody that binds to a HER receptor. Optionally, the HER antibody further inhibits HER activation or function. Preferably, the HER antibody binds to a HER2 receptor. The HER2 antibody according to this specification is trastuzumab and a second anti-HER2 antibody, which includes CDRs.

[0039] “HER activation” refers to the activation or phosphorylation of any one or more HER receptors. Generally, HER activation triggers signal transduction (e.g., phosphorylation of tyrosine residues within the HER receptor or substrate polypeptide induced by the intracellular kinase domain of the HER receptor). HER activation can be mediated by a HER ligand binding to a HER dimer containing a HER receptor. A HER ligand binding to a HER dimer can activate the kinase domains of one or more HER receptors within the dimer, thereby inducing phosphorylation of one or more tyrosine residues within the HER receptor and / or phosphorylation of tyrosine residues within other substrate polypeptides or intracellular kinases, such as Akt or MAPK.

[0040] “Phosphorylation” means the addition of one or more phosphate groups to a protein such as a HER receptor or its substrate.

[0041] An antibody that “inhibits HER dimerization” refers to an antibody that inhibits or interferes with the formation of HER dimers. Preferably, antibodies of this class bind to the heterodimer binding site of HER2. The most preferred dimerization-inhibiting antibody in this specification is trastuzumab or a second anti-HER2 antibody. Other examples of antibodies that inhibit HER dimerization include an antibody that binds to EGFR and inhibits it from dimerizing with one or more other HER receptors; an antibody that binds to HER3 and inhibits it from dimerizing with one or more other HER receptors; and an antibody that binds to HER4 and inhibits it from dimerizing with one or more other HER receptors.

[0042] “HER2 dimerization inhibitors” are drugs that inhibit the formation of dimers or heterodimers containing HER2.

[0043] The “heterodimer binding site” on HER2 refers to a region that contacts a specific region within the extracellular domain of EGFR, HER3, or HER4, or forms an interface with a specific region within the extracellular domain of EGFR, HER3, or HER4, when forming a dimer with EGFR, HER3, or HER4 in the extracellular domain of HER2. The said region was found to be located within Domain II of HER2.

[0044] As used herein, “Trastuzumab” refers to an antibody comprising the heavy chain of SEQ ID NO:11 and the light chain of SEQ ID NO:12 and the CDRs contained therein; the term “Trastuzumab” is understood herein to encompass “rhuMb4D5” (e.g., the antibody disclosed in U.S. Patent No. 5,821,337) and bio-analogous drugs of trastuzumab.

[0045] “Pertuzumab” refers to an antibody comprising the heavy chain of SEQ ID NO:13 and the light chain of SEQ ID NO:14 and the CDRs contained therein; the term “Pertuzumab” is understood herein to encompass “RhuMAb 2C4” (e.g., disclosed in WO01 / 00245, WO2006 / 007398 and U.S. Patent US2006 / 0034842) and bio-analogous drugs of pertuzumab.

[0046] The term “antibody” is used in the broadest sense herein and specifically encompasses monoclonal antibodies, polyclonal antibodies, multispecific antibodies, and antibody fragments. In some embodiments, the term “antibody” refers to a protein comprising at least two heavy chains (H) and two light chains (L) connected to each other by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated as VH herein) and a heavy chain constant region (abbreviated as CH herein). In certain antibodies, e.g., naturally occurring IgG antibodies, the heavy chain constant region comprises a hinge and three domains CH1, CH2, and CH3. In some antibodies, e.g., naturally occurring IgG antibodies, each light chain comprises a light chain variable region (abbreviated as VL herein) and a light chain constant region. The light chain constant region consists of a single domain (abbreviated as CL herein). The VH and VL regions can be further subdivided into highly variable regions called complementation determining regions (CDRs), with more conserved regions called framework regions (FRs) interspersed between them. Each VH and VL consists of three CDRs and four FRs, which are arranged in the following order from amino terminus to carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, said host tissues or factors including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The heavy chain may or may not have C-terminal lysine. Unless otherwise stated in this specification, amino acids in the variable region are numbered according to the Kabat numbering system, and amino acids in the invariant region are numbered according to the EU system.

[0047] “Complete antibody” refers to an antibody comprising two antigen-binding regions and an Fc region in this specification.

[0048] “Antigen-binding fragment” refers to any antibody fragment capable of binding to an antigen as specified herein, including Fab, F(ab'), F(ab')2, Fv, etc. Fab has a single antigen-binding site composed of a heavy chain variable domain, a light chain variable domain, a light chain constant domain, and a heavy chain first constant domain (CH1) of the antibody. Fab’ differs from Fab in that a hinge region containing one or more cysteine ​​residues exists at the C-terminus of the heavy chain CH1 domain. F(ab')2 antibody is produced by forming disulfide bonds between the cysteine ​​residues of the Fab’ hinge region. Fv is the smallest antibody fragment composed of a heavy chain variable domain and a light chain variable domain, and recombinant techniques for producing the Fv fragment are disclosed in PCT WO 88 / 10649, WO 88 / 106630, WO 88 / 07085, WO 88 / 07086, and WO 88 / 09344. In double chains, the variable regions of the heavy and light chains are connected by non-covalent bonds, whereas in single-chain Fvs, the variable regions of the heavy and light chains are typically connected by covalent bonds via peptide linkers or directly connected to each other at the C-terminus to form a dimer (e.g., double-chain Fv). These antibody fragments can be obtained using proteases (e.g., digesting a complete antibody with papain to produce a Fab fragment and treating it with pepsin to produce an F(ab')2 fragment), and these antibody fragments can be produced by recombinant DNA technology.

[0049] As used herein, the term “heavy chain” means a full-length heavy chain comprising a variable domain (VH) having an amino acid sequence containing a variable region sequence for specifically binding to an antigen, and three constant domains (CH1, CH2, and CH3), and all of the same. As used herein, the term “light chain” means a full-length light chain comprising a variable domain (VL) having an amino acid sequence containing a variable region sequence for specifically binding to an antigen, and a constant domain (CL), and all of the same.

[0050] As used herein, the term “CDR (complementarity determining region)” refers to the amino acid sequences of the heavy chain highly variable region and the light chain highly variable region of an immunoglobulin (Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., US Department of Health and Human Services, National Institutes of Health (1987)). Each heavy chain and light chain comprises three CDRs (heavy chain (HCDR1, HCDR2, and HCDR3), light chain (LCDR1, LCDR2, and LCDR3)). The CDRs provide contact residues that play an important role in the binding of the antibody to the antigen or epitope.

[0051] “Epitope” or “binding epitope” is also called an antigenic determinant and refers to a site on an antigen molecule that specifically binds to an antibody binding site and determines antigenic specificity.

[0052] As used in the present invention, an “immune checkpoint” is a type of immunosuppressive molecule that is primarily expressed on immune cells to regulate the degree of immune activation and prevent autoimmunity; examples include PD1, CTLA4, LMTK3, LAG3, TIM3, TIGIT, etc. An “immune checkpoint inhibitor” refers to a molecule capable of reducing, blocking, inhibiting, eliminating, or interfering with the interaction between an immune checkpoint molecule and its ligand. In some embodiments, immune checkpoint inhibitors include anti-PD-1 antibodies, anti-CTLA4 antibodies, anti-LMTK3 antibodies, anti-LAG3 antibodies, anti-TIM3 antibodies, and anti-TIGIT antibodies. In a specific embodiment of the present invention, the immune checkpoint inhibitor is preferably an anti-PD-1 antibody.

[0053] “PD-1” refers to programmed cell death receptor 1, an immunosuppressive receptor belonging to the CD28 family. PD-1 is primarily expressed on the surface of activated T cells in vivo and can bind to two ligands, PD-L1 and PD-L2. The term “PD-1” typically includes human PD-1, its variants, isoforms, or analogs having at least one common epitope. As used herein, anti-PD-1 antibodies may degrade, block, inhibit, eliminate, or interfere with signal transduction caused by the interaction between PD-1 and PD-L1 and / or PD-L2.

[0054] As used herein, “ADCC or antibody-dependent cell-mediated cytotoxicity” refers to the action in which an IgG antibody specifically binds to a surface antigenic determinant of a target cell (e.g., a tumor cell or an infected cell) through a Fab fragment, and then the Fc fragment of the antibody binds to an effector cell having FcγR, such as an NK cell, monocyte / macrophage, or neutrophil, thereby inducing the killer activity of the effector cell and directly killing the target cell, wherein the NK cell is the primary cell mediating ADCC.

[0055] A “cell line-derived xenograft tumor model, or CDX” refers to a tumor model constructed by transplanting xenogeneic (e.g., human-derived) tumor cell lines cultured in vitro into immunodeficient mice, and is currently one of the most common in vivo models for the nonclinical pharmacodynamic evaluation of anti-tumor drugs.

[0056] A “PDX model or patient-derived tumor xenograft model” refers to a method in which tumor tissue derived from a tumor patient is transplanted into a mouse with severe immunodeficiency, allowing the tumor tissue to grow within the mouse to form a transplanted tumor; this model can maintain the growth microenvironment of the parent tumor, is advantageous for better expression of the parent tumor's traits, and preserves tumor heterogeneity.

[0057] As used herein, “cancer” or “cancer disease” refers to a physiological disease of mammals characterized by uncontrolled cell overgrowth. As used herein, “cancer” refers to a broad range of diseases characterized by the uncontrolled growth of abnormal cells within the body. “Cancer” or “cancer tissue” may include tumors. Uncontrolled cell division may result in the formation of malignant tumors or cells that invade adjacent tissues and may metastasize to distant parts of the body via the lymphatic system or bloodstream. After metastasis, the distant tumor may be considered “derived” from a pre-metastasis tumor. For example, a tumor “derived” from melanoma refers to a tumor caused by metastatic melanoma. Because the distant tumor is derived from a pre-metastasis tumor, the “derived” tumor may include the pre-metastasis tumor; for example, a tumor derived from melanoma may include melanoma. In some embodiments, cancer or tumor includes solid tumors. In some embodiments, the cancer or tumor comprises an advanced solid tumor. In some embodiments, the cancer or tumor comprises a diffuse solid tumor. In some embodiments, the cancer or tumor comprises an advanced malignant tumor. In some embodiments, the cancer or tumor is a metastatic cancer or tumor (e.g., stage 4 cancer or tumor).

[0058] As used herein, “advanced gastric cancer” refers to cancer that has spread outside the original site or organ due to local invasion or metastasis, and advanced gastric cancer is typically determined according to the AJCC / UICC gastric cancer TNM staging rules, for example, tissue invasion of the tumor (e.g., visceral peritoneum or adjacent structures), regional lymph node metastasis and / or distant metastasis, or CT staging signs.

[0059] “Irresectable” cancer refers to cancer that cannot be surgically removed; this is primarily due to causes inherent to the tumor itself, such as cases where the primary tumor has severe external invasion that prevents separation from surrounding normal tissue or engulfs major blood vessels; cases where regional lymph node metastasis is fixed and forms a fused mass, or where metastatic lymph nodes are not within a surgically clearable range; or cases involving distant metastasis or peritoneal dissemination of the tumor.

[0060] “Metastatic” cancer refers to cancer that has spread from one part of the body (typically the primary site) to another part of the body.

[0061] “HER2-positive” cancer refers to cancer containing cancer cells with HER2 levels above normal. Typically, HER2-positive cancer has an immunohistochemistry (IHC) score of 2+ or 3+ and / or an in situ hybridization (ISH) amplification ratio of ≥2.0.

[0062] The term “patient” refers to a human subject receiving preventive or therapeutic treatment.

[0063] As used herein, the term “subject” refers to a human. In some embodiments, the subject is in an untreated state. In some embodiments, the subject has already received at least one prior therapy to treat the cancer or tumor. In some embodiments, the subject has progressed, relapsed, or developed resistance to at least one standard therapy. For a specific type of cancer or tumor, various standard therapy regimens are known in the art. In some embodiments, at least one standard therapy regimen includes treatment in an advanced or metastatic setting according to solid tumor histology.

[0064] “Treatment” refers to therapeutic treatment and protective or preventive measures taken to achieve beneficial or desirable outcomes (including clinical outcomes). Achieving beneficial or desirable outcomes includes, but is not limited to, one or more of the following: relief of one or more symptoms caused by the disease; reduction of the severity of the disease; stabilization of the disease (e.g., prevention or delay of disease exacerbation); delay or remission of disease progression; improvement of the disease state; increase or improvement of quality of life; weight gain and / or extension of survival.

[0065] “Administration” means introducing a therapeutic drug to a subject (e.g., a subject) using one of various methods and delivery modes or systems known to those skilled in the art. Routes of administration of the antibody include intravenous, intramuscular, subcutaneous, intraperitoneal, and other parenteral routes. In some embodiments, intravenous use is by, for example, injection or infusion. Routes of administration of the chemotherapy agent include intravenous, intramuscular, subcutaneous, and other parenteral routes, or oral administration.

[0066] As used herein, the terms “about once every 1 week,” “about once every 2 weeks,” “about once every 3 weeks,” or other similar dosage interval terms refer to approximations. “About once every 1 week” may include 7 days ± 1 day, i.e., every 6 to 8 days. “About once every 2 weeks” may include 14 days ± 3 days, i.e., every 11 to 17 days. “About once every 3 weeks” may include 21 days ± 3 days, i.e., every 18 to 24 days. For example, similar approximations also apply to about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks. In some embodiments, a dose interval of about 6 weeks or about 12 weeks means that the first dose may be administered on any day of the first week, and then the next dose may be administered on any day of the sixth week or the twelfth week. In some embodiments, a dose interval of about 6 weeks or about 12 weeks means that the first dose is administered on a specific day of the first week (e.g., Monday), and then the next dose is administered on the same day of the sixth week or the twelfth week (i.e., Monday).

[0067] As used herein, “effective dose or effective amount” refers to a dose capable of producing a therapeutic effect in an individual with each administration. This dose may vary depending on various factors such as the purpose of treatment, frequency of treatment, the individual’s body weight and tolerance, severity of symptoms, risk of side effects, and route of administration. Specifically, the term “effective dose” or “effective amount” is defined as an amount sufficient to achieve, or at least partially achieve, the desired effect. The “therapeutic effective dose” or “therapeutic effective amount” of a drug or therapeutic agent refers to any amount of the drug capable of promoting disease regression when administered alone or in combination with other therapeutic agents, wherein said disease regression is demonstrated by a reduction in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods, or the prevention of damage or disability caused by the suffering of the disease. The therapeutic effective dose or amount of a drug includes a “preventive effective dose” or “preventive effective amount,” which is any amount of the drug capable of suppressing the onset or recurrence of the disease when administered alone or in combination with other therapeutic agents to subjects at risk of disease onset or disease recurrence. The ability of a therapeutic agent to promote disease regression or to suppress the onset or recurrence of disease can be evaluated using various methods known to those skilled in the art, for example, through human subjects in clinical trials, by predicting the efficacy of the therapeutic agent in humans in animal model systems, or by measuring the activity of the drug through in vitro analysis methods.

[0068] For example, an anticancer drug is a drug that promotes cancer regression in subjects. In some embodiments, a therapeutically effective dose of the drug promotes cancer regression to the extent that the cancer is eliminated. “Promotion of cancer regression” means that administering an effective dose of the drug alone or in combination with an antitumor agent results in a reduction in tumor growth or size, tumor necrosis, a reduction in the severity of at least one disease symptom, an increase in the frequency and duration of symptom-free periods, prevention of damage or disability due to the suffering of the disease, or alleviation of the patient’s disease symptoms in other ways. Additionally, the terms “effective” and “effectiveness” related to treatment include pharmacological efficacy and physiological safety. Pharmacological efficacy refers to the ability of the drug to promote cancer regression in the patient. Physiological safety refers to toxic levels or other undesirable physiological effects (adverse reactions) occurring at the cellular, organ, and / or biological level due to the administration of the drug.

[0069] As an example of tumor treatment, compared to subjects who have not received treatment, the therapeutically effective dose or amount of the drug inhibits cell growth or tumor growth by at least about 20%, at least about 40%, at least about 60%, or at least about 80%. In some embodiments, the therapeutically effective dose or amount of the drug completely inhibits cell growth or tumor growth, that is, inhibits cell growth or tumor growth by 100%. The tumor growth inhibitory ability of the compound can be evaluated using the analytical method described below. Alternatively, this property of the composition can be evaluated by examining the cell growth inhibitory ability of the compound, and this inhibitory action can be measured in vitro using analytical methods known to those skilled in the art.

[0070] As used herein, the term “weight-based” amount or dose means calculating the dose to be administered to a patient based on the patient’s weight. For example, if a patient weighing 60 kg requires 15 mg / kg of the second antibody, a suitable amount of the second antibody (i.e., 900 mg) can be calculated and administered.

[0071] “Chemotherapy agents” refers to chemical compounds that can be used for cancer treatment. For example, chemotherapy agents used in chemotherapy include alkylating agents, ethyleneimines and methylamelamines, acetogenin, colchicines, camptothecin, antibiotics, folic acid analogs, purine analogs, pyrimidine analogs, platinum analogs, or platinum-based analogs. The chemotherapy agents used in the present invention relate to fluorouracil-based compounds and platinum-based chemotherapy agents, specifically including 5-fluorouracil (5-FU), capecitabine, cisplatin, and oxaliplatin. In addition, “XELOX” as used in the present invention refers to a combination chemotherapy agent comprising the drugs capecitabine (Xeloda) and oxaliplatin (Oxaliplatin), which is commonly used in the chemotherapy of gastrointestinal cancers such as advanced gastric cancer and advanced colorectal cancer.

[0072] As used herein, “chemotherapy” refers to a method of chemotherapy for cancer treatment and includes standard regimens of chemotherapy with fluorouracil-based compounds and chemotherapy with platinum-based chemotherapy agents according to the present invention. In specific embodiments of the present invention, the chemotherapy agent comprises 5-fluorouracil, capecitabine + cisplatin, or oxaliplatin, preferably capecitabine + oxaliplatin.

[0073] “Immunotherapy or immunotherapy” refers to treating a subject who has a disease, is infected, or is at risk of disease recurrence by a certain method, and includes the induction, enhancement, suppression, or other modification of the immune response.

[0074] As used herein, “fixed” or “flat” doses refer to doses applied to a patient without taking into account the patient’s body weight and body surface area.

[0075] The “loading” dose generally comprises an initial dose of the therapeutic agent (including trastuzumab, a second anti-HER2 antibody, a chemotherapy agent, etc.) administered to the patient, followed by one or more maintenance doses. Typically, a single loading dose is administered; whereas in other embodiments of the present invention, multiple loading doses are administered. Typically, the amount of the loading dose administered exceeds the amount of the maintenance dose administered, and / or, the loading dose is administered more frequently than the maintenance dose, thereby reaching the target steady-state concentration of the therapeutic agent more quickly than when the maintenance dose is used.

[0076] The “maintenance” dose refers to one or more doses of the therapeutic agent administered to a patient during the treatment period in this specification. Typically, the maintenance dose is administered at regular treatment intervals, for example, once every approximately 1 week, once every approximately 2 weeks, once every approximately 3 weeks, or once every approximately 4 weeks, and preferably once every 3 weeks.

[0077] “Intravenous (IV) administration” refers to the administration of a drug (e.g., trastuzumab, 2nd anti-HER2 antibody, or chemotherapy agent) into a patient’s vein by means of infusion or the like.

[0078] “Subcutaneous” administration means administering a drug (including trastuzumab, 2nd anti-HER2 antibody, or chemotherapy agent) under the patient’s skin.

[0079] As used herein, “overall survival” or “OS” means that a patient survives for a specific period, such as one year, five years, etc., from the time of diagnosis or treatment. According to the purpose of the clinical trial described in the examples, overall survival (OS) is defined as the time from the date of randomization of the patient group to death from all causes.

[0080] “Progression-free survival” or “PFS” refers to a state in which a patient remains alive without the cancer progressing or worsening. Progression-free survival (PFS) is defined as the time from the time of randomization of the study population to the first recorded disease progression, unmanageable toxicity, or death from any cause (whichever occurs first). Disease progression may be recorded in any clinically acceptable manner.

[0081] “Disease-free survival” or “DFS” means that a patient has survived for a certain period, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc., from the time of treatment initiation or initial diagnosis, and that the cancer has not recurred. In the study forming the basis of the present invention, DFS is analyzed according to the treatment intention principle, that is, the patient is evaluated based on the assigned treatment. Events used in the DFS analysis typically include local recurrence, regional recurrence and distant recurrence, the occurrence of a secondary cancer (or a second primary cancer), and all-cause death in patients without antecedent events (e.g., cancer recurrence or a second primary cancer).

[0082] “Invasive disease-free survival” or “iDFS” is the time during which a patient survives after adjuvant therapy and has not experienced a recurrence of invasive cancer in any area or has not died from any cause. That is, iDFS is defined as a state in which a patient survives for a certain period, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 10 years after adjuvant therapy, from the time of treatment initiation or initial diagnosis, without a recurrence of invasive disease. In one embodiment, iDFS is about 1 year or about 3 years from the time of treatment initiation.

[0083] “Prolonged survival” means that the overall survival or progression-free survival of a patient treated according to the present invention is extended compared to an untreated patient and / or a patient treated with one or more approved antitumor agents but not treated according to the present invention. In a specific example, “prolonged survival” means that the progression-free survival (PFS) and / or overall survival of a cancer patient receiving the combination therapy of the present invention is extended compared to a patient treated only with trastuzumab and chemotherapy. In another specific example, “prolonged survival” means that the progression-free survival (PFS) and / or overall survival (OS) of a cancer patient receiving the combination therapy of the present invention is extended compared to a patient treated only with antibodies and / or chemotherapy.

[0084] “Objective response” refers to a measurable response and includes a complete response (CR) or a partial response (PR).

[0085] “Complete Response” or “CR” means that all signs of cancer have disappeared in response to treatment. This does not always mean that the cancer has been cured.

[0086] “Partial response” or “PR” means that the size of one or more tumors or lesions, or the extent of cancer within the body, decreases in response to treatment.

[0087] As used herein, “Adverse Reaction (AE)” refers to any adverse, often unintended, or undesirable sign (including abnormal laboratory findings), symptom, or condition associated with the application of a medical treatment. For example, an adverse reaction may be associated with the activation of the immune system or the proliferation of immune system cells in response to treatment.

[0088] As used herein, “safety data” refers to data obtained from controlled clinical trials, which indicates the prevalence and severity of adverse reactions to provide guidance to users regarding drug safety, and includes guidance on how to monitor and prevent adverse reactions to the drug.

[0089] “Efficacy data” refers to data obtained from controlled clinical trials, indicating that the drug effectively treats diseases such as gastric cancer.

[0090] As used herein, “simultaneous” use means administering on the same day as the day of treatment with one or more other drugs during the same treatment cycle, and optionally at the same time as said one or more other drugs.

[0091] As used herein, “concurrent use” or “concurrent use” means applying two or more active substances to a patient or subject together in the form of a mixture, simultaneously as a single preparation, or sequentially as a single preparation in any order.

[0092] The term “synergy” or “synergy effect” refers to a situation where the effect generated by two or more active molecules is greater than the simple sum of the effects of each component administered individually.

[0093] The term “approximately” is used to indicate a range of roughly, generally, or typically. When the term “approximately” is used with a numerical range, it adjusts the range by extending the upper and lower limits of the presented value. Typically, the term “approximately” means adjusting the value to be higher or lower than the stated value, for example, within a range of 10% variation.

[0094] II. Overview

[0095] The present invention provides a use for manufacturing a drug for treating gastric cancer by combining an anti-HER2 antibody combination with a chemotherapy agent, specifically, a use for manufacturing a drug for treating HER2-positive gastric cancer, particularly HER2-positive advanced gastric cancer, by combining trastuzumab, a second anti-HER2 antibody or its antigen-binding fragment, and a chemotherapy agent, and more preferably, a use for manufacturing a drug for treating a patient diagnosed with unresectable advanced or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0096] The present invention also provides a method for treating a patient diagnosed with the above disease, particularly unresectable advanced or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, the method comprising the step of administering a therapeutically effective amount of trastuzumab, a second anti-HER2 antibody or its antigen-binding fragment, and a chemotherapy agent (e.g., a fluorouracil-based chemotherapy agent and a platinum-based drug) to the patient.

[0097] In some embodiments of the present invention, this treatment extends the patient's progression-free survival (PFS) and / or overall survival (OS), and the patient's condition is significantly improved according to the objective response rate (ORR).

[0098] III. Anti-HER2 Antibodies and Chemotherapy Agents

[0099] The anti-HER2 antibody according to the present invention comprises trastuzumab and a second anti-HER2 antibody, and its mechanism of action includes inhibition of the PI3K / AKT signaling pathway, induction of cell cycle arrest, mediation of antibody-dependent cell-mediated cytotoxicity (ADCC), inhibition of DNA damage repair, inhibition of angiogenesis, and induction of an immune response.

[0100] Trastuzumab

[0101] Trastuzumab includes Herceptin (Trastuzumab) and its biosimilars, wherein the heavy chain of the monoclonal antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:11, and the light chain comprises or is composed of the amino acid sequence described in SEQ ID NO:12.

[0102] Trastuzumab is used to treat HER2-positive metastatic breast cancer, HER2-positive early breast cancer, and metastatic gastric cancer (US FDA approved drug information, China NMPA approved drug information). In the applicable regimen for HER2-positive metastatic breast cancer, trastuzumab is used as a monotherapy to treat metastatic breast cancer that has received one or more chemotherapy regimens, and is used in patients with metastatic breast cancer who have not received chemotherapy in combination with paclitaxel or docetaxel, with an initial loading dose of 4 mg / kg administered intravenously (IV) over 90 minutes or more, and a maintenance dose of 2 mg / kg; in the applicable regimen for metastatic gastric cancer related to the present invention, trastuzumab is administered once every 3 weeks, with an initial loading dose of 8 mg / kg, followed by 6 mg / kg administered once every 3 weeks, wherein trastuzumab is administered to patients with metastatic gastric cancer until disease progression or unbearable toxicity occurs.

[0103] Second antibody (also called second anti-HER2 antibody)

[0104] The second antibody or the second anti-HER2 antibody according to the present invention is different from trastuzumab and is a monoclonal antibody that binds to a HER2 site. In some embodiments, the second anti-HER2 antibody comprises a heavy chain variable region and a light chain variable region, wherein,

[0105] (a) The heavy chain variable region includes HCDR1 listed as SEQ ID NO:1, HCDR2 listed as SEQ ID NO:2, and HCDR3 listed as SEQ ID NO:3;

[0106] (b) The light chain variable region includes LCDR1 described as SEQ ID NO:6, LCDR2 described as SEQ ID NO:7, and LCDR3 described as SEQ ID NO:8.

[0107] In some embodiments, the second anti-HER2 antibody comprises a heavy chain variable region and a light chain variable region, wherein,

[0108] (a) The heavy chain variable region comprises the amino acid sequence described in SEQ ID NO:4, or is composed of the amino acid sequence described in SEQ ID NO:4;

[0109] (b) The light chain variable region contains the amino acid sequence described in SEQ ID NO:9, or consists of the amino acid sequence described in SEQ ID NO:9.

[0110] In some embodiments, the second anti-HER2 antibody comprises a heavy chain and a light chain, wherein,

[0111] (a) The heavy chain comprises the amino acid sequence described in SEQ ID NO:5, or is composed of the amino acid sequence described in SEQ ID NO:5;

[0112] (b) The light chain contains the amino acid sequence described in SEQ ID NO:10, or consists of the amino acid sequence described in SEQ ID NO:10.

[0113] In another embodiment of the present invention, the invention relates to the use of a second anti-HER2 antigen-binding fragment comprising the defined amino acid sequence, in particular an antigen-binding region, e.g., HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, examples thereof, including a Fab, Fab', F(ab')2 and Fv fragment, a bispecific antibody, a linear antibody, a single-strand antibody molecule and other antibody fragments.

[0114] The second anti-HER2 antibody used in the present invention is a humanized IgG1 monoclonal antibody that has the same HER2 target domain as trastuzumab, namely domain IV of HER2, but trastuzumab and the second anti-HER2 antibody act on different epitopes, and the second anti-HER2 antibody does not bind competitively to domain IV of HER2 with trastuzumab, as can be confirmed in the HER2 antigen epitope binding analysis of the second anti-HER2 antibody, pertuzumab, and trastuzumab shown in Fig. 1. Endocytosis is one of the mechanisms by which antibodies act as tumor therapeutic drugs, and antibody-receptor interactions or complexes promote the efficient endocytosis of receptor molecules within cells, inducing the reduction and degradation of cell surface receptors, inhibiting receptor-dependent signaling, and affecting the growth of tumor cells. By combining the second anti-HER2 antibody and trastuzumab used in the present invention, the applicant discovered that when the second anti-HER2 antibody and trastuzumab act alone on HER2-positive gastric cancer cells, the HER2 endocytosis on the surface of gastric cancer cells induced is relatively weak, and the effects of apoptosis and tumor cell growth inhibition are also relatively weak. Referring to FIG. 2, when the second anti-HER2 antibody, trastuzumab, and pertuzumab are used alone, they induce relatively weak endocytosis in gastric cancer cells (NCI-N87, SNU216), and the combined action of the second anti-HER2 antibody and trastuzumab significantly enhances endocytosis in gastric cancer cells, but the combined action of trastuzumab and pertuzumab does not induce enhancement of endocytosis in gastric cancer cells. Referring to Figure 3, endocytosis in gastric cancer cells induced by the combined action of the second anti-HER2 antibody and trastuzumab caused a decrease in HER2 expression levels and EGFR expression levels in gastric cancer cells, whereas the combined action of trastuzumab and pertuzumab caused a decrease in HER2 expression levels in gastric cancer cells, but the decrease in EGFR levels was minimal.Therefore, as can be reasonably inferred, the combination of trastuzumab and pertuzumab can be used for adjuvant treatment of HER2-positive breast cancer (e.g., described in CN110337450, Roche), but due to differences in the characteristics of different tumor cells and antibody mechanisms, the combination of trastuzumab and pertuzumab may be difficult to apply for the treatment or adjuvant treatment of HER2-positive gastric cancer, whereas, according to the study of the embodiments of the present invention, the combination of trastuzumab and a second anti-HER2 antibody can be used for a novel treatment regimen for HER2-positive gastric cancer.

[0115] In some embodiments, the present invention relates to a composition comprising trastuzumab and a second anti-HER2 antibody or a binding fragment thereof, and a pharmaceutically acceptable carrier; wherein the second anti-HER2 antibody is as previously defined.

[0116] Fluorouracil-based compounds and platinum-based chemotherapeutic agents

[0117] Fluorouracyl compounds

[0118] Fluorouracil compounds are one of the most widely used clinical antitumor drugs, killing cancer cells by disrupting DNA synthesis through the prevention of pyrimidine nucleotide formation, and include drugs such as 5-FU (5-fluorouracil) and orally administered prodrugs such as capecitabine and tegafur, which are clinically used mainly for the treatment of breast cancer, gastrointestinal cancer, ovarian cancer, and primary bronchopulmonary adenocarcinoma.

[0119] Some embodiments of the present invention relate to the use of 5-FU or capecitabine. In a more preferred embodiment, capecitabine is applied to the uses and methods of the present invention.

[0120] Platinum-based chemotherapy agents

[0121] Platinum-based chemotherapy agents are also widely used antitumor drugs that can crosslink DNA into single adducts, inter-chain crosslinks, intra-chain crosslinks, or DNA-protein crosslinks, which act on the adjacent N-7 position of guanine to form 1,2-intra-chain crosslinks (Poklar et al. (1996). Proc. Natl. Acad. Sci. USA 93(15): 7606-11; Rudd et al. (1995). Cancer Chemother. Pharmacol. 35(4): 323-6); the resulting crosslinks inhibit DNA repair and / or DNA synthesis within cancer cells. Platinum-based chemotherapy agents include cisplatin, carboplatin, oxaliplatin, and staraplatin.

[0122] Some embodiments of the present invention relate to the use of cisplatin or oxaliplatin. In a more preferred embodiment, oxaliplatin is applied to the use and method of the present invention.

[0123] IV. Treatment Methods and Uses

[0124] The present invention relates to the use of a drug for treating a patient diagnosed with HER2-positive gastric cancer, particularly unresectable advanced or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, by combining trastuzumab, a second anti-HER2 antibody or its binding fragment, and a chemotherapy agent.

[0125] In another aspect, the present invention also relates to a method for treating a patient diagnosed with HER2-positive gastric cancer, particularly unresectable advanced or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, comprising the step of administering to the patient a therapeutically effective amount of trastuzumab, a second anti-HER2 antibody or a binding fragment thereof, and a chemotherapy agent. In some embodiments, the treatment of the present invention extends the patient's progression-free survival (PFS) and / or overall survival (OS), and the patient's condition is significantly improved according to the objective response rate (ORR).

[0126] The present invention specifically relates to a treatment regimen for advanced gastric cancer, particularly unresectable advanced or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma. Here, the advanced gastric cancer according to the present invention may be determined according to AJCC / UICC TNM rules, for example, based on the degree of invasion of the tumor into surrounding tissues, the presence of regional lymph node metastasis or distant metastasis, and CT staging findings. HER2 testing is applied to patients with advanced gastric cancer treated in the present invention, and HER2 positivity may be defined, for example as defined in the KEYNOT811 study, as a result of being determined as 3+ in immunohistochemistry (IHC) or as 2+ in immunohistochemistry (IHC) and confirmed as positive in the in-situ hybridization (ISH) test; on the other hand, in some embodiments of the present invention, HER2-positive cancer is based on a HER2 expression level defined as 3+ or 2+ in immunohistochemistry (IHC) and ISH positivity. Here, immunohistochemistry (IHC) and in situ hybridization (ISH) of HER2 must be performed throughout the entire process in accordance with the operating rules of the gastric cancer HER2 detection guidelines, and for the relevant tests, IHC and ISH, commercial testing methods approved by the FDA or the National Medical Products Administration (NMPA) may be selected.

[0127] In some embodiments of the present invention, the use or method comprises the combination of trastuzumab, a second anti-HER2 antibody or its binding fragment, and a chemotherapy agent. In some embodiments, the second anti-HER2 antibody or its binding fragment is as previously defined. The chemotherapy agent consists of a combination of a fluorouracil-based compound and a platinum-based chemotherapy agent. In some specific embodiments, the fluorouracil-based compound is 5-fluorouracil or capecitabine. In some specific embodiments, the platinum-based compound is cisplatin or oxaliplatin. In some more preferred embodiments, the chemotherapy agent consists of a combination of 5-fluorouracil and oxaliplatin.

[0128] Specifically, in one aspect, the present invention provides a method for treating a patient's HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, comprising a therapeutically effective amount of the following component to the patient, namely:

[0129] (1) Trastuzumab;

[0130] (2) Second antibody - The second antibody is a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of trastuzumab, and comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region, and the heavy chain variable region comprises HCDR1 described in SEQ ID NO:1, HCDR2 described in SEQ ID NO:2, and HCDR3 described in SEQ ID NO:3, and the light chain comprises a light chain variable region, and the light chain variable region comprises LCDR1 described in SEQ ID NO:6, LCDR2 described in SEQ ID NO:7, and LCDR3 described in SEQ ID NO:8 - ;

[0131] (3) Includes the step of administering a chemotherapy agent.

[0132] In an additional embodiment, the chemotherapy agent is a fluorouracil-based drug. In an additional embodiment, the chemotherapy agent is a platinum-based drug.

[0133] In an additional embodiment, the chemotherapy agent is composed of a fluorouracil-based drug and a platinum-based drug in combination.

[0134] In an additional embodiment, the fluorouracil-based drug is selected from 5-fluorouracil and capecitabine.

[0135] In an additional embodiment, the platinum-based drug is selected from cisplatin and oxaliplatin. In an additional embodiment, the fluorouracil-based drug is capecitabine. In an additional embodiment, the platinum-based drug is oxaliplatin. In an additional embodiment, the chemotherapeutic agent is composed of capecitabine and oxaliplatin in combination.

[0136] In an additional embodiment, the cancer is HER2-positive advanced gastric cancer.

[0137] In an additional embodiment, the cancer is an unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0138] In an additional embodiment, the heavy chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:9.

[0139] In an additional embodiment, the heavy chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:5, and the light chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:10.

[0140] In an additional embodiment, trastuzumab is administered at a dose of about 0.1 mg / kg to about 10 mg / kg based on body weight.

[0141] In additional embodiments, trastuzumab is administered based on body weight at an amount of about 0.1 mg / kg to about 10 mg / kg, about 0.3 mg / kg to about 10 mg / kg, 0.9 mg / kg to about 10 mg / kg, about 1 mg / kg to about 10 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 3 mg / kg to about 10 mg / kg, about 4 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 6 mg / kg to about 10 mg / kg, about 7 mg / kg to about 10 mg / kg, about 8 mg / kg to about 10 mg / kg, about 9 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 8 mg / kg, about 0.3 mg / kg to about 8 mg / kg, and 0.9 mg / kg to about 8 mg / kg. It is administered at doses of mg / kg, about 1 mg / kg to about 8 mg / kg, about 2.5 mg / kg to about 8 mg / kg, about 3 mg / kg to about 8 mg / kg, about 4 mg / kg to about 8 mg / kg, about 5 mg / kg to about 8 mg / kg, about 6 mg / kg to about 8 mg / kg, about 7 mg / kg to about 8 mg / kg, about 0.1 mg / kg to about 6 mg / kg, about 0.3 mg / kg to about 6 mg / kg, 0.9 mg / kg to about 6 mg / kg, about 1 mg / kg to about 6 mg / kg, about 2.5 mg / kg to about 6 mg / kg, about 3 mg / kg to about 6 mg / kg, about 4 mg / kg to about 6 mg / kg, or about 5 mg / kg to about 6 mg / kg.

[0142] In additional embodiments, trastuzumab is administered at a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg based on body weight.

[0143] In an additional embodiment, trastuzumab is administered at an initial loading dose of about 8 mg / kg based on body weight, followed by a dose of about 6 mg / kg.

[0144] In additional embodiments, trastuzumab is administered once about once every 1 week, once about every 2 weeks, once about every 3 weeks, once about every 4 weeks, once about every 1 month, once about every 3 to 6 months or at longer intervals.

[0145] In an additional embodiment, trastuzumab is administered intravenously.

[0146] In a further embodiment, the second antibody is, based on body weight, about 0.1 mg / kg to about 30 mg / kg, about 0.3 mg / kg to about 30 mg / kg, 0.9 mg / kg to about 30 mg / kg, about 1 mg / kg to about 30 mg / kg, about 2.5 mg / kg to about 30 mg / kg, about 3 mg / kg to about 30 mg / kg, about 4 mg / kg to about 30 mg / kg, about 5 mg / kg to about 30 mg / kg, about 6 mg / kg to about 30 mg / kg, about 7 mg / kg to about 30 mg / kg, about 8 mg / kg to about 30 mg / kg, about 9 mg / kg to about 30 mg / kg, about 10 mg / kg to about 30 mg / kg, about 11 mg / kg to about 30 mg / kg, about 12 mg / kg to about 30 mg / kg, about 13 mg / kg to about 30 mg / kg, about 14 mg / kg to about 30 mg / kg, about 15 mg / kg to about 30 mg / kg, about 16 mg / kg to about 30 mg / kg, about 17 mg / kg to about 30 mg / kg, about 18 mg / kg to about 30 mg / kg, about 19 mg / kg to about 30 mg / kg, about 20 mg / kg to about 30 mg / kg, about 21 mg / kg to about 30 mg / kg, about 22 mg / kg to about 30 mg / kg, about 23 mg / kg to about 30 mg / kg, about 24 mg / kg to about 30 mg / kg, about 25 mg / kg to about 30 mg / kg, about 26 mg / kg to about 30 mg / kg, about 27 mg / kg to about 30 mg / kg, about 28 mg / kg to about 30 mg / kg, about 29 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.3 mg / kg to about 25 mg / kg, 0.9 mg / kg to about 25 mg / kg, about 1 mg / kg to about 25 mg / kg, about 2.5 mg / kg to about 25 mg / kg, about 3 mg / kg to about 25 mg / kg, about 4 mg / kg to about 25 mg / kg, about 5 mg / kg to about 25 mg / kg, about 6 mg / kg to about 25 mg / kg, about 7 mg / kg to about 25 mg / kg, about 8 mg / kg to about 25 mg / kg, about 9 mg / kg to about 25 mg / kg, about 10 mg / kg to about 25 mg / kg, about 11 mg / kg to about 25 mg / kg, about 12 mg / kg to about 25 mg / kg, about 13 mg / kg to about 25 mg / kg, about 14 mg / kg to about 25 mg / kg, about 15 mg / kg to about 25 mg / kg, about 16 mg / kg to about 25 mg / kg, about 17 mg / kg to about 25 mg / kg, about 18 mg / kg to about 25 mg / kg, about 19 mg / kg to about 25 mg / kg, about 20 mg / kg to about 25 mg / kg, about 21 mg / kg to about 25 mg / kg, about 22 mg / kg to about 25 mg / kg, about 23 mg / kg to about 25 mg / kg, about 24 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.3 mg / kg to about 20 mg / kg, 0.9 mg / kg to about 20 mg / kg, about 1 mg / kg to about 20 mg / kg, about 2.5 mg / kg to about 20 mg / kg, about 3 mg / kg to about 20 mg / kg, about 4 mg / kg to about 20 mg / kg, about 5 mg / kg to about 20 mg / kg, about 6 mg / kg to about 20 mg / kg, about 7 mg / kg to about 20 mg / kg, about 8 mg / kg to about 20 mg / kg, about 9 mg / kg to about 20 mg / kg, about 10 mg / kg to about 20 mg / kg, about 11 mg / kg to about 20 mg / kg, about 12 mg / kg to about 20 mg / kg, about 13 mg / kg to about 20 mg / kg, about 14 mg / kg to about 20 mg / kg, about 15 mg / kg to about 20 mg / kg, about 16 mg / kg to about 20 mg / kg, about 17 mg / kg to about 20 mg / kg, about 18 mg / kg to about 20 mg / kg, about 19 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.3 mg / kg to about 15 mg / kg, 0.9 mg / kg to about 15 mg / kg, about 1 mg / kg to about 15 mg / kg, about 2.5 mg / kg to about 15 mg / kg, about 3 mg / kg to about 15 mg / kg, about 4 mg / kg to about 15 mg / kg, about 5 mg / kg to about 15 mg / kg, about 6 mg / kg to about 15 mg / kg, about 7 mg / kg to about 15 mg / kg, about 8 mg / kg to about 15 mg / kg, about 9 mg / kg to about 15 mg / kg, about 10 mg / kg to about 15 mg / kg, about 11 mg / kg It is administered at a dose of about 15 mg / kg, about 12 mg / kg to about 15 mg / kg, about 13 mg / kg to about 15 mg / kg, or about 14 mg / kg to about 15 mg / kg.

[0147] In additional embodiments, the second antibody is present in an amount of about 0.1 mg / kg, about 0.3 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg based on body weight, It is administered at a dose of about 28 mg / kg, about 29 mg / kg, or about 30 mg / kg.

[0148] In an additional embodiment, the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight.

[0149] In additional embodiments, the second antibody is administered once every approximately 1 week, once every approximately 2 weeks, once every approximately 3 weeks, once every approximately 4 weeks, once every approximately 1 month, once every approximately 3 to 6 months, or at longer intervals.

[0150] In an additional embodiment, the second antibody is administered intravenously.

[0151] In an additional embodiment, oxaliplatin is about 10 to about 150 mg / m² based on body surface area. 2 , about 20 to about 150 mg / m² 2 , about 30 to about 150 mg / m² 2 , about 40 to about 150 mg / m² 2 , about 50 to about 150 mg / m² 2 , about 60 to about 150 mg / m² 2 , about 70 to about 150 mg / m² 2, about 75 to about 150 mg / m² 2 , about 80 to about 150 mg / m² 2 , about 85 to about 150 mg / m² 2 , about 90 to about 150 mg / m² 2 , about 95 to about 150 mg / m² 2 , about 100 to about 150 mg / m² 2 , about 105 to about 150 mg / m² 2 , about 110 to about 150 mg / m² 2 , about 115 to about 150 mg / m² 2 , about 120 to about 150 mg / m² 2 , about 125 to about 150 mg / m² 2 , about 130 to about 150 mg / m² 2 , about 135 to about 150 mg / m² 2 , about 140 to about 150 mg / m² 2 , about 145 to about 150 mg / m² 2 , about 10 to about 140 mg / m² 2 , about 20 to about 140 mg / m² 2 , about 30 to about 140 mg / m² 2 , about 40 to about 140 mg / m² 2 , about 50 to about 140 mg / m² 2 , about 60 to about 140 mg / m² 2 , about 70 to about 140 mg / m² 2 , about 75 to about 140 mg / m² 2 , about 80 to about 140 mg / m² 2 , about 85 to about 140 mg / m² 2 , about 90 to about 140 mg / m² 2 , about 95 to about 140 mg / m² 2 , about 100 to about 140 mg / m² 2 , about 105 to about 140 mg / m² 2 , about 110 to about 140 mg / m² 2, about 115 to about 140 mg / m² 2 , about 120 to about 140 mg / m² 2 , about 125 to about 140 mg / m² 2 , about 130 to about 140 mg / m² 2 , about 135 to about 140 mg / m² 2 , about 10 to about 130 mg / m² 2 , about 20 to about 130 mg / m² 2 , about 30 to about 130 mg / m² 2 , about 40 to about 130 mg / m² 2 , about 50 to about 130 mg / m² 2 , about 60 to about 130 mg / m² 2 , about 70 to about 130 mg / m² 2 , about 75 to about 130 mg / m² 2 , about 80 to about 130 mg / m² 2 , about 85 to about 130 mg / m² 2 , about 90 to about 130 mg / m² 2 , about 95 to about 130 mg / m² 2 , about 100 to about 130 mg / m² 2 , about 105 to about 130 mg / m² 2 , about 110 to about 130 mg / m² 2 , about 115 to about 130 mg / m² 2 , about 120 to about 130 mg / m² 2 or about 125 to about 130 mg / m² 2 It is administered at a dosage of .

[0152] In an additional embodiment, oxaliplatin is about 10 mg / m² based on body surface area. 2 , approximately 20 mg / m² 2 , approximately 30 mg / m² 2 , approximately 40 mg / m² 2 , approximately 50 mg / m² 2 , approximately 60 mg / m² 2 , approximately 70 mg / m²2 , approximately 75 mg / m² 2 , approximately 80 mg / m² 2 , approximately 85 mg / m² 2 , approximately 90 mg / m² 2 , approximately 95 mg / m² 2 , approximately 100 mg / m² 2 , approximately 105 mg / m² 2 , approximately 110 mg / m² 2 , approximately 115 mg / m² 2 , approximately 120 mg / m² 2 , approximately 125 mg / m² 2 , approximately 130 mg / m² 2 , approximately 135 mg / m² 2 , approximately 140 mg / m² 2 , approximately 145 mg / m² 2 or about 150 mg / m² 2 It is administered at a dosage of .

[0153] In an additional embodiment, oxaliplatin is approximately 130 mg / m² based on body surface area. 2 It is administered at a dosage of .

[0154] In additional embodiments, oxaliplatin is administered once about once every 1 week, once about every 2 weeks, once about every 3 weeks, once about every 4 weeks, once about every 1 month, once about every 3 to 6 months, or at longer intervals.

[0155] In an additional embodiment, oxaliplatin is administered intravenously.

[0156] In an additional embodiment, capecitabine is about 100 to about 1200 mg / m² based on body surface area. 2 , about 200 to about 1200 mg / m² 2 , about 300 to about 1200 mg / m² 2 , about 400 to about 1200 mg / m² 2 , about 500 to about 1200 mg / m² 2 , about 600 to about 1200 mg / m² 2 , about 650 to about 1200 mg / m² 2, about 700 to about 1200 mg / m² 2 , about 750 to about 1200 mg / m² 2 , about 800 to about 1200 mg / m² 2 , about 850 to about 1200 mg / m² 2 , about 900 to about 1200 mg / m² 2 , about 950 to about 1200 mg / m² 2 , about 1000 to about 1200 mg / m² 2 , about 1050 to about 1200 mg / m² 2 , about 1100 to about 1200 mg / m² 2 , about 1150 to about 1200 mg / m² 2 , about 100 to about 1100 mg / m² 2 , about 200 to about 1100 mg / m² 2 , about 300 to about 1100 mg / m² 2 , about 400 to about 1100 mg / m² 2 , about 500 to about 1100 mg / m² 2 , about 600 to about 1100 mg / m² 2 , about 650 to about 1100 mg / m² 2 , about 700 to about 1100 mg / m² 2 , about 750 to about 1100 mg / m² 2 , about 800 to about 1100 mg / m² 2 , about 850 to about 1100 mg / m² 2 , about 900 to about 1100 mg / m² 2 , about 950 to about 1100 mg / m² 2 , about 1000 to about 1100 mg / m² 2 , about 100 to about 1000 mg / m² 2 , about 200 to about 1000 mg / m² 2 , about 300 to about 1000 mg / m² 2 , about 400 to about 1000 mg / m² 2, about 500 to about 1000 mg / m² 2 , about 600 to about 1000 mg / m² 2 , about 650 to about 1000 mg / m² 2 , about 700 to about 1000 mg / m² 2 , about 750 to about 1000 mg / m² 2 , about 800 to about 1000 mg / m² 2 , about 850 to about 1000 mg / m² 2 , about 900 to about 1000 mg / m² 2 or about 950 to about 1000 mg / m² 2 It is administered at a dosage of .

[0157] In an additional embodiment, capecitabine is about 100 mg / m² based on body surface area. 2 , approximately 200 mg / m² 2 , approximately 300 mg / m² 2 , approximately 400 mg / m² 2 , approximately 500 mg / m² 2 , approximately 600 mg / m² 2 , approximately 650 mg / m² 2 , approximately 700 mg / m² 2 , approximately 750 mg / m² 2 , approximately 800 mg / m² 2 , approximately 850 mg / m² 2 , approximately 900 mg / m² 2 , approximately 950 mg / m² 2 , approximately 1000 mg / m² 2 , approximately 1050 mg / m² 2 , approximately 1100 mg / m² 2 , approximately 1150 mg / m² 2 or about 1200 mg / m² 2 It is administered at a dosage of .

[0158] In an additional embodiment, capecitabine is about 1000 mg / m² based on body surface area. 2 It is administered at a dosage of .

[0159] In additional embodiments, capecitabine is administered once a day, twice a day, or three times a day.

[0160] In an additional embodiment, capecitabine is administered orally.

[0161] In a further embodiment, trastuzumab is administered at an initial loading dose of about 8 mg / kg based on body weight, followed by a dose of about 6 mg / kg, the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight, and oxaliplatin is about 130 mg / m² based on body surface area. 2 It is administered at a dose of approximately 1000 mg / m² based on body surface area, and capecitabine is 2 It is administered at a dosage of .

[0162] In an additional embodiment, the second antibody is administered to the patient before administering trastuzumab.

[0163] In an additional embodiment, after administering trastuzumab, the second antibody is administered to the patient.

[0164] In an additional embodiment, trastuzumab and the second antibody are administered simultaneously.

[0165] In an additional embodiment, the method further includes the step of administering an immune checkpoint inhibitor.

[0166] In an additional embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0167] In an additional embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0168] In another aspect, the present invention also provides a combination therapy for treating a patient's HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, said therapy comprising the step of administering the combination therapy to the patient, said combination therapy comprising the following components, namely:

[0169] (1) Trastuzumab;

[0170] (2) Second antibody - The second antibody is a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of trastuzumab, and comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region, and the heavy chain variable region comprises HCDR1 described in SEQ ID NO:1, HCDR2 described in SEQ ID NO:2, and HCDR3 described in SEQ ID NO:3, and the light chain comprises a light chain variable region, and the light chain variable region comprises LCDR1 described in SEQ ID NO:6, LCDR2 described in SEQ ID NO:7, and LCDR3 described in SEQ ID NO:8 - ;

[0171] (3) Includes chemotherapy agents.

[0172] In an additional embodiment, the chemotherapy agent is a fluorouracil-based drug. In an additional embodiment, the chemotherapy agent is a platinum-based drug.

[0173] In an additional embodiment, the chemotherapy agent is composed of a fluorouracil-based drug and a platinum-based drug in combination.

[0174] In an additional embodiment, the fluorouracil-based drug is selected from 5-fluorouracil and capecitabine.

[0175] In an additional embodiment, the platinum-based drug is selected from cisplatin and oxaliplatin. In an additional embodiment, the fluorouracil-based drug is capecitabine. In an additional embodiment, the platinum-based drug is oxaliplatin. In an additional embodiment, the chemotherapeutic agent is composed of capecitabine and oxaliplatin in combination.

[0176] In an additional embodiment, the cancer is HER2-positive advanced gastric cancer.

[0177] In an additional embodiment, the cancer is an unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0178] In an additional embodiment, the heavy chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:9.

[0179] In an additional embodiment, the heavy chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:5, and the light chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:10.

[0180] In an additional embodiment, trastuzumab is administered at a dose of about 0.1 mg / kg to about 10 mg / kg based on body weight.

[0181] In additional embodiments, trastuzumab is administered based on body weight at an amount of about 0.1 mg / kg to about 10 mg / kg, about 0.3 mg / kg to about 10 mg / kg, 0.9 mg / kg to about 10 mg / kg, about 1 mg / kg to about 10 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 3 mg / kg to about 10 mg / kg, about 4 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 6 mg / kg to about 10 mg / kg, about 7 mg / kg to about 10 mg / kg, about 8 mg / kg to about 10 mg / kg, about 9 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 8 mg / kg, about 0.3 mg / kg to about 8 mg / kg, and 0.9 mg / kg to about 8 mg / kg. It is administered at doses of mg / kg, about 1 mg / kg to about 8 mg / kg, about 2.5 mg / kg to about 8 mg / kg, about 3 mg / kg to about 8 mg / kg, about 4 mg / kg to about 8 mg / kg, about 5 mg / kg to about 8 mg / kg, about 6 mg / kg to about 8 mg / kg, about 7 mg / kg to about 8 mg / kg, about 0.1 mg / kg to about 6 mg / kg, about 0.3 mg / kg to about 6 mg / kg, 0.9 mg / kg to about 6 mg / kg, about 1 mg / kg to about 6 mg / kg, about 2.5 mg / kg to about 6 mg / kg, about 3 mg / kg to about 6 mg / kg, about 4 mg / kg to about 6 mg / kg, or about 5 mg / kg to about 6 mg / kg.

[0182] In additional embodiments, trastuzumab is administered at a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg based on body weight.

[0183] In an additional embodiment, trastuzumab is administered at an initial loading dose of about 8 mg / kg based on body weight, followed by a dose of about 6 mg / kg.

[0184] In additional embodiments, trastuzumab is administered once about once every 1 week, once about every 2 weeks, once about every 3 weeks, once about every 4 weeks, once about every 1 month, once about every 3 to 6 months or at longer intervals.

[0185] In an additional embodiment, trastuzumab is administered intravenously.

[0186] In a further embodiment, the second antibody is, based on body weight, about 0.1 mg / kg to about 30 mg / kg, about 0.3 mg / kg to about 30 mg / kg, 0.9 mg / kg to about 30 mg / kg, about 1 mg / kg to about 30 mg / kg, about 2.5 mg / kg to about 30 mg / kg, about 3 mg / kg to about 30 mg / kg, about 4 mg / kg to about 30 mg / kg, about 5 mg / kg to about 30 mg / kg, about 6 mg / kg to about 30 mg / kg, about 7 mg / kg to about 30 mg / kg, about 8 mg / kg to about 30 mg / kg, about 9 mg / kg to about 30 mg / kg, about 10 mg / kg to about 30 mg / kg, about 11 mg / kg to about 30 mg / kg, about 12 mg / kg to about 30 mg / kg, about 13 mg / kg to about 30 mg / kg, about 14 mg / kg to about 30 mg / kg, about 15 mg / kg to about 30 mg / kg, about 16 mg / kg to about 30 mg / kg, about 17 mg / kg to about 30 mg / kg, about 18 mg / kg to about 30 mg / kg, about 19 mg / kg to about 30 mg / kg, about 20 mg / kg to about 30 mg / kg, about 21 mg / kg to about 30 mg / kg, about 22 mg / kg to about 30 mg / kg, about 23 mg / kg to about 30 mg / kg, about 24 mg / kg to about 30 mg / kg, about 25 mg / kg to about 30 mg / kg, about 26 mg / kg to about 30 mg / kg, about 27 mg / kg to about 30 mg / kg, about 28 mg / kg to about 30 mg / kg, about 29 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.3 mg / kg to about 25 mg / kg, 0.9 mg / kg to about 25 mg / kg, about 1 mg / kg to about 25 mg / kg, about 2.5 mg / kg to about 25 mg / kg, about 3 mg / kg to about 25 mg / kg, about 4 mg / kg to about 25 mg / kg, about 5 mg / kg to about 25 mg / kg, about 6 mg / kg to about 25 mg / kg, about 7 mg / kg to about 25 mg / kg, about 8 mg / kg to about 25 mg / kg, about 9 mg / kg to about 25 mg / kg, about 10 mg / kg to about 25 mg / kg, about 11 mg / kg to about 25 mg / kg, about 12 mg / kg to about 25 mg / kg, about 13 mg / kg to about 25 mg / kg, about 14 mg / kg to about 25 mg / kg, about 15 mg / kg to about 25 mg / kg, about 16 mg / kg to about 25 mg / kg, about 17 mg / kg to about 25 mg / kg, about 18 mg / kg to about 25 mg / kg, about 19 mg / kg to about 25 mg / kg, about 20 mg / kg to about 25 mg / kg, about 21 mg / kg to about 25 mg / kg, about 22 mg / kg to about 25 mg / kg, about 23 mg / kg to about 25 mg / kg, about 24 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.3 mg / kg to about 20 mg / kg, 0.9 mg / kg to about 20 mg / kg, about 1 mg / kg to about 20 mg / kg, about 2.5 mg / kg to about 20 mg / kg, about 3 mg / kg to about 20 mg / kg, about 4 mg / kg to about 20 mg / kg, about 5 mg / kg to about 20 mg / kg, about 6 mg / kg to about 20 mg / kg, about 7 mg / kg to about 20 mg / kg, about 8 mg / kg to about 20 mg / kg, about 9 mg / kg to about 20 mg / kg, about 10 mg / kg to about 20 mg / kg, about 11 mg / kg to about 20 mg / kg, about 12 mg / kg to about 20 mg / kg, about 13 mg / kg to about 20 mg / kg, about 14 mg / kg to about 20 mg / kg, about 15 mg / kg to about 20 mg / kg, about 16 mg / kg to about 20 mg / kg, about 17 mg / kg to about 20 mg / kg, about 18 mg / kg to about 20 mg / kg, about 19 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.3 mg / kg to about 15 mg / kg, 0.9 mg / kg to about 15 mg / kg, about 1 mg / kg to about 15 mg / kg, about 2.5 mg / kg to about 15 mg / kg, about 3 mg / kg to about 15 mg / kg, about 4 mg / kg to about 15 mg / kg, about 5 mg / kg to about 15 mg / kg, about 6 mg / kg to about 15 mg / kg, about 7 mg / kg to about 15 mg / kg, about 8 mg / kg to about 15 mg / kg, about 9 mg / kg to about 15 mg / kg, about 10 mg / kg to about 15 mg / kg, about 11 mg / kg It is administered at a dose of about 15 mg / kg, about 12 mg / kg to about 15 mg / kg, about 13 mg / kg to about 15 mg / kg, or about 14 mg / kg to about 15 mg / kg.

[0187] In additional embodiments, the second antibody is present in an amount of about 0.1 mg / kg, about 0.3 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg based on body weight, It is administered at a dose of about 28 mg / kg, about 29 mg / kg, or about 30 mg / kg.

[0188] In an additional embodiment, the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight.

[0189] In additional embodiments, the second antibody is administered once every approximately 1 week, once every approximately 2 weeks, once every approximately 3 weeks, once every approximately 4 weeks, once every approximately 1 month, once every approximately 3 to 6 months, or at longer intervals.

[0190] In an additional embodiment, the second antibody is administered intravenously.

[0191] In an additional embodiment, oxaliplatin is about 10 to about 150 mg / m² based on body surface area. 2 , about 20 to about 150 mg / m² 2 , about 30 to about 150 mg / m² 2 , about 40 to about 150 mg / m² 2 , about 50 to about 150 mg / m² 2 , about 60 to about 150 mg / m² 2 , about 70 to about 150 mg / m² 2, about 75 to about 150 mg / m² 2 , about 80 to about 150 mg / m² 2 , about 85 to about 150 mg / m² 2 , about 90 to about 150 mg / m² 2 , about 95 to about 150 mg / m² 2 , about 100 to about 150 mg / m² 2 , about 105 to about 150 mg / m² 2 , about 110 to about 150 mg / m² 2 , about 115 to about 150 mg / m² 2 , about 120 to about 150 mg / m² 2 , about 125 to about 150 mg / m² 2 , about 130 to about 150 mg / m² 2 , about 135 to about 150 mg / m² 2 , about 140 to about 150 mg / m² 2 , about 145 to about 150 mg / m² 2 , about 10 to about 140 mg / m² 2 , about 20 to about 140 mg / m² 2 , about 30 to about 140 mg / m² 2 , about 40 to about 140 mg / m² 2 , about 50 to about 140 mg / m² 2 , about 60 to about 140 mg / m² 2 , about 70 to about 140 mg / m² 2 , about 75 to about 140 mg / m² 2 , about 80 to about 140 mg / m² 2 , about 85 to about 140 mg / m² 2 , about 90 to about 140 mg / m² 2 , about 95 to about 140 mg / m² 2 , about 100 to about 140 mg / m² 2 , about 105 to about 140 mg / m² 2 , about 110 to about 140 mg / m² 2, about 115 to about 140 mg / m² 2 , about 120 to about 140 mg / m² 2 , about 125 to about 140 mg / m² 2 , about 130 to about 140 mg / m² 2 , about 135 to about 140 mg / m² 2 , about 10 to about 130 mg / m² 2 , about 20 to about 130 mg / m² 2 , about 30 to about 130 mg / m² 2 , about 40 to about 130 mg / m² 2 , about 50 to about 130 mg / m² 2 , about 60 to about 130 mg / m² 2 , about 70 to about 130 mg / m² 2 , about 75 to about 130 mg / m² 2 , about 80 to about 130 mg / m² 2 , about 85 to about 130 mg / m² 2 , about 90 to about 130 mg / m² 2 , about 95 to about 130 mg / m² 2 , about 100 to about 130 mg / m² 2 , about 105 to about 130 mg / m² 2 , about 110 to about 130 mg / m² 2 , about 115 to about 130 mg / m² 2 , about 120 to about 130 mg / m² 2 or about 125 to about 130 mg / m² 2 It is administered at a dosage of .

[0192] In an additional embodiment, oxaliplatin is about 10 mg / m² based on body surface area. 2 , approximately 20 mg / m² 2 , approximately 30 mg / m² 2 , approximately 40 mg / m² 2 , approximately 50 mg / m² 2 , approximately 60 mg / m² 2 , approximately 70 mg / m²2 , approximately 75 mg / m² 2 , approximately 80 mg / m² 2 , approximately 85 mg / m² 2 , approximately 90 mg / m² 2 , approximately 95 mg / m² 2 , approximately 100 mg / m² 2 , approximately 105 mg / m² 2 , approximately 110 mg / m² 2 , approximately 115 mg / m² 2 , approximately 120 mg / m² 2 , approximately 125 mg / m² 2 , approximately 130 mg / m² 2 , approximately 135 mg / m² 2 , approximately 140 mg / m² 2 , approximately 145 mg / m² 2 or about 150 mg / m² 2 It is administered at a dosage of .

[0193] In an additional embodiment, oxaliplatin is approximately 130 mg / m² based on body surface area. 2 It is administered at a dosage of .

[0194] In additional embodiments, oxaliplatin is administered once about once every 1 week, once about every 2 weeks, once about every 3 weeks, once about every 4 weeks, once about every 1 month, once about every 3 to 6 months, or at longer intervals.

[0195] In an additional embodiment, oxaliplatin is administered intravenously.

[0196] In an additional embodiment, capecitabine is about 100 to about 1200 mg / m² based on body surface area. 2 , about 200 to about 1200 mg / m² 2 , about 300 to about 1200 mg / m² 2 , about 400 to about 1200 mg / m² 2 , about 500 to about 1200 mg / m² 2 , about 600 to about 1200 mg / m² 2 , about 650 to about 1200 mg / m² 2, about 700 to about 1200 mg / m² 2 , about 750 to about 1200 mg / m² 2 , about 800 to about 1200 mg / m² 2 , about 850 to about 1200 mg / m² 2 , about 900 to about 1200 mg / m² 2 , about 950 to about 1200 mg / m² 2 , about 1000 to about 1200 mg / m² 2 , about 1050 to about 1200 mg / m² 2 , about 1100 to about 1200 mg / m² 2 , about 1150 to about 1200 mg / m² 2 , about 100 to about 1100 mg / m² 2 , about 200 to about 1100 mg / m² 2 , about 300 to about 1100 mg / m² 2 , about 400 to about 1100 mg / m² 2 , about 500 to about 1100 mg / m² 2 , about 600 to about 1100 mg / m² 2 , about 650 to about 1100 mg / m² 2 , about 700 to about 1100 mg / m² 2 , about 750 to about 1100 mg / m² 2 , about 800 to about 1100 mg / m² 2 , about 850 to about 1100 mg / m² 2 , about 900 to about 1100 mg / m² 2 , about 950 to about 1100 mg / m² 2 , about 1000 to about 1100 mg / m² 2 , about 100 to about 1000 mg / m² 2 , about 200 to about 1000 mg / m² 2 , about 300 to about 1000 mg / m² 2 , about 400 to about 1000 mg / m² 2, about 500 to about 1000 mg / m² 2 , about 600 to about 1000 mg / m² 2 , about 650 to about 1000 mg / m² 2 , about 700 to about 1000 mg / m² 2 , about 750 to about 1000 mg / m² 2 , about 800 to about 1000 mg / m² 2 , about 850 to about 1000 mg / m² 2 , about 900 to about 1000 mg / m² 2 or about 950 to about 1000 mg / m² 2 It is administered at a dosage of .

[0197] In an additional embodiment, capecitabine is about 100 mg / m² based on body surface area. 2 , approximately 200 mg / m² 2 , approximately 300 mg / m² 2 , approximately 400 mg / m² 2 , approximately 500 mg / m² 2 , approximately 600 mg / m² 2 , approximately 650 mg / m² 2 , approximately 700 mg / m² 2 , approximately 750 mg / m² 2 , approximately 800 mg / m² 2 , approximately 850 mg / m² 2 , approximately 900 mg / m² 2 , approximately 950 mg / m² 2 , approximately 1000 mg / m² 2 , approximately 1050 mg / m² 2 , approximately 1100 mg / m² 2 , approximately 1150 mg / m² 2 or about 1200 mg / m² 2 It is administered at a dosage of .

[0198] In an additional embodiment, capecitabine is about 1000 mg / m² based on body surface area. 2 It is administered at a dosage of .

[0199] In additional embodiments, capecitabine is administered once a day, twice a day, or three times a day.

[0200] In an additional embodiment, capecitabine is administered orally.

[0201] In a further embodiment, trastuzumab is administered at an initial loading dose of about 8 mg / kg based on body weight, followed by a dose of about 6 mg / kg, the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight, and oxaliplatin is about 130 mg / m² based on body surface area. 2 It is administered at a dose of approximately 1000 mg / m² based on body surface area, and capecitabine is 2 It is administered at a dosage of .

[0202] In an additional embodiment, the second antibody is administered to the patient before administering trastuzumab.

[0203] In an additional embodiment, after administering trastuzumab, the second antibody is administered to the patient.

[0204] In an additional embodiment, trastuzumab and the second antibody are administered simultaneously.

[0205] In an additional embodiment, the method further includes the step of administering an immune checkpoint inhibitor.

[0206] In an additional embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0207] In an additional embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0208] In another aspect, the present invention provides a use of a second antibody in the manufacture of a drug for treating a patient's HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, said treatment comprising the step of administering a combination therapy to the patient, said combination therapy comprising the following components, namely:

[0209] (1) Trastuzumab;

[0210] (2) Second antibody - The second antibody is a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of trastuzumab, and comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region, and the heavy chain variable region comprises HCDR1 described in SEQ ID NO:1, HCDR2 described in SEQ ID NO:2, and HCDR3 described in SEQ ID NO:3, and the light chain comprises a light chain variable region, and the light chain variable region comprises LCDR1 described in SEQ ID NO:6, LCDR2 described in SEQ ID NO:7, and LCDR3 described in SEQ ID NO:8 - ;

[0211] (3) Includes chemotherapy agents.

[0212] In an alternative aspect, the present invention also provides the use of a second antibody, trastuzumab, and a chemotherapy agent in the manufacture of a drug for treating a patient's HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, said treatment comprising the step of administering a combination therapy to the patient, said combination therapy comprising the following components, namely:

[0213] (1) Trastuzumab;

[0214] (2) Second antibody - The second antibody is a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of trastuzumab, and comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region, and the heavy chain variable region comprises HCDR1 described in SEQ ID NO:1, HCDR2 described in SEQ ID NO:2, and HCDR3 described in SEQ ID NO:3, and the light chain comprises a light chain variable region, and the light chain variable region comprises LCDR1 described in SEQ ID NO:6, LCDR2 described in SEQ ID NO:7, and LCDR3 described in SEQ ID NO:8 - ;

[0215] (3) Includes chemotherapy agents.

[0216] In an additional embodiment, the chemotherapy agent is a fluorouracil-based drug. In an additional embodiment, the chemotherapy agent is a platinum-based drug.

[0217] In an additional embodiment, the chemotherapy agent is composed of a fluorouracil-based drug and a platinum-based drug in combination.

[0218] In an additional embodiment, the fluorouracil-based drug is selected from 5-fluorouracil and capecitabine.

[0219] In an additional embodiment, the platinum-based drug is selected from cisplatin and oxaliplatin. In an additional embodiment, the fluorouracil-based drug is capecitabine. In an additional embodiment, the platinum-based drug is oxaliplatin. In an additional embodiment, the chemotherapeutic agent is composed of capecitabine and oxaliplatin in combination.

[0220] In an additional embodiment, the cancer is HER2-positive advanced gastric cancer.

[0221] In an additional embodiment, the cancer is an unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0222] In an additional embodiment, the heavy chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:9.

[0223] In an additional embodiment, the heavy chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:5, and the light chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:10.

[0224] In an additional embodiment, trastuzumab is administered at a dose of about 0.1 mg / kg to about 10 mg / kg based on body weight.

[0225] In additional embodiments, trastuzumab is administered based on body weight at an amount of about 0.1 mg / kg to about 10 mg / kg, about 0.3 mg / kg to about 10 mg / kg, 0.9 mg / kg to about 10 mg / kg, about 1 mg / kg to about 10 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 3 mg / kg to about 10 mg / kg, about 4 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 6 mg / kg to about 10 mg / kg, about 7 mg / kg to about 10 mg / kg, about 8 mg / kg to about 10 mg / kg, about 9 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 8 mg / kg, about 0.3 mg / kg to about 8 mg / kg, and 0.9 mg / kg to about 8 mg / kg. It is administered at doses of mg / kg, about 1 mg / kg to about 8 mg / kg, about 2.5 mg / kg to about 8 mg / kg, about 3 mg / kg to about 8 mg / kg, about 4 mg / kg to about 8 mg / kg, about 5 mg / kg to about 8 mg / kg, about 6 mg / kg to about 8 mg / kg, about 7 mg / kg to about 8 mg / kg, about 0.1 mg / kg to about 6 mg / kg, about 0.3 mg / kg to about 6 mg / kg, 0.9 mg / kg to about 6 mg / kg, about 1 mg / kg to about 6 mg / kg, about 2.5 mg / kg to about 6 mg / kg, about 3 mg / kg to about 6 mg / kg, about 4 mg / kg to about 6 mg / kg, or about 5 mg / kg to about 6 mg / kg.

[0226] In additional embodiments, trastuzumab is administered at a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg based on body weight.

[0227] In an additional embodiment, trastuzumab is administered at an initial loading dose of about 8 mg / kg based on body weight, followed by a dose of about 6 mg / kg.

[0228] In additional embodiments, trastuzumab is administered once about once every 1 week, once about every 2 weeks, once about every 3 weeks, once about every 4 weeks, once about every 1 month, once about every 3 to 6 months or at longer intervals.

[0229] In an additional embodiment, trastuzumab is administered intravenously.

[0230] In a further embodiment, the second antibody is, based on body weight, about 0.1 mg / kg to about 30 mg / kg, about 0.3 mg / kg to about 30 mg / kg, 0.9 mg / kg to about 30 mg / kg, about 1 mg / kg to about 30 mg / kg, about 2.5 mg / kg to about 30 mg / kg, about 3 mg / kg to about 30 mg / kg, about 4 mg / kg to about 30 mg / kg, about 5 mg / kg to about 30 mg / kg, about 6 mg / kg to about 30 mg / kg, about 7 mg / kg to about 30 mg / kg, about 8 mg / kg to about 30 mg / kg, about 9 mg / kg to about 30 mg / kg, about 10 mg / kg to about 30 mg / kg, about 11 mg / kg to about 30 mg / kg, about 12 mg / kg to about 30 mg / kg, about 13 mg / kg to about 30 mg / kg, about 14 mg / kg to about 30 mg / kg, about 15 mg / kg to about 30 mg / kg, about 16 mg / kg to about 30 mg / kg, about 17 mg / kg to about 30 mg / kg, about 18 mg / kg to about 30 mg / kg, about 19 mg / kg to about 30 mg / kg, about 20 mg / kg to about 30 mg / kg, about 21 mg / kg to about 30 mg / kg, about 22 mg / kg to about 30 mg / kg, about 23 mg / kg to about 30 mg / kg, about 24 mg / kg to about 30 mg / kg, about 25 mg / kg to about 30 mg / kg, about 26 mg / kg to about 30 mg / kg, about 27 mg / kg to about 30 mg / kg, about 28 mg / kg to about 30 mg / kg, about 29 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.3 mg / kg to about 25 mg / kg, 0.9 mg / kg to about 25 mg / kg, about 1 mg / kg to about 25 mg / kg, about 2.5 mg / kg to about 25 mg / kg, about 3 mg / kg to about 25 mg / kg, about 4 mg / kg to about 25 mg / kg, about 5 mg / kg to about 25 mg / kg, about 6 mg / kg to about 25 mg / kg, about 7 mg / kg to about 25 mg / kg, about 8 mg / kg to about 25 mg / kg, about 9 mg / kg to about 25 mg / kg, about 10 mg / kg to about 25 mg / kg, about 11 mg / kg to about 25 mg / kg, about 12 mg / kg to about 25 mg / kg, about 13 mg / kg to about 25 mg / kg, about 14 mg / kg to about 25 mg / kg, about 15 mg / kg to about 25 mg / kg, about 16 mg / kg to about 25 mg / kg, about 17 mg / kg to about 25 mg / kg, about 18 mg / kg to about 25 mg / kg, about 19 mg / kg to about 25 mg / kg, about 20 mg / kg to about 25 mg / kg, about 21 mg / kg to about 25 mg / kg, about 22 mg / kg to about 25 mg / kg, about 23 mg / kg to about 25 mg / kg, about 24 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.3 mg / kg to about 20 mg / kg, 0.9 mg / kg to about 20 mg / kg, about 1 mg / kg to about 20 mg / kg, about 2.5 mg / kg to about 20 mg / kg, about 3 mg / kg to about 20 mg / kg, about 4 mg / kg to about 20 mg / kg, about 5 mg / kg to about 20 mg / kg, about 6 mg / kg to about 20 mg / kg, about 7 mg / kg to about 20 mg / kg, about 8 mg / kg to about 20 mg / kg, about 9 mg / kg to about 20 mg / kg, about 10 mg / kg to about 20 mg / kg, about 11 mg / kg to about 20 mg / kg, about 12 mg / kg to about 20 mg / kg, about 13 mg / kg to about 20 mg / kg, about 14 mg / kg to about 20 mg / kg, about 15 mg / kg to about 20 mg / kg, about 16 mg / kg to about 20 mg / kg, about 17 mg / kg to about 20 mg / kg, about 18 mg / kg to about 20 mg / kg, about 19 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.3 mg / kg to about 15 mg / kg, 0.9 mg / kg to about 15 mg / kg, about 1 mg / kg to about 15 mg / kg, about 2.5 mg / kg to about 15 mg / kg, about 3 mg / kg to about 15 mg / kg, about 4 mg / kg to about 15 mg / kg, about 5 mg / kg to about 15 mg / kg, about 6 mg / kg to about 15 mg / kg, about 7 mg / kg to about 15 mg / kg, about 8 mg / kg to about 15 mg / kg, about 9 mg / kg to about 15 mg / kg, about 10 mg / kg to about 15 mg / kg, about 11 mg / kg It is administered at a dose of about 15 mg / kg, about 12 mg / kg to about 15 mg / kg, about 13 mg / kg to about 15 mg / kg, or about 14 mg / kg to about 15 mg / kg.

[0231] In additional embodiments, the second antibody is present in an amount of about 0.1 mg / kg, about 0.3 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg based on body weight, It is administered at a dose of about 28 mg / kg, about 29 mg / kg, or about 30 mg / kg.

[0232] In an additional embodiment, the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight.

[0233] In additional embodiments, the second antibody is administered once every approximately 1 week, once every approximately 2 weeks, once every approximately 3 weeks, once every approximately 4 weeks, once every approximately 1 month, once every approximately 3 to 6 months, or at longer intervals.

[0234] In an additional embodiment, the second antibody is administered intravenously.

[0235] In an additional embodiment, oxaliplatin is about 10 to about 150 mg / m² based on body surface area. 2 , about 20 to about 150 mg / m² 2 , about 30 to about 150 mg / m² 2 , about 40 to about 150 mg / m² 2 , about 50 to about 150 mg / m² 2 , about 60 to about 150 mg / m² 2 , about 70 to about 150 mg / m² 2, about 75 to about 150 mg / m² 2 , about 80 to about 150 mg / m² 2 , about 85 to about 150 mg / m² 2 , about 90 to about 150 mg / m² 2 , about 95 to about 150 mg / m² 2 , about 100 to about 150 mg / m² 2 , about 105 to about 150 mg / m² 2 , about 110 to about 150 mg / m² 2 , about 115 to about 150 mg / m² 2 , about 120 to about 150 mg / m² 2 , about 125 to about 150 mg / m² 2 , about 130 to about 150 mg / m² 2 , about 135 to about 150 mg / m² 2 , about 140 to about 150 mg / m² 2 , about 145 to about 150 mg / m² 2 , about 10 to about 140 mg / m² 2 , about 20 to about 140 mg / m² 2 , about 30 to about 140 mg / m² 2 , about 40 to about 140 mg / m² 2 , about 50 to about 140 mg / m² 2 , about 60 to about 140 mg / m² 2 , about 70 to about 140 mg / m² 2 , about 75 to about 140 mg / m² 2 , about 80 to about 140 mg / m² 2 , about 85 to about 140 mg / m² 2 , about 90 to about 140 mg / m² 2 , about 95 to about 140 mg / m² 2 , about 100 to about 140 mg / m² 2 , about 105 to about 140 mg / m² 2 , about 110 to about 140 mg / m² 2, about 115 to about 140 mg / m² 2 , about 120 to about 140 mg / m² 2 , about 125 to about 140 mg / m² 2 , about 130 to about 140 mg / m² 2 , about 135 to about 140 mg / m² 2 , about 10 to about 130 mg / m² 2 , about 20 to about 130 mg / m² 2 , about 30 to about 130 mg / m² 2 , about 40 to about 130 mg / m² 2 , about 50 to about 130 mg / m² 2 , about 60 to about 130 mg / m² 2 , about 70 to about 130 mg / m² 2 , about 75 to about 130 mg / m² 2 , about 80 to about 130 mg / m² 2 , about 85 to about 130 mg / m² 2 , about 90 to about 130 mg / m² 2 , about 95 to about 130 mg / m² 2 , about 100 to about 130 mg / m² 2 , about 105 to about 130 mg / m² 2 , about 110 to about 130 mg / m² 2 , about 115 to about 130 mg / m² 2 , about 120 to about 130 mg / m² 2 or about 125 to about 130 mg / m² 2 It is administered at a dosage of .

[0236] In an additional embodiment, oxaliplatin is about 10 mg / m² based on body surface area. 2 , approximately 20 mg / m² 2 , approximately 30 mg / m² 2 , approximately 40 mg / m² 2 , approximately 50 mg / m² 2 , approximately 60 mg / m² 2 , approximately 70 mg / m²2 , approximately 75 mg / m² 2 , approximately 80 mg / m² 2 , approximately 85 mg / m² 2 , approximately 90 mg / m² 2 , approximately 95 mg / m² 2 , approximately 100 mg / m² 2 , approximately 105 mg / m² 2 , approximately 110 mg / m² 2 , approximately 115 mg / m² 2 , approximately 120 mg / m² 2 , approximately 125 mg / m² 2 , approximately 130 mg / m² 2 , approximately 135 mg / m² 2 , approximately 140 mg / m² 2 , approximately 145 mg / m² 2 or about 150 mg / m² 2 It is administered at a dosage of .

[0237] In an additional embodiment, oxaliplatin is approximately 130 mg / m² based on body surface area. 2 It is administered at a dosage of .

[0238] In additional embodiments, oxaliplatin is administered once about once every 1 week, once about every 2 weeks, once about every 3 weeks, once about every 4 weeks, once about every 1 month, once about every 3 to 6 months, or at longer intervals.

[0239] In an additional embodiment, oxaliplatin is administered intravenously.

[0240] In an additional embodiment, capecitabine is about 100 to about 1200 mg / m² based on body surface area. 2 , about 200 to about 1200 mg / m² 2 , about 300 to about 1200 mg / m² 2 , about 400 to about 1200 mg / m² 2 , about 500 to about 1200 mg / m² 2 , about 600 to about 1200 mg / m² 2 , about 650 to about 1200 mg / m² 2, about 700 to about 1200 mg / m² 2 , about 750 to about 1200 mg / m² 2 , about 800 to about 1200 mg / m² 2 , about 850 to about 1200 mg / m² 2 , about 900 to about 1200 mg / m² 2 , about 950 to about 1200 mg / m² 2 , about 1000 to about 1200 mg / m² 2 , about 1050 to about 1200 mg / m² 2 , about 1100 to about 1200 mg / m² 2 , about 1150 to about 1200 mg / m² 2 , about 100 to about 1100 mg / m² 2 , about 200 to about 1100 mg / m² 2 , about 300 to about 1100 mg / m² 2 , about 400 to about 1100 mg / m² 2 , about 500 to about 1100 mg / m² 2 , about 600 to about 1100 mg / m² 2 , about 650 to about 1100 mg / m² 2 , about 700 to about 1100 mg / m² 2 , about 750 to about 1100 mg / m² 2 , about 800 to about 1100 mg / m² 2 , about 850 to about 1100 mg / m² 2 , about 900 to about 1100 mg / m² 2 , about 950 to about 1100 mg / m² 2 , about 1000 to about 1100 mg / m² 2 , about 100 to about 1000 mg / m² 2 , about 200 to about 1000 mg / m² 2 , about 300 to about 1000 mg / m² 2 , about 400 to about 1000 mg / m² 2, about 500 to about 1000 mg / m² 2 , about 600 to about 1000 mg / m² 2 , about 650 to about 1000 mg / m² 2 , about 700 to about 1000 mg / m² 2 , about 750 to about 1000 mg / m² 2 , about 800 to about 1000 mg / m² 2 , about 850 to about 1000 mg / m² 2 , about 900 to about 1000 mg / m² 2 or about 950 to about 1000 mg / m² 2 It is administered at a dosage of .

[0241] In an additional embodiment, capecitabine is about 100 mg / m² based on body surface area. 2 , approximately 200 mg / m² 2 , approximately 300 mg / m² 2 , approximately 400 mg / m² 2 , approximately 500 mg / m² 2 , approximately 600 mg / m² 2 , approximately 650 mg / m² 2 , approximately 700 mg / m² 2 , approximately 750 mg / m² 2 , approximately 800 mg / m² 2 , approximately 850 mg / m² 2 , approximately 900 mg / m² 2 , approximately 950 mg / m² 2 , approximately 1000 mg / m² 2 , approximately 1050 mg / m² 2 , approximately 1100 mg / m² 2 , approximately 1150 mg / m² 2 or about 1200 mg / m² 2 It is administered at a dosage of .

[0242] In an additional embodiment, capecitabine is about 1000 mg / m² based on body surface area. 2 It is administered at a dosage of .

[0243] In additional embodiments, capecitabine is administered once a day, twice a day, or three times a day.

[0244] In an additional embodiment, capecitabine is administered orally.

[0245] In a further embodiment, trastuzumab is administered at an initial loading dose of about 8 mg / kg based on body weight, followed by a dose of about 6 mg / kg, the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight, and oxaliplatin is about 130 mg / m² based on body surface area. 2 It is administered at a dose of approximately 1000 mg / m² based on body surface area, and capecitabine is 2 It is administered at a dosage of .

[0246] In an additional embodiment, the second antibody is administered to the patient before administering trastuzumab.

[0247] In an additional embodiment, after administering trastuzumab, the second antibody is administered to the patient.

[0248] In an additional embodiment, trastuzumab and the second antibody are administered simultaneously.

[0249] In an additional embodiment, the treatment further includes the step of administering an immune checkpoint inhibitor.

[0250] In an additional embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0251] In an additional embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0252] In some embodiments of the present invention, the patient refers to an untreated patient, and includes, for example, a patient who has never received any systemic antitumor therapy for unresectable advanced or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, or a patient who has received adjuvant therapy in the past but for whom the period from the end of the last treatment to the first administration of the treatment regimen of the present invention is 6 months or more, or a patient who has received antitumor Chinese or neutral drug treatment but for whom the end of the last treatment is prior to the randomization of the study related to the present invention.

[0253] In some embodiments of the present invention, the trastuzumab, the second anti-HER2 antibody, or its binding fragment is administered intravenously every three weeks.

[0254] In some embodiments, the second anti-HER2 antibody is administered at a dose of about 25 mg / kg.

[0255] In some embodiments, the second anti-HER2 antibody is administered at a dose of about 15 mg / kg.

[0256] In some embodiments, trastuzumab is administered at an initial loading dose of about 8 mg / kg, followed by about 6 mg / kg every 3 weeks.

[0257] In some embodiments of the present invention, the chemotherapy agent is composed of capecitabine and oxaliplatin in combination.

[0258] In some embodiments, oxaliplatin is about 130 mg / m² 2 It is administered intravenously at a dose, once every 3 weeks; typically, the intravenous infusion is carried out over 2 to 6 hours and is administered on the 1st day of each cycle; in specific cases, e.g., when the body surface area is 2.0 m² 2 If it exceeds, the researcher may determine the drug dosage by considering the clinical situation.

[0259] In some embodiments, capecitabine is about 1000 mg / m² 2It is administered orally at a dose of 3 weeks twice a day in a 3-week cycle; typically administered from day 1 to day 14 of each cycle; in specific cases, the researcher may determine the drug dose based on the clinical situation, for example, when the theoretical dose is calculated to exceed 1500 mg, the dose of capecitabine may be determined to be approximately 1500 mg.

[0260] Immune checkpoint inhibitors are also an important part of the treatment regimen for advanced gastric cancer; for example, in the Phase 3 study KEYNOTE-811 for the treatment of HER2-positive gastric cancer, the response rate was significantly improved when pembrolizumab was added to the combination compared to trastuzumab plus chemotherapy, and the FDA approved the combination of pembrolizumab, trastuzumab, fluorouracil, and platinum-based chemotherapy as a first-line treatment regimen for patients with unresectable advanced or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma. The response rate may also be improved by combining the trastuzumab + second anti-HER2 antibody + chemotherapy regimen according to the present invention with an immune checkpoint inhibitor. In some embodiments of the present invention, in use or therapeutic regimen according to the present invention, immune checkpoint inhibitors may be administered simultaneously or at time intervals, preferably an anti-PD-1 antibody or an anti-PD-L1 antibody, more preferably an anti-PD-1 antibody, and may be administered, for example, nivolumab, pembrolizumab, syntilimab, tislizumab, camrelizumab, toripalimab, cerflurimab, etc.

[0261] V. Drug Combinations / Drug Compositions

[0262] The present invention provides a drug combination for the combined use of trastuzumab and the second anti-HER2 antibody, comprising trastuzumab and the second anti-HER2 antibody or a binding fragment thereof.

[0263] The present invention also provides a drug composition, for example, a drug composition for treating gastric cancer, comprising trastuzumab, the second anti-HER2 antibody, and a pharmaceutically acceptable carrier.

[0264] In some embodiments, the drug composition according to the present invention is in the form of a liquid formulation or a lyophilized powder, typically in the form of a liquid formulation. The formulation comprises an antibody (trastuzumab, 2nd anti-HER2 antibody), a surfactant (e.g., polysorbate 20, 80), a buffer (histidine buffer, acetic acid buffer, citrate buffer, or a mixture of both buffers), a stabilizer (e.g., sugars, alcohols, salts, amino acids, etc.), and an appropriate pH value.

[0265] In one aspect, the present invention also provides a combination product, which is

[0266] Trastuzumab;

[0267] Second antibody - The second antibody is a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of the trastuzumab, and

[0268] A heavy chain variable region comprising HCDR1 listed in SEQ ID NO:1, HCDR2 listed in SEQ ID NO:2, and HCDR3 listed in SEQ ID NO:3, and

[0269] Includes a light chain variable region comprising LCDR1 listed in SEQ ID NO:6, LCDR2 listed in SEQ ID NO:7, and LCDR3 listed in SEQ ID NO:8 - ; and

[0270] Includes chemotherapy agents.

[0271] In an additional embodiment, the chemotherapy agent is a fluorouracil-based drug. In an additional embodiment, the chemotherapy agent is a platinum-based drug.

[0272] In an additional embodiment, the chemotherapy agent is composed of a fluorouracil-based drug and a platinum-based drug in combination.

[0273] In an additional embodiment, the fluorouracil-based drug is selected from 5-fluorouracil and capecitabine. In an additional embodiment, the platinum-based drug is selected from cisplatin and oxaliplatin. In an additional embodiment, the fluorouracil-based drug is capecitabine. In an additional embodiment, the platinum-based drug is oxaliplatin. In an additional embodiment, the chemotherapeutic agent is composed of capecitabine and oxaliplatin in combination.

[0274] In an additional embodiment, the heavy chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:9.

[0275] In an additional embodiment, the heavy chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:5, and the light chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:10.

[0276] In additional embodiments, the combination product further comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0277] In an additional embodiment, the combination product further comprises an anti-PD-1 antibody.

[0278] VI. Kit

[0279] The present invention also relates to the above-described kit for treating gastric cancer, which typically comprises an antibody, a chemotherapy agent, and / or a label and instructions for use for an intended use. Specifically, the kit according to the present invention is used for the treatment of gastric cancer, particularly for the treatment of unresectable advanced or metastatic HER2-positive gastric cancer, and comprises at least one cycle dose of trastuzumab, a second anti-HER2 antibody, and a chemotherapy agent. In some exemplary embodiments, the trastuzumab, the second anti-HER2 antibody, and / or the chemotherapy agent are packaged in unit dose forms. Here, the second anti-HER2 antibody is as previously defined. In a preferred embodiment of the present invention, the chemotherapy agent included in the kit is a fluorouracil-based compound and a platinum-based drug, for example, the fluorouracil-based compound is 5-fluorouracil or capecitabine, and the platinum-based drug is cisplatin or oxaliplatin. In a more preferred embodiment, the kit comprises trastuzumab, a second anti-HER2 antibody, capecitabine, and oxaliplatin.

[0280] Specifically, in one aspect, the present invention also provides a kit for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, said kit comprising the following components, namely:

[0281] Trastuzumab;

[0282] Second antibody - The second antibody is a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of the trastuzumab, and

[0283] A heavy chain variable region comprising HCDR1 listed in SEQ ID NO:1, HCDR2 listed in SEQ ID NO:2, and HCDR3 listed in SEQ ID NO:3, and

[0284] Includes a light chain variable region comprising LCDR1 listed in SEQ ID NO:6, LCDR2 listed in SEQ ID NO:7, and LCDR3 listed in SEQ ID NO:8 - ; and

[0285] Includes chemotherapy agents.

[0286] In an additional embodiment, the chemotherapy agent is a fluorouracil-based drug.

[0287] In an additional embodiment, the chemotherapy agent is a platinum-based drug.

[0288] In an additional embodiment, the chemotherapy agent is composed of a fluorouracil-based drug and a platinum-based drug in combination.

[0289] In an additional embodiment, the fluorouracil-based drug is selected from 5-fluorouracil and capecitabine.

[0290] In an additional embodiment, the platinum-based drug is selected from cisplatin and oxaliplatin.

[0291] In an additional embodiment, the fluorouracil-based drug is capecitabine.

[0292] In an additional embodiment, the platinum-based drug is oxaliplatin.

[0293] In an additional embodiment, the chemotherapy agent is composed of capecitabine and oxaliplatin in combination.

[0294] In an additional embodiment, the cancer is HER2-positive advanced gastric cancer.

[0295] In an additional embodiment, the cancer is an unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0296] In an additional embodiment, the heavy chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:9.

[0297] In an additional embodiment, the heavy chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:5, and the light chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:10.

[0298] In an additional embodiment, the kit further includes an instruction manual.

[0299] In an additional embodiment, the kit further comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0300] In an additional embodiment, the kit further comprises an anti-PD-1 antibody.

[0301] Sequence information regarding the present invention is summarized in Table 1.

[0302] Table 1 Order Table

[0303]

[0304]

[0305] Table 2 Abbreviation Table

[0306]

[0307]

[0308] Drug Source: Trastuzumab (or Biosimilar): Provided by Henlius, brand name Hanquyou.

[0309] 2. Anti-HER2 antibody: Prepared according to the method described in Chinese Patent Application No. 201480024152.3, wherein the antibody with the number hz1E11-133 is a reference antibody;

[0310] Pertuzumab: Manufactured according to the methods described in WO01 / 00245 and WO2006 / 007398, using a medicine purchased through commercial channels, or using a biosimilar approved for clinical studies;

[0311] Chemotherapy agents:

[0312] Capecitabine and oxaliplatin, Qilu Pharmaceutical;

[0313] Cells used in the experiment: Gastric cancer cell line NCI-N87 was purchased from the National Cancer Institute (NCI); SNU216 was purchased from CoBioer.

[0314] The HER2-Fc protein used in Example 1 was supplied by Cyno Biology (PA, USA), and the product number is 10004-H02H, LC10JA1203.

[0315] The present invention will be described below through non-limiting embodiments.

[0316] Example 1. HER2 Epitope Study of Trastuzumab and Second Anti-HER2 Antibody

[0317] The competition for epitope binding between trastuzumab, the second anti-HER2 antibody, and pertuzumab was analyzed. The second anti-HER2 antibody was immobilized on a Biacore CM5 sensor chip and amine coupled with approximately 1000 RU, and then (a) HER2-Fc protein, trastuzumab, and pertuzumab, and (b) HER2-Fc protein, pertuzumab, and trastuzumab were added sequentially.

[0318] Referring to the HER2 epitope affinity study shown in Figure 1, the second anti-HER2 antibody did not bind competitively to trastuzumab and pertuzumab, the second anti-HER2 antibody has a different binding site from trastuzumab, and the second anti-HER2 antibody binds to HER2 subdomain IV but did not compete with trastuzumab.

[0319] Example 2 A study on the effects of combination treatment with trastuzumab and a second anti-HER2 antibody on HER2-mediated internalization ability and EGFR cell surface expression levels in gastric cancer cells NCI-N87 and SNU216

[0320] Research on internalized ability

[0321] Time-dependent changes in the intracellular uptake patterns of HER2 antibodies in gastric cancer cell lines NCI-N87 and SNU216 following treatment with trastuzumab, a second anti-HER2 antibody, and pertuzumab, either alone or in combination, were observed using the PHrodoiFL Green staining method. HER2 internalization analysis was performed using the esteramine-reactive dye (P35369, Invitrogen). NCI-N87, SNU216 (1.5×10⁻⁶ 5 Gastric cancer cells were seeded into a 96-well plate (CLS3799, Corning) and incubated on ice for 1 h with trastuzumab, the second anti-HER2 antibody, pertuzumab, trastuzumab + pertuzumab, or trastuzumab + anti-HER2 antibody (10 μg / mL). After briefly washing with wash buffer to remove unbound antibodies, one group of cells was placed on ice to stop internalization, while the remaining cells were continued in a 37°C incubator. After antibody incubation, the cells were fixed with fixation buffer (420801, BioLegend) for 30 minutes. Finally, all stained cells were washed with staining buffer and analyzed using a CytoFLEX LX flow cytometer (Beckman Coulter, USA).

[0322] As shown in Figure 2, trastuzumab + pertuzumab showed limited HER2 internalization in gastric cancer cell lines NCI-N87 and SNU216, whereas trastuzumab + anti-HER2 antibody induced stronger HER2 internalization in NCI-N87 and SNU216 gastric cancer cell lines. Since the combination of anti-HER2 antibody and trastuzumab binds to HER2 subdomain IV simultaneously, whereas the combination of trastuzumab and pertuzumab binds to HER2 subdomains IV and II, antibodies binding to different subdomains cause differences in the receptor internalization rate, which demonstrates the unique synergistic effect of the combination of anti-HER2 antibody and trastuzumab.

[0323] Study of EGFR cell expression levels

[0324] EGFR and HER2 protein expression levels were detected using BV421 anti-human EGF receptor (749755, BD) and AF647 anti-human CD340 (erbB2 / HER-2) (324412, BioLegend). All stained cells were analyzed using a CytoFLEX LX flow cytometer (Beckman Coulter, USA). Data were analyzed using FlowJo software.

[0325] As shown in Figure 3, treatment with an anti-HER2 antibody and trastuzumab in NCI-N87 gastric cancer cells reduced HER2 expression (Figure 3 a, b, c) as well as cell surface EGFR expression (Figure 3 d, e, f), indicating that EGFR was internalized with HER2 in the form of a HER2 / EGFR heterodimer, whereas treatment with pertuzumab and trastuzumab was able to reduce HER2 expression, but the reduction in cell surface EGFR expression was limited.

[0326] Example 3 . Study on the synergistic effects of combination therapy with trastuzumab and a second anti-HER2 antibody in the treatment of HER2-positive gastric cancer

[0327] We investigated the antitumor synergy effects of trastuzumab and a second anti-HER2 antibody through the cell viability of gastric cancer cells NCI-N87 and a HER2-positive gastric cancer PDX model.

[0328] Cell viability of NCI-N87 gastric cancer cells was measured 72 hours after treatment with trastuzumab, a second anti-HER2 antibody, pertuzumab, a combination of trastuzumab and a second anti-HER2 antibody, or a combination of trastuzumab and pertuzumab; apoptosis was evaluated by measuring the activity of caspases 3 / 7 within NCI-N87 gastric cancer cells using the Caspase-Glo®3 / 7 Assay system. Xenogeneic human gastric cancer NCI-N87 models treated with predetermined doses of antibodies and human gastric cancer PDX models treated with predetermined doses of antibodies were used. All data were expressed as mean ± SEM. P-values ​​were calculated using Student's t-test. ** p < 0.01, *p < 0.05.

[0329] In vitro proliferation experiment research

[0330] Cell proliferation was detected using the CellTiter-Glo luminescent cell viability kit (G7571, Promega). 1.5×10 4 Cells were seeded into 96-well plates (CLS3799, Corning) and incubated overnight at 37°C. They were treated with IgG1, trastuzumab, second anti-HER2 antibody, pertuzumab, or trastuzumab / second anti-HER2 antibody, or trastuzumab / pertuzumab, respectively. Simultaneously, luminescence values ​​were measured on the T=0 hour plates. After 72 hours of incubation, luminescence values ​​on the T=72 hour plates were measured using a Spark (Tecan, Switzerland). Cell viability calculation: Cell viability = (T72 - T0) / (T72(c) - T0) × 100%, where T: treatment group, c: control group.

[0331] Detection of apoptosis

[0332] Apoptosis was evaluated by measuring the activity of caspases 3 / 7 in NCI-N87 cells using the Caspase-Glo® 3 / 7 Assay (G8093, Promega) system. Approximately 1.5 × 10⁶ 4 Canine cells were seeded into a 96-well plate (CLS3799, Corning) and cultured overnight. The existing medium was replaced with 100 μL of medium containing the drug and treated for 24 hours. After incubating at room temperature for 30 minutes, 100 μL of Caspase-Glo 3 / 7 reagent was added. After incubating in the dark for 30 minutes and gently shaking, detection was performed using a Spark (Tecan, Switzerland).

[0333] Animal Tumor Model Research

[0334] In the xenogeneic human gastric cancer NCI-N87 model, 5×10 BALB / c nude female mice 6 NCI-N87 cells were subcutaneously transplanted. The average tumor volume of the mice was approximately 120-150 mm³. 3 When the target was reached, mice were randomly divided into groups and administered the following regimen. The second anti-HER2 antibody or the control reagent was injected intraperitoneally at a dose of 10 mg / kg twice weekly, with 8 mice per group, for a continuous administration period of 28 days. In the PDX model, tumor xenografts were generated from patient gastric cancer tissue and implanted subcutaneously into the right dorsal area of ​​each NCG mouse. Trastuzumab, trastuzumab / second anti-HER2 antibody, and trastuzumab / pertuzumab were administered at different dosages in the PDX model, with n = 5 mice per group receiving the treatment twice weekly for a continuous administration period of 52–60 days. Tumor volume and body weight were measured twice weekly.

[0335] As shown in Fig. 4a, in a study on inhibiting the in vitro growth of gastric cancer cell line NCI-N87 using the second anti-HER2 antibody or trastuzumab alone and in combination, the combination of trastuzumab and the second anti-HER2 antibody significantly enhanced the antiproliferative activity compared to when used alone, and the inhibitory effect on cell proliferation was superior to that of the combination of trastuzumab and pertuzumab. As shown in Fig. 4b, according to the detection of caspases 3 / 7 activity, when gastric cancer cells NCI-N87 were treated with the combination of the second anti-HER2 antibody and trastuzumab, apoptosis of NCI-N87 cells could be induced, whereas when NCI-N87 gastric cancer cells were treated with trastuzumab, the second anti-HER2 antibody, and pertuzumab alone, or with the combination of trastuzumab and pertuzumab, apoptosis of NCI-N87 cells could not be significantly induced. Referring to the study on the treatment of the xenogeneic human gastric cancer NCI-N87 model shown in Fig. 4c, the combination of trastuzumab and a second anti-HER2 antibody significantly inhibited the tumor size of NCI-N87 in the model. Referring to the study on the treatment of the PDX model shown in Figs. 4d and 4e, the combination of trastuzumab and a second anti-HER2 antibody was able to inhibit the tumor size.

[0336] In studies using the aforementioned human gastric cancer cell lines, the xenogeneic human gastric cancer NCI-N87 model, and the PDX model, the combination of trastuzumab and a second anti-HER2 antibody demonstrated a potent antitumor effect on gastric cancer cells, inhibiting tumor growth and promoting tumor regression. Furthermore, the combination of trastuzumab and the second anti-HER2 antibody showed enhanced antitumor effects, proving a unique synergistic effect. This is attributed to the fact that both the second anti-HER2 antibody and trastuzumab can induce apoptosis in gastric cancer cells; however, this effect was not observed in studies of gastric cancer cells treated with trastuzumab, the second anti-HER2 antibody, or pertuzumab alone, or in studies of trastuzumab and pertuzumab in combination.

[0337] Example 4. Clinical study of combination therapy with trastuzumab, a second anti-HER2 antibody, and chemotherapy agents in patients diagnosed with unresectable advanced or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma

[0338] This study is a randomized, double-blind, multi-center, phase 2 clinical trial designed to evaluate the clinical efficacy and safety of trastuzumab + second anti-HER2 antibody + chemotherapy compared to placebo and trastuzumab + chemotherapy as a first-line treatment regimen for patients with unresectable advanced or metastatic gastric cancer.

[0339] Research Design

[0340] This study is a randomized, double-blind study; approximately 53 untreated patients diagnosed with unresectable advanced or metastatic gastric cancer were randomly assigned to three groups at a ratio of approximately 1:1:1 and administered the treatment regimen corresponding to each group;

[0341] Group A (Test Group): 2nd anti-HER2 antibody (25 mg / kg) + trastuzumab + chemotherapy agent (XELOX);

[0342] Group B (Test Group): 2nd anti-HER2 antibody (15 mg / kg) + trastuzumab + chemotherapy agent (XELOX);

[0343] Group C (Standard Treatment Group): Placebo (no placebo used in unblinded and open-label subjects) + Trastuzumab + Chemotherapy agent (XELOX).

[0344] The randomization procedure adopted a central randomization system and an interactive web response system (IWRS), and random codes were generated in a 1:1:1 ratio by randomly stratifying according to HER2 expression levels (3+ or 2+) confirmed by immunohistochemistry (IHC / FISH).

[0345] The method of administration is as follows.

[0346] 2nd anti-HER2 antibody: 25 mg / kg or 15 mg / kg was administered intravenously (IV), once every 3 weeks, and on the 1st day of each cycle.

[0347] Placebo: Refer to the method of administering the second anti-HER2 antibody (dosage used varies by stage).

[0348] Trastuzumab: The initial loading dose is 8 mg / kg, followed by 6 mg / kg once every 3 weeks, administered on the 1st day of each cycle; the first infusion time must be at least 90 minutes (including 90 minutes), and 6 mg / kg is administered repeatedly.

[0349] Oxaliplatin: 130 mg / m² 2 Administered intravenously over 2–6 hours (used after completion of trastuzumab infusion), once every 3 weeks on Day 1 of each cycle, for up to 8 cycles; body surface area 2.0 m² 2 If it exceeds, the researcher shall, depending on the clinical situation, 2.0 m 2 The dosage can be calculated by using [this method].

[0350] Capecitabine: 1000 mg / m² 2It is administered orally twice daily, with a 3-week administration cycle from day 1 to day 14 of each cycle; if the calculated theoretical dose exceeds 1500 mg, the investigator may select a capecitabine dose of 1500 mg and administer it orally twice daily depending on the clinical situation.

[0351] Evaluation of the patient's tumor is terminated after the investigator assesses progression according to RECIST v1.1 criteria, and the treatment regimen continues until one of the following occurs: loss of clinical benefit, occurrence of intolerable toxicity, decision by the patient or investigator to discontinue treatment (abnormal termination of treatment regimen), death of the subject receiving the study treatment, withdrawal of informed consent by the subject, pregnancy of the subject, non-compliance with the requirements of the regimen or procedure, or administrative reasons (whichever occurs first).

[0352] patient

[0353] Patients must meet the participation criteria for this study as patients who have not received treatment and have been diagnosed with unresectable advanced or metastatic gastric cancer.

[0354] Selection Criteria

[0355] 1) Voluntarily participate in the clinical study; sign the Informed Consent Form (ICF) after fully understanding the study; be capable of complying with and completing all study procedures;

[0356] 2) No gender restrictions, and the age at the time of signing the ICF must be between 18 and 80 years old;

[0357] 3) Patients with HER2-positive locally advanced / metastatic gastric cancer or gastroesophageal junction adenocarcinoma confirmed by histopathological examination to be incurable by surgical treatment, and confirmed to be primarily adenocarcinoma by histological examination;

[0358] 4) Must not have previously received systemic antitumor therapy for locally advanced / metastatic gastric cancer or gastroesophageal junction adenocarcinoma;

[0359] 5) For subjects who have previously received neoadjuvant / adjuvant therapy, at least 6 months must have elapsed between the end date of the last treatment and the first administration of the drug in this study;

[0360] 6) For subjects who have previously received anti-tumor Chinese or neutral drug treatment, the last treatment must be completed prior to randomization;

[0361] 7) Adverse events (AEs) associated with previous treatment must have recovered to NCI-CTCAE Grade 1 or lower (excluding hair loss);

[0362] 8) At least one measurable lesion must be present on central imaging according to the Solid Tumor Response Evaluation Criteria (RECIST v1.1), and the measurable lesion must not have received local treatment such as radiation therapy (provided, even a lesion within the previous radiation area may be selected as a target lesion if progression is confirmed, and a target lesion cannot be selected solely due to bone metastasis);

[0363] 9) The patient must provide tumor tissue for testing of HER2 expression levels and be confirmed as a HER2-positive tumor. That is:

[0364] a. If confirmed to be HER2 positive 3+ (+++) or higher by immunohistochemistry (IHC), or

[0365] b. When confirmed as HER2 positive 2+ (++) or higher by immunohistochemistry (IHC) and confirmed as positive by fluorescence in situ hybridization (FISH);

[0366] 10) ECOG performance status must be 0 to 1 within 7 days prior to randomization;

[0367] 11) Expected survival time must be 6 months or more;

[0368] 12) Hepatitis B surface antigen (HBsAg) (-) and hepatitis B core antibody (HBcAb) (-); if HBsAg (+) or HBcAb (+), hepatitis B virus deoxyribonucleic acid (HBV-DNA) must be less than 2500 copies / mL or 500 IU / mL, or within the normal range of this center.

[0369] 13) Must have HCV antibodies (-); if HCV antibodies (+), registration is possible only if the HCV-RNA test is negative. Subjects co-infected with hepatitis B and hepatitis C (those who test positive for HBsAg or HBcAb and also test positive for HCV antibodies) are excluded.

[0370] 14) Major organ function must be normal and meet the following criteria (not having received blood transfusion, albumin, recombinant human thrombopoietin, or colony-stimulating factor (CSF) treatment within 14 days prior to the first administration in this study):

[0371] Table 3. Criteria for Major Organ Function

[0372]

[0373] 15) Female subjects of childbearing age must have a negative serum pregnancy test result within 7 days prior to randomization. Female subjects of childbearing age and male subjects with a female partner of childbearing age must use at least one medically recognized contraceptive measure (e.g., intrauterine device, oral contraceptive, condom) during the study treatment period and for at least 6 months after the last administration of the second anti-HER2 antibody / trastuzumab / placebo and chemotherapy.

[0374] Exclusion criteria

[0375] Patients meeting one of the following exclusion criteria cannot participate in this study.

[0376] 1) Cases where another malignant tumor was diagnosed within 2 years prior to the first administration of the study drug. However, remission of localized tumors such as basal cell carcinoma of the cutaneous, squamous cell carcinoma of the cutaneous, superficial bladder cancer, prostate intraepithelial carcinoma in situ, cervical intraepithelial carcinoma in situ, breast intraepithelial carcinoma in situ, and thyroid cancer is eligible for participation;

[0377] 2) When disease progression is confirmed within 6 months after completion of neoadjuvant or adjuvant chemotherapy (or concomitant) or radiation therapy for gastric adenocarcinoma or gastroesophageal junction adenocarcinoma;

[0378] 3) If there is a history of previous HER2 targeted therapy or immune checkpoint therapy (PD-1, PD-L1, CTLA-4, etc.);

[0379] 4) Previous cumulative doxorubicin dose was 360 mg / m² 2 In cases where administered in excess of (or an equivalent dose); Note: For equivalent drugs, epirubicin > 720 mg / m² 2 , Mithoxantrone > 120 mg / m² 2 , Idarubicin > 90 mg / m² 2 , 360 mg / m 2 This includes liposomal doxorubicin or other anthracycline antibiotics exceeding the doxorubicin equivalent dose. If one or more anthracycline antibiotics are used, the cumulative dose is 360 mg / m² 2 The doxorubicin equivalent must not be exceeded;

[0380] 5) In cases of uncontrolled pleural effusion, pericardial effusion, or ascites requiring frequent drainage even after appropriate intervention;

[0381] 6) In cases of active gastrointestinal bleeding requiring blood transfusion or invasive interventional treatment;

[0382] 7) In cases of central nervous system (CNS) or leptomeningeal metastasis;

[0383] 8) If a cerebrovascular event, myocardial infarction, unstable angina, or uncontrolled arrhythmia (including QTc interval ≥ 450 ms for men and QTc interval ≥ 470 ms for women) occurred within 6 months prior to the initial administration (QTc interval is calculated using the Fridericia formula);

[0384] 9) Grade III or IV heart failure according to New York Heart Association (NYHA) standards, or left ventricular ejection fraction (LVEF) < 55% on echocardiography;

[0385] 10) In the case of active pulmonary tuberculosis;

[0386] 11) Patients with a history or present condition suspected of interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe pulmonary dysfunction, or other conditions that may interfere with the evaluation and treatment of drug-related pulmonary toxicity;

[0387] 12) If a live attenuated vaccine was received within 28 days prior to randomization; provided that seasonal influenza or COVID-19 inactivated virus vaccines are excluded;

[0388] 13) When active pneumonia is suspected on baseline chest imaging and accompanied by clinically relevant symptoms or signs;

[0389] 14) Patients requiring treatment with systemic corticosteroids (> 10 mg / day prednisolone equivalent) or other immunosuppressants within 14 days prior to randomization or during the study period. However, in the absence of active autoimmune disease, topical or inhaled steroids, or corticosteroid replacement therapy at ≤ 10 mg / day prednisolone equivalent dose are permitted;

[0390] 15) Cases where major surgery was performed within 28 days prior to the first administration of the study drug. In this study, major surgery is defined as surgery requiring a minimum recovery period of 3 weeks to receive the study treatment;

[0391] 16) If curative radiation therapy was received within 3 months prior to the start of study treatment; provided, however, that palliative radiation therapy for bone lesions and superficial lesions is permitted, provided that it must be completed by 14 days prior to the first dose; and radiation therapy involving more than 30% of the bone marrow area within 28 days prior to the first dose is not permitted;

[0392] 17) If currently participating in another clinical trial, or if less than 14 days have passed between the end of treatment in a previous clinical trial and the start of treatment in this study;

[0393] 18) In the case of a history of severe allergic reactions to any monoclonal antibody or foreign drug excipient;

[0394] 19) If there is evidence of the presence of intra-abdominal air not explained by puncture or recent surgical intervention;

[0395] 20) If there is a history of psychiatric substance abuse or drug use;

[0396] 21) Women who are pregnant or breastfeeding;

[0397] 22) Where there are other factors that, in the researcher's judgment, may cause a subject to drop out during the study (e.g., other severe diseases requiring concomitant treatment (including mental illness), serious abnormalities in laboratory results, family or social factors, etc., that may affect the subject's safety or the collection of study data).

[0398] result

[0399] The primary efficacy endpoints of this study are progression-free survival (PFS) and objective response rate (ORR); PFS is defined as the time (in months) from the time of randomization to the first identified disease progression or death (based on whichever occurs) for subjects evaluated according to RECIST v1.1 (IRRC) criteria. For subjects who did not experience disease progression or death by the time of analysis, the date of the last objective tumor evaluation is used as the PFS screening date; the objective response rate (ORR) is defined as the proportion of subjects with a CR or PR optimal response evaluated according to RECIST v1.1 (investigator and IRRC) criteria. Descriptive analysis is performed on the objective response rates of each group, and the corresponding 95% confidence intervals are presented. The median progression-free survival is estimated using the Kaplan-Meier method, and Kaplan-Meier curves are constructed. The hazard ratio (HR) and 95% confidence interval for PFS are estimated using a stratified COX proportional hazards model. PFS between groups is compared using the stratified log-rank test. Differences in ORR between groups are tested using the stratified Cochran-Mantel-Haenszel (CMH) method, and odds ratios and 95% confidence intervals are estimated.

[0400] The secondary efficacy endpoint of this study is overall survival, and the statistical methods for progression-free survival and objective response rate, assessed by the investigator according to RECIST v1.1 criteria, are the same as those for the primary efficacy endpoint. Duration of response refers to the time from the date of first CR or PR attainment (based on the first recorded state) to the date of first recorded disease progression or death (based on whichever occurs first). The DOR is assessed separately for subjects determined to have an objective response by the investigator and the IRRC. The median is estimated using the Kaplan-Meier method, and Kaplan-Meier curves are constructed.

[0401] efficacy

[0402] A total of 53 patients were randomly assigned to the analysis in this study, comprising 18 in Group A, 17 in Group B, and 18 in Group C. The image-assessed median progression-free survival (PFS) for the 53 subjects was as follows: PFS for Group A patients was 15.1 months (95% confidence interval: 6.8 months to unestimated), PFS for Group B patients was not reached (95% confidence interval: 9.9 months to unestimated), and PFS for Group C patients was 8.2 months (95% confidence interval: 9.9 months to unestimated). At the time of this analysis, a total of 12 subjects (28.3%) had died, and since the overall survival data was not yet mature, neither group had reached the median overall survival. The KM curves for the subjects' progression-free survival are shown in Figure 5, and a summary of the patients' efficacy data is presented in Table 4.

[0403] Table 4. Summary of Efficacy Data

[0404]

[0405] As shown in Table 4, the median progression-free survival for group A was 15.11 months and the median duration of response was 12.4 months, while the median progression-free survival and median duration of response for group B were not reached, and the median progression-free survival for group C was 8.21 months and the median duration of response was 6.8 months. In other words, the combination of trastuzumab + second anti-HER2 antibody + chemotherapy (groups A and B) was found to significantly extend the median progression-free survival and median duration of response of patients compared to the combination of trastuzumab + chemotherapy. The median progression-free survival hazard ratio for group A was 0.5 (95% CI: 0.17-1.27, P=0.1272) and for group B was 0.1 (95% CI: 0.04-0.52, P=0.0007); additionally, the median duration of response hazard ratio for group A was 0.6 (95% CI: 0.20-1.62, P=0.2848) and for group B was 0.1 (95% CI: 0.02-0.50, P=0.0006), showing favorable results for the trastuzumab + second anti-HER2 antibody + chemotherapy combination group.

[0406] The objective response rates of both test groups (Group A and Group B) were significantly higher than those of the control group (Group C), and the objective response rates at 36 weeks for Group A and Group B were 44.4% and 64.7%, respectively, while the objective response rates at 48 weeks for Group A and Group B were 38.9% and 58.8%, respectively.

[0407] In the treatment of HER2-positive advanced gastric cancer patients who were the subjects of this study, the combination therapy of a second anti-HER2 antibody and standard treatment (trastuzumab + XELOX) showed clear and sustained remission, and these patients achieved significantly extended progression-free survival.

[0408] safety

[0409] In the Phase 1 clinical trial for the second anti-HER2 antibody, a total of 11 subjects were enrolled as of April 22, 2022, and received at least one dose of the anti-HER2 antibody; 11 subjects were included in the safety analysis group. The results showed that each dose group of the second anti-HER2 antibody was well tolerated. No dose-related toxicity events were observed, and no adverse events occurred during the treatment period that caused discontinuation of the investigational drug infusion, reduction of the investigational drug dose, or reduction of the investigational drug infusion rate. Adverse events that occurred during the study period included lymphocytopenia, leukocytopenia, and hypokalemia.

[0410] In this study, as of July 30, 2023, a total of 53 subjects were enrolled and received at least one dose of trastuzumab + 2nd anti-HER2 antibody + chemotherapy, and 53 subjects were included in the safety analysis group. Among them, the most common adverse events during the study period (TEAEs) were thrombocytopenia (Group A vs Group B vs Group C: 55.6% vs 76.5% vs 83.3%), anemia (66.7% vs 58.8% vs 72.2%), neutrophil count (72.2% vs 64.7% vs 55.6%), and leukopenia (72.2% vs 52.9% vs 61.1%). During the study period, the incidence of grade 3 or higher adverse events was 13 in Group A (72.2%), 7 in Group B (41.2%), and 8 in Group C (44.4%), and the most common adverse events were decreased platelet count and decreased neutrophil count. A summary of the subjects' safety data is shown in Table 5.

[0411] Table 5. Safety Data Summary

[0412]

[0413] In the study group, safety data for the test groups (Groups A and B), particularly Group B, were generally consistent with the standard treatment group (Group C, trastuzumab + XELOX), and no subjects in the test groups experienced death-related adverse events associated with the second anti-HER2 antibody, demonstrating good safety and tolerability.

[0414] summation

[0415] The median overall survival for the combination of trastuzumab and chemotherapy, the first-line standard therapy for HER2-positive advanced gastric cancer, is 13.8 months, and the median progression-free survival is 6.7 months. In this study, the combination therapy of a second anti-HER2 antibody and standard treatment (trastuzumab + chemotherapy) demonstrated a clear efficacy advantage over current standard treatment. The median progression-free survival of the high-dose group (Group A) reached 15.1 months, already exceeding the median overall survival data from previous enrollment records, whereas the median progression-free survival of the low-dose group (Group B) was not reached but is expected to exceed that of Group A, with a hazard ratio of 0.71 (95% confidence interval: 0.04, 0.52, p=0.0007) compared to the standard treatment group (Group C). Therefore, the combination therapy of the second anti-HER2 antibody + trastuzumab + chemotherapy agent of the present invention demonstrated a significantly superior efficacy compared to standard treatment, while also showing good safety and tolerability.

[0416] After reviewing the above contents of the present invention, those skilled in the art should understand that various changes or modifications can be made to the present invention, and that such equivalent forms are also within the scope defined by the appended claims of this application.

Claims

Claim 1 A method for treating a patient's HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, comprising the step of administering to the patient a therapeutically effective amount of: (1) trastuzumab; (2) a second antibody - the second antibody is a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of the trastuzumab, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises HCDR1 described in SEQ ID NO:1, HCDR2 described in SEQ ID NO:2, and HCDR3 described in SEQ ID NO:3, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises LCDR1 described in SEQ ID NO:6, LCDR2 described in SEQ ID NO:7, and LCDR3 described in SEQ ID NO:8 -; and (3) a chemotherapy agent. Claim 2 In claim 1, the method wherein the chemotherapy agent is a fluorouracil-based drug. Claim 3 In claim 1, the method wherein the chemotherapy agent is a platinum-based drug. Claim 4 A method according to any one of claims 1 to 3, wherein the chemotherapy agent is a combination of a fluorouracil-based drug and a platinum-based drug. Claim 5 A method according to any one of paragraphs 2 to 4, wherein the fluorouracil-based drug is selected from 5-fluorouracil and capecitabine. Claim 6 A method according to any one of paragraphs 3 to 4, wherein the platinum-based drug is selected from cisplatin and oxaliplatin. Claim 7 A method according to any one of paragraphs 2 to 6, wherein the fluorouracil-based drug is capecitabine. Claim 8 A method in which, in any one of paragraphs 3 to 6, the platinum-based drug is oxaliplatin. Claim 9 A method according to any one of claims 1 to 8, wherein the chemotherapy agent is a combination of capecitabine and oxaliplatin. Claim 10 A method according to any one of claims 1 to 9, wherein the cancer is HER2-positive advanced gastric cancer. Claim 11 A method according to any one of claims 1 to 10, wherein the cancer is unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma. Claim 12 A method according to any one of claims 1 to 11, wherein the heavy chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:

9. Claim 13 A method according to any one of claims 1 to 12, wherein the heavy chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:5, and the light chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:

10. Claim 14 A method according to any one of claims 1 to 13, wherein trastuzumab is administered at a dose of about 0.1 mg / kg to about 10 mg / kg based on body weight. Claim 15 In any one of claims 1 to 14, trastuzumab is based on body weight and is about 0.1 mg / kg to about 10 mg / kg, about 0.3 mg / kg to about 10 mg / kg, 0.9 mg / kg to about 10 mg / kg, about 1 mg / kg to about 10 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 3 mg / kg to about 10 mg / kg, about 4 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 6 mg / kg to about 10 mg / kg, about 7 mg / kg to about 10 mg / kg, about 8 mg / kg to about 10 mg / kg, about 9 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 8 mg / kg, about 0.3 mg / kg to about 8 mg / kg, 0.9 A method of administration at a dose of mg / kg to about 8 mg / kg, about 1 mg / kg to about 8 mg / kg, about 2.5 mg / kg to about 8 mg / kg, about 3 mg / kg to about 8 mg / kg, about 4 mg / kg to about 8 mg / kg, about 5 mg / kg to about 8 mg / kg, about 6 mg / kg to about 8 mg / kg, about 7 mg / kg to about 8 mg / kg, about 0.1 mg / kg to about 6 mg / kg, about 0.3 mg / kg to about 6 mg / kg, 0.9 mg / kg to about 6 mg / kg, about 1 mg / kg to about 6 mg / kg, about 2.5 mg / kg to about 6 mg / kg, about 3 mg / kg to about 6 mg / kg, about 4 mg / kg to about 6 mg / kg, or about 5 mg / kg to about 6 mg / kg. Claim 16 A method according to any one of claims 1 to 15, wherein trastuzumab is administered at a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg based on body weight. Claim 17 A method according to any one of claims 1 to 16, wherein trastuzumab is administered at an initial loading dose of about 8 mg / kg based on body weight, followed by administration at a dose of about 6 mg / kg. Claim 18 A method according to any one of claims 1 to 17, wherein trastuzumab is administered once about every 1 week, once about every 2 weeks, once about every 3 weeks, once about every 4 weeks, once about every 1 month, once about every 3 to 6 months, or at longer intervals. Claim 19 In any one of claims 1 to 18, the method of administering trastuzumab intravenously. Claim 20 In any one of claims 1 to 19, the second antibody is, based on body weight, about 0.1 mg / kg to about 30 mg / kg, about 0.3 mg / kg to about 30 mg / kg, 0.9 mg / kg to about 30 mg / kg, about 1 mg / kg to about 30 mg / kg, about 2.5 mg / kg to about 30 mg / kg, about 3 mg / kg to about 30 mg / kg, about 4 mg / kg to about 30 mg / kg, about 5 mg / kg to about 30 mg / kg, about 6 mg / kg to about 30 mg / kg, about 7 mg / kg to about 30 mg / kg, about 8 mg / kg to about 30 mg / kg, about 9 mg / kg to about 30 mg / kg, about 10 mg / kg to about 30 mg / kg, about 11 mg / kg to about 30 mg / kg, about 12 mg / kg to about 30 mg / kg, about 13 mg / kg to about 30 mg / kg, about 14 mg / kg to about 30 mg / kg, about 15 mg / kg to about 30 mg / kg, about 16 mg / kg to about 30 mg / kg, about 17 mg / kg to about 30 mg / kg, about 18 mg / kg to about 30 mg / kg, about 19 mg / kg to about 30 mg / kg, about 20 mg / kg to about 30 mg / kg, about 21 mg / kg to about 30 mg / kg, about 22 mg / kg to about 30 mg / kg, about 23 mg / kg to about 30 mg / kg, about 24 mg / kg to about 30 mg / kg, about 25 mg / kg to about 30 mg / kg, about 26 mg / kg to about 30 mg / kg, about 27 mg / kg to about 30 mg / kg, about 28 mg / kg to about 30 mg / kg, about 29 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.3 mg / kg to about 25 mg / kg, 0.9 mg / kg to about 25 mg / kg, about 1 mg / kg to about 25 mg / kg, about 2.5 mg / kg to about 25 mg / kg, about 3 mg / kg to about 25 mg / kg, about 4 mg / kg to about 25 mg / kg, about 5 mg / kg to about 25 mg / kg, about 6 mg / kg to about 25 mg / kg, about 7 mg / kg to about 25 mg / kg, about 8 mg / kg to about 25 mg / kg, about 9 mg / kg to about 25 mg / kg, about 10 mg / kg to about 25 mg / kg, about 11 mg / kg to about 25 mg / kg, about 12 mg / kg to about 25 mg / kg, about 13 mg / kg to about 25 mg / kg, about 14 mg / kg to about 25 mg / kg, about 15 mg / kg to about 25 mg / kg, about 16 mg / kg to about 25 mg / kg, about 17 mg / kg to about 25 mg / kg, about 18 mg / kg to about 25 mg / kg, about 19 mg / kg to about 25 mg / kg, about 20 mg / kg to about 25 mg / kg, about 21 mg / kg to about 25 mg / kg, about 22 mg / kg to about 25 mg / kg, about 23 mg / kg to about 25 mg / kg, about 24 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.3 mg / kg to about 20 mg / kg, 0.9 mg / kg to about 20 mg / kg, about 1 mg / kg to about 20 mg / kg, about 2.5 mg / kg to about 20 mg / kg, about 3 mg / kg to about 20 mg / kg, about 4 mg / kg to about 20 mg / kg, about 5 mg / kg to about 20 mg / kg, about 6 mg / kg to about 20 mg / kg, about 7 mg / kg to about 20 mg / kg, about 8 mg / kg to about 20 mg / kg, about 9 mg / kg to about 20 mg / kg, about 10 mg / kg to about 20 mg / kg, about 11 mg / kg to about 20 mg / kg, about 12 mg / kg to about 20 mg / kg, about 13 mg / kg to about 20 mg / kg, about 14 mg / kg to about 20 mg / kg, about 15 mg / kg to about 20 mg / kg, about 16 mg / kg to about 20 mg / kg, about 17 mg / kg to about 20 mg / kg, about 18 mg / kg to about 20 mg / kg, about 19 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.3 mg / kg to about 15 mg / kg, 0.9 mg / kg to about 15 mg / kg, about 1 mg / kg to about 15 mg / kg, about 2.5 mg / kg to about 15 mg / kg, about 3 mg / kg to about 15 mg / kg, about 4 mg / kg to about 15 mg / kg, about 5 mg / kg to about 15 mg / kg, about 6 mg / kg to about 15 mg / kg, about 7 mg / kg to about 15 mg / kg, about 8 mg / kg to about 15 mg / kg, about 9 mg / kg to about 15 mg / kg, about 10 mg / kg to about 15 mg / kg, about 11 mg / kg A method of administration at a dose of about 15 mg / kg, about 12 mg / kg to about 15 mg / kg, about 13 mg / kg to about 15 mg / kg, or about 14 mg / kg to about 15 mg / kg. Claim 21 In any one of claims 1 to 20, the second antibody is about 0.1 mg / kg, about 0.3 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 based on body weight A method of administration at a dose of mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, or about 30 mg / kg. Claim 22 A method according to any one of claims 1 to 21, wherein the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight. Claim 23 A method according to any one of claims 1 to 22, wherein the second antibody is administered once every approximately 1 week, once every approximately 2 weeks, once every approximately 3 weeks, once every approximately 4 weeks, once every approximately 1 month, once every approximately 3 to 6 months, or at a longer interval. Claim 24 A method in which, in any one of claims 1 to 23, the second antibody is administered intravenously. Claim 25 In any one of paragraphs 6 to 24, oxaliplatin is about 10 to about 150 mg / m² based on body surface area. 2 , about 20 to about 150 mg / m² 2 , about 30 to about 150 mg / m² 2 , about 40 to about 150 mg / m² 2 , about 50 to about 150 mg / m² 2 , about 60 to about 150 mg / m² 2 , about 70 to about 150 mg / m² 2 , about 75 to about 150 mg / m² 2 , about 80 to about 150 mg / m² 2 , about 85 to about 150 mg / m² 2 , about 90 to about 150 mg / m² 2 , about 95 to about 150 mg / m² 2 , about 100 to about 150 mg / m² 2 , about 105 to about 150 mg / m² 2 , about 110 to about 150 mg / m² 2 , about 115 to about 150 mg / m² 2 , about 120 to about 150 mg / m² 2 , about 125 to about 150 mg / m² 2 , about 130 to about 150 mg / m² 2 , about 135 to about 150 mg / m² 2 , about 140 to about 150 mg / m² 2 , about 145 to about 150 mg / m² 2 , about 10 to about 140 mg / m² 2 , about 20 to about 140 mg / m² 2 , about 30 to about 140 mg / m² 2 , about 40 to about 140 mg / m² 2 , about 50 to about 140 mg / m² 2 , about 60 to about 140 mg / m² 2 , about 70 to about 140 mg / m² 2 , about 75 to about 140 mg / m² 2 , about 80 to about 140 mg / m² 2 , about 85 to about 140 mg / m² 2 , about 90 to about 140 mg / m² 2 , about 95 to about 140 mg / m² 2 , about 100 to about 140 mg / m² 2 , about 105 to about 140 mg / m² 2 , about 110 to about 140 mg / m² 2 , about 115 to about 140 mg / m² 2 , about 120 to about 140 mg / m² 2 , about 125 to about 140 mg / m² 2 , about 130 to about 140 mg / m² 2 , about 135 to about 140 mg / m² 2 , about 10 to about 130 mg / m² 2 , about 20 to about 130 mg / m² 2 , about 30 to about 130 mg / m² 2 , about 40 to about 130 mg / m² 2 , about 50 to about 130 mg / m² 2 , about 60 to about 130 mg / m² 2 , about 70 to about 130 mg / m² 2 , about 75 to about 130 mg / m² 2 , about 80 to about 130 mg / m² 2 , about 85 to about 130 mg / m² 2 , about 90 to about 130 mg / m² 2 , about 95 to about 130 mg / m² 2 , about 100 to about 130 mg / m² 2 , about 105 to about 130 mg / m² 2 , about 110 to about 130 mg / m² 2 , about 115 to about 130 mg / m² 2 , about 120 to about 130 mg / m² 2 or about 125 to about 130 mg / m² 2 Method of administration at a dosage. Claim 26 In any one of paragraphs 6 to 25, oxaliplatin is about 10 mg / m² based on body surface area. 2 , approximately 20 mg / m² 2 , approximately 30 mg / m² 2 , approximately 40 mg / m² 2 , approximately 50 mg / m² 2 , approximately 60 mg / m² 2 , approximately 70 mg / m² 2 , approximately 75 mg / m² 2 , approximately 80 mg / m² 2 , approximately 85 mg / m² 2 , approximately 90 mg / m² 2 , approximately 95 mg / m² 2 , approximately 100 mg / m² 2 , approximately 105 mg / m² 2 , approximately 110 mg / m² 2 , approximately 115 mg / m² 2 , approximately 120 mg / m² 2 , approximately 125 mg / m² 2 , approximately 130 mg / m² 2 , approximately 135 mg / m² 2 , approximately 140 mg / m² 2 , approximately 145 mg / m² 2 or about 150 mg / m² 2 Method of administration at a dosage. Claim 27 In any one of paragraphs 6 to 26, oxaliplatin is about 130 mg / m² based on body surface area. 2 Method of administration at a dosage. Claim 28 A method according to any one of paragraphs 6 to 27, wherein oxaliplatin is administered once every approximately 1 week, once every approximately 2 weeks, once every approximately 3 weeks, once every approximately 4 weeks, once every approximately 1 month, once every approximately 3 to 6 months, or at longer intervals. Claim 29 In any one of paragraphs 6 to 28, the method of administering oxaliplatin intravenously. Claim 30 In any one of paragraphs 7 to 29, capecitabine is about 100 to about 1200 mg / m² based on body surface area. 2 , about 200 to about 1200 mg / m² 2 , about 300 to about 1200 mg / m² 2 , about 400 to about 1200 mg / m² 2 , about 500 to about 1200 mg / m² 2 , about 600 to about 1200 mg / m² 2 , about 650 to about 1200 mg / m² 2 , about 700 to about 1200 mg / m² 2 , about 750 to about 1200 mg / m² 2 , about 800 to about 1200 mg / m² 2 , about 850 to about 1200 mg / m² 2 , about 900 to about 1200 mg / m² 2 , about 950 to about 1200 mg / m² 2 , about 1000 to about 1200 mg / m² 2 , about 1050 to about 1200 mg / m² 2 , about 1100 to about 1200 mg / m² 2 , about 1150 to about 1200 mg / m² 2 , about 100 to about 1100 mg / m² 2 , about 200 to about 1100 mg / m² 2 , about 300 to about 1100 mg / m² 2 , about 400 to about 1100 mg / m² 2 , about 500 to about 1100 mg / m² 2 , about 600 to about 1100 mg / m² 2 , about 650 to about 1100 mg / m² 2 , about 700 to about 1100 mg / m² 2 , about 750 to about 1100 mg / m² 2 , about 800 to about 1100 mg / m² 2 , about 850 to about 1100 mg / m² 2 , about 900 to about 1100 mg / m² 2 , about 950 to about 1100 mg / m² 2 , about 1000 to about 1100 mg / m² 2 , about 100 to about 1000 mg / m² 2 , about 200 to about 1000 mg / m² 2 , about 300 to about 1000 mg / m² 2 , about 400 to about 1000 mg / m² 2 , about 500 to about 1000 mg / m² 2 , about 600 to about 1000 mg / m² 2 , about 650 to about 1000 mg / m² 2 , about 700 to about 1000 mg / m² 2 , about 750 to about 1000 mg / m² 2 , about 800 to about 1000 mg / m² 2 , about 850 to about 1000 mg / m² 2 , about 900 to about 1000 mg / m² 2 or about 950 to about 1000 mg / m² 2 Method of administration at a dosage. Claim 31 In any one of paragraphs 7 to 30, capecitabine is about 100 mg / m² based on body surface area. 2 , approximately 200 mg / m² 2 , approximately 300 mg / m² 2 , approximately 400 mg / m² 2 , approximately 500 mg / m² 2 , approximately 600 mg / m² 2 , approximately 650 mg / m² 2 , approximately 700 mg / m² 2 , approximately 750 mg / m² 2 , approximately 800 mg / m² 2 , approximately 850 mg / m² 2 , approximately 900 mg / m² 2 , approximately 950 mg / m² 2 , approximately 1000 mg / m² 2 , approximately 1050 mg / m² 2 , approximately 1100 mg / m² 2 , approximately 1150 mg / m² 2 or about 1200 mg / m² 2 Method of administration at a dosage. Claim 32 In any one of paragraphs 7 to 31, capecitabine is about 1000 mg / m² based on body surface area. 2 Method of administration at a dosage. Claim 33 A method in which capecitabine is administered once a day, twice a day, or three times a day in any one of paragraphs 7 to 32. Claim 34 In any one of paragraphs 7 to 33, capecitabine is administered orally. Claim 35 In any one of claims 1 to 34, trastuzumab is administered at an initial loading dose of about 8 mg / kg based on body weight, followed by administration at a dose of about 6 mg / kg, the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight, and oxaliplatin is about 130 mg / m² based on body surface area. 2 It is administered at a dose of approximately 1000 mg / m² based on body surface area, and capecitabine is 2 Method of administration at a dosage. Claim 36 A method of administering the second antibody to the patient before administering trastuzumab, in any one of claims 1 to 35. Claim 37 A method of administering the second antibody to the patient after administering trastuzumab in any one of claims 1 to 36. Claim 38 A method of simultaneously administering trastuzumab and the second antibody in any one of claims 1 to 37. Claim 39 A method according to any one of claims 1 to 38, wherein the method further comprises the step of administering an immune checkpoint inhibitor. Claim 40 In paragraph 39, the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody. Claim 41 A method according to claim 39 or 40, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody. Claim 42 A combination therapy for treating a patient's HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, wherein the therapy comprises the step of administering the combination therapy to the patient, wherein the combination therapy comprises: (1) trastuzumab; (2) a second antibody - the second antibody is a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of the trastuzumab, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises HCDR1 described in SEQ ID NO:1, HCDR2 described in SEQ ID NO:2, and HCDR3 described in SEQ ID NO:3, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises LCDR1 described in SEQ ID NO:6, LCDR2 described in SEQ ID NO:7, and LCDR3 described in SEQ ID NO:8 -; and (3) a chemotherapy agent. Claim 43 In paragraph 42, the above chemotherapy agent is a fluorouracil-based drug in combination therapy. Claim 44 In Paragraph 42, the above chemotherapy agent is a platinum-based drug combination therapy. Claim 45 In any one of paragraphs 42 to 44, the chemotherapy agent is a combination therapy in which a fluorouracil-based drug and a platinum-based drug. Claim 46 In any one of claims 43 to 45, the fluorouracil-based drug is a combination therapy selected from 5-fluorouracil and capecitabine. Claim 47 In any one of claims 44 to 46, the platinum-based drug is a combination therapy selected from cisplatin and oxaliplatin. Claim 48 A combination therapy according to any one of paragraphs 43 to 47, wherein the fluorouracil-based drug is capecitabine. Claim 49 In any one of paragraphs 44 to 47, the platinum-based drug is oxaliplatin in combination therapy. Claim 50 In any one of paragraphs 42 to 49, the chemotherapy agent is a combination therapy of capecitabine and oxaliplatin. Claim 51 A combination therapy in which, in any one of paragraphs 42 to 50, the cancer is HER2-positive advanced gastric cancer. Claim 52 A combination therapy according to any one of claims 42 to 51, wherein the cancer is unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma. Claim 53 A combination therapy according to any one of claims 42 to 52, wherein the heavy chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:

9. Claim 54 A combination therapy according to any one of claims 42 to 53, wherein the heavy chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:5, and the light chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:

10. Claim 55 In any one of paragraphs 42 to 54, a combination therapy in which trastuzumab is administered at a dose of about 0.1 mg / kg to about 10 mg / kg based on body weight. Claim 56 In any one of paragraphs 42 to 55, trastuzumab is present in an amount of about 0.1 mg / kg to about 10 mg / kg, about 0.3 mg / kg to about 10 mg / kg, 0.9 mg / kg to about 10 mg / kg, about 1 mg / kg to about 10 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 3 mg / kg to about 10 mg / kg, about 4 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 6 mg / kg to about 10 mg / kg, about 7 mg / kg to about 10 mg / kg, about 8 mg / kg to about 10 mg / kg, about 9 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 8 mg / kg, about 0.3 mg / kg to about 8 mg / kg, based on body weight. Combination therapy administered at doses of 0.9 mg / kg to about 8 mg / kg, about 1 mg / kg to about 8 mg / kg, about 2.5 mg / kg to about 8 mg / kg, about 3 mg / kg to about 8 mg / kg, about 4 mg / kg to about 8 mg / kg, about 5 mg / kg to about 8 mg / kg, about 6 mg / kg to about 8 mg / kg, about 7 mg / kg to about 8 mg / kg, about 0.1 mg / kg to about 6 mg / kg, about 0.3 mg / kg to about 6 mg / kg, 0.9 mg / kg to about 6 mg / kg, about 1 mg / kg to about 6 mg / kg, about 2.5 mg / kg to about 6 mg / kg, about 3 mg / kg to about 6 mg / kg, about 4 mg / kg to about 6 mg / kg, or about 5 mg / kg to about 6 mg / kg. Claim 57 In any one of claims 42 to 56, trastuzumab is administered in a combination therapy at a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg based on body weight. Claim 58 A combination therapy according to any one of claims 42 to 57, wherein trastuzumab is administered at an initial loading dose of about 8 mg / kg based on body weight, followed by a dose of about 6 mg / kg. Claim 59 In any one of paragraphs 42 to 58, trastuzumab is administered as a combination therapy at intervals longer than that, approximately once every 1 week, approximately once every 2 weeks, approximately once every 3 weeks, approximately once every 4 weeks, approximately once every 1 month, approximately once every 3 to 6 months, or longer. Claim 60 In any one of paragraphs 42 to 59, trastuzumab is a combination therapy administered intravenously. Claim 61 In any one of claims 42 to 60, the second antibody is, based on body weight, about 0.1 mg / kg to about 30 mg / kg, about 0.3 mg / kg to about 30 mg / kg, 0.9 mg / kg to about 30 mg / kg, about 1 mg / kg to about 30 mg / kg, about 2.5 mg / kg to about 30 mg / kg, about 3 mg / kg to about 30 mg / kg, about 4 mg / kg to about 30 mg / kg, about 5 mg / kg to about 30 mg / kg, about 6 mg / kg to about 30 mg / kg, about 7 mg / kg to about 30 mg / kg, about 8 mg / kg to about 30 mg / kg, about 9 mg / kg to about 30 mg / kg, about 10 mg / kg to about 30 mg / kg, about 11 mg / kg to about 30 mg / kg, about 12 mg / kg to about 30 mg / kg, about 13 mg / kg to about 30 mg / kg, about 14 mg / kg to about 30 mg / kg, about 15 mg / kg to about 30 mg / kg, about 16 mg / kg to about 30 mg / kg, about 17 mg / kg to about 30 mg / kg, about 18 mg / kg to about 30 mg / kg, about 19 mg / kg to about 30 mg / kg, about 20 mg / kg to about 30 mg / kg, about 21 mg / kg to about 30 mg / kg, about 22 mg / kg to about 30 mg / kg, about 23 mg / kg to about 30 mg / kg, about 24 mg / kg to about 30 mg / kg, about 25 mg / kg to about 30 mg / kg, about 26 mg / kg to about 30 mg / kg, about 27 mg / kg to about 30 mg / kg, about 28 mg / kg to about 30 mg / kg, about 29 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.3 mg / kg to about 25 mg / kg, 0.9 mg / kg to about 25 mg / kg, about 1 mg / kg to about 25 mg / kg, about 2.5 mg / kg to about 25 mg / kg, about 3 mg / kg to about 25 mg / kg, about 4 mg / kg to about 25 mg / kg, about 5 mg / kg to about 25 mg / kg, about 6 mg / kg to about 25 mg / kg, about 7 mg / kg to about 25 mg / kg, about 8 mg / kg to about 25 mg / kg, about 9 mg / kg to about 25 mg / kg, about 10 mg / kg to about 25 mg / kg, about 11 mg / kg to about 25 mg / kg, about 12 mg / kg to about 25 mg / kg, about 13 mg / kg to about 25 mg / kg, about 14 mg / kg to about 25 mg / kg, about 15 mg / kg to about 25 mg / kg, about 16 mg / kg to about 25 mg / kg, about 17 mg / kg to about 25 mg / kg, about 18 mg / kg to about 25 mg / kg, about 19 mg / kg to about 25 mg / kg, about 20 mg / kg to about 25 mg / kg, about 21 mg / kg to about 25 mg / kg, about 22 mg / kg to about 25 mg / kg, about 23 mg / kg to about 25 mg / kg, about 24 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.3 mg / kg to about 20 mg / kg, 0.9 mg / kg to about 20 mg / kg, about 1 mg / kg to about 20 mg / kg, about 2.5 mg / kg to about 20 mg / kg, about 3 mg / kg to about 20 mg / kg, about 4 mg / kg to about 20 mg / kg, about 5 mg / kg to about 20 mg / kg, about 6 mg / kg to about 20 mg / kg, about 7 mg / kg to about 20 mg / kg, about 8 mg / kg to about 20 mg / kg, about 9 mg / kg to about 20 mg / kg, about 10 mg / kg to about 20 mg / kg, about 11 mg / kg to about 20 mg / kg, about 12 mg / kg to about 20 mg / kg, about 13 mg / kg to about 20 mg / kg, about 14 mg / kg to about 20 mg / kg, about 15 mg / kg to about 20 mg / kg, about 16 mg / kg to about 20 mg / kg, about 17 mg / kg to about 20 mg / kg, about 18 mg / kg to about 20 mg / kg, about 19 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.3 mg / kg to about 15 mg / kg, 0.9 mg / kg to about 15 mg / kg, about 1 mg / kg to about 15 mg / kg, about 2.5 mg / kg to about 15 mg / kg, about 3 mg / kg to about 15 mg / kg, about 4 mg / kg to about 15 mg / kg, about 5 mg / kg to about 15 mg / kg, about 6 mg / kg to about 15 mg / kg, about 7 mg / kg to about 15 mg / kg, about 8 mg / kg to about 15 mg / kg, about 9 mg / kg to about 15 mg / kg, about 10 mg / kg to about 15 mg / kg, about 11 mg / kg Combination therapy administered at doses of approximately 15 mg / kg, approximately 12 mg / kg to approximately 15 mg / kg, approximately 13 mg / kg to approximately 15 mg / kg, or approximately 14 mg / kg to approximately 15 mg / kg. Claim 62 In any one of paragraphs 42 to 61, the second antibody is about 0.1 mg / kg, about 0.3 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 based on body weight Combination therapy administered at doses of mg / kg, approx. 27 mg / kg, approx. 28 mg / kg, approx. 29 mg / kg, or approx. 30 mg / kg. Claim 63 A combination therapy according to any one of claims 42 to 62, wherein the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight. Claim 64 A combination therapy according to any one of claims 42 to 63, wherein the second antibody is administered once every approximately 1 week, once every approximately 2 weeks, once every approximately 3 weeks, once every approximately 4 weeks, once every approximately 1 month, once every approximately 3 to 6 months, or at a longer interval. Claim 65 In any one of paragraphs 42 to 64, the second antibody is a combination therapy administered intravenously. Claim 66 In any one of paragraphs 47 to 65, oxaliplatin is about 10 to about 150 mg / m² based on body surface area. 2 , about 20 to about 150 mg / m² 2 , about 30 to about 150 mg / m² 2 , about 40 to about 150 mg / m² 2 , about 50 to about 150 mg / m² 2 , about 60 to about 150 mg / m² 2 , about 70 to about 150 mg / m² 2 , about 75 to about 150 mg / m² 2 , about 80 to about 150 mg / m² 2 , about 85 to about 150 mg / m² 2 , about 90 to about 150 mg / m² 2 , about 95 to about 150 mg / m² 2 , about 100 to about 150 mg / m² 2 , about 105 to about 150 mg / m² 2 , about 110 to about 150 mg / m² 2 , about 115 to about 150 mg / m² 2 , about 120 to about 150 mg / m² 2 , about 125 to about 150 mg / m² 2 , about 130 to about 150 mg / m² 2 , about 135 to about 150 mg / m² 2 , about 140 to about 150 mg / m² 2 , about 145 to about 150 mg / m² 2 , about 10 to about 140 mg / m² 2 , about 20 to about 140 mg / m² 2 , about 30 to about 140 mg / m² 2 , about 40 to about 140 mg / m² 2 , about 50 to about 140 mg / m² 2 , about 60 to about 140 mg / m² 2 , about 70 to about 140 mg / m² 2 , about 75 to about 140 mg / m² 2 , about 80 to about 140 mg / m² 2 , about 85 to about 140 mg / m² 2 , about 90 to about 140 mg / m² 2 , about 95 to about 140 mg / m² 2 , about 100 to about 140 mg / m² 2 , about 105 to about 140 mg / m² 2 , about 110 to about 140 mg / m² 2 , about 115 to about 140 mg / m² 2 , about 120 to about 140 mg / m² 2 , about 125 to about 140 mg / m² 2 , about 130 to about 140 mg / m² 2 , about 135 to about 140 mg / m² 2 , about 10 to about 130 mg / m² 2 , about 20 to about 130 mg / m² 2 , about 30 to about 130 mg / m² 2 , about 40 to about 130 mg / m² 2 , about 50 to about 130 mg / m² 2 , about 60 to about 130 mg / m² 2 , about 70 to about 130 mg / m² 2 , about 75 to about 130 mg / m² 2 , about 80 to about 130 mg / m² 2 , about 85 to about 130 mg / m² 2 , about 90 to about 130 mg / m² 2 , about 95 to about 130 mg / m² 2 , about 100 to about 130 mg / m² 2 , about 105 to about 130 mg / m² 2 , about 110 to about 130 mg / m² 2 , about 115 to about 130 mg / m² 2 , about 120 to about 130 mg / m² 2 or about 125 to about 130 mg / m² 2 Combination therapy administered at the dose of Claim 67 In any one of paragraphs 47 to 66, oxaliplatin is about 10 mg / m² based on body surface area. 2 , approximately 20 mg / m² 2 , approximately 30 mg / m² 2 , approximately 40 mg / m² 2 , approximately 50 mg / m² 2 , approximately 60 mg / m² 2 , approximately 70 mg / m² 2 , approximately 75 mg / m² 2 , approximately 80 mg / m² 2 , approximately 85 mg / m² 2 , approximately 90 mg / m² 2 , approximately 95 mg / m² 2 , approximately 100 mg / m² 2 , approximately 105 mg / m² 2 , approximately 110 mg / m² 2 , approximately 115 mg / m² 2 , approximately 120 mg / m² 2 , approximately 125 mg / m² 2 , approximately 130 mg / m² 2 , approximately 135 mg / m² 2 , approximately 140 mg / m² 2 , approximately 145 mg / m² 2 or about 150 mg / m² 2 Combination therapy administered at the dose of Claim 68 In any one of paragraphs 47 to 67, oxaliplatin is about 130 mg / m² based on body surface area. 2 Combination therapy administered at the dose of Claim 69 In any one of paragraphs 47 to 68, a combination therapy in which oxaliplatin is administered approximately once every 1 week, approximately once every 2 weeks, approximately once every 3 weeks, approximately once every 4 weeks, approximately once every 1 month, approximately once every 3 to 6 months, or at longer intervals. Claim 70 In any one of paragraphs 47 to 69, oxaliplatin is a combination therapy administered intravenously. Claim 71 In any one of paragraphs 48 to 70, capecitabine is about 100 to about 1200 mg / m² based on body surface area. 2 , about 200 to about 1200 mg / m² 2 , about 300 to about 1200 mg / m² 2 , about 400 to about 1200 mg / m² 2 , about 500 to about 1200 mg / m² 2 , about 600 to about 1200 mg / m² 2 , about 650 to about 1200 mg / m² 2 , about 700 to about 1200 mg / m² 2 , about 750 to about 1200 mg / m² 2 , about 800 to about 1200 mg / m² 2 , about 850 to about 1200 mg / m² 2 , about 900 to about 1200 mg / m² 2 , about 950 to about 1200 mg / m² 2 , about 1000 to about 1200 mg / m² 2 , about 1050 to about 1200 mg / m² 2 , about 1100 to about 1200 mg / m² 2 , about 1150 to about 1200 mg / m² 2 , about 100 to about 1100 mg / m² 2 , about 200 to about 1100 mg / m² 2 , about 300 to about 1100 mg / m² 2 , about 400 to about 1100 mg / m² 2 , about 500 to about 1100 mg / m² 2 , about 600 to about 1100 mg / m² 2 , about 650 to about 1100 mg / m² 2 , about 700 to about 1100 mg / m² 2 , about 750 to about 1100 mg / m² 2 , about 800 to about 1100 mg / m² 2 , about 850 to about 1100 mg / m² 2 , about 900 to about 1100 mg / m² 2 , about 950 to about 1100 mg / m² 2 , about 1000 to about 1100 mg / m² 2 , about 100 to about 1000 mg / m² 2 , about 200 to about 1000 mg / m² 2 , about 300 to about 1000 mg / m² 2 , about 400 to about 1000 mg / m² 2 , about 500 to about 1000 mg / m² 2 , about 600 to about 1000 mg / m² 2 , about 650 to about 1000 mg / m² 2 , about 700 to about 1000 mg / m² 2 , about 750 to about 1000 mg / m² 2 , about 800 to about 1000 mg / m² 2 , about 850 to about 1000 mg / m² 2 , about 900 to about 1000 mg / m² 2 or about 950 to about 1000 mg / m² 2 Combination therapy administered at the dose of Claim 72 In any one of paragraphs 48 to 71, capecitabine is about 100 mg / m² based on body surface area. 2 , approximately 200 mg / m² 2 , approximately 300 mg / m² 2 , approximately 400 mg / m² 2 , approximately 500 mg / m² 2 , approximately 600 mg / m² 2 , approximately 650 mg / m² 2 , approximately 700 mg / m² 2 , approximately 750 mg / m² 2 , approximately 800 mg / m² 2 , approximately 850 mg / m² 2 , approximately 900 mg / m² 2 , approximately 950 mg / m² 2 , approximately 1000 mg / m² 2 , approximately 1050 mg / m² 2 , approximately 1100 mg / m² 2 , approximately 1150 mg / m² 2 or about 1200 mg / m² 2 Combination therapy administered at the dose of Claim 73 In any one of paragraphs 48 to 72, capecitabine is about 1000 mg / m² based on body surface area. 2 Combination therapy administered at the dose of Claim 74 In any one of paragraphs 48 to 73, capecitabine is a combination therapy administered once a day, twice a day, or three times a day. Claim 75 In any one of paragraphs 48 to 74, capecitabine is a combination therapy administered orally. Claim 76 In any one of paragraphs 42 to 75, trastuzumab is administered at an initial loading dose of about 8 mg / kg based on body weight, followed by a dose of about 6 mg / kg, the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight, and oxaliplatin is about 130 mg / m² based on body surface area. 2 It is administered at a dose of approximately 1000 mg / m² based on body surface area, and capecitabine is 2 Combination therapy administered at the dose of Claim 77 A combination therapy in which the second antibody is administered to the patient before administering trastuzumab, in any one of claims 42 to 76. Claim 78 A combination therapy in which the second antibody is administered to the patient after administering trastuzumab in any one of claims 42 to 77. Claim 79 A combination therapy in which trastuzumab and the second antibody are administered simultaneously in any one of claims 42 to 78. Claim 80 In any one of claims 42 to 79, the method further comprises a combination therapy including the step of administering an immune checkpoint inhibitor. Claim 81 In paragraph 80, the immune checkpoint inhibitor is a combination therapy in which the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody. Claim 82 In paragraph 80 or 81, the immune checkpoint inhibitor is a combination therapy in which the immune checkpoint inhibitor is an anti-PD-1 antibody. Claim 83 A combination product comprising: trastuzumab; a second antibody—the second antibody being a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of trastuzumab, comprising a heavy chain variable region including HCDR1 as described in SEQ ID NO:1, HCDR2 as described in SEQ ID NO:2, and HCDR3 as described in SEQ ID NO:3, and a light chain variable region including LCDR1 as described in SEQ ID NO:6, LCDR2 as described in SEQ ID NO:7, and LCDR3 as described in SEQ ID NO:8—; and a combination product comprising a chemotherapy agent. Claim 84 In paragraph 83, the above chemotherapy agent is a combination product of fluorouracil-based drugs. Claim 85 In Paragraph 83, the above chemotherapy agent is a combination product of platinum-based drugs. Claim 86 In any one of paragraphs 83 to 85, the chemotherapy agent is a combination product of a fluorouracil-based drug and a platinum-based drug. Claim 87 In any one of claims 84 to 86, the fluorouracil-based drug is a combination product selected from 5-fluorouracil and capecitabine. Claim 88 In any one of claims 85 to 87, the platinum-based drug is a combination product selected from cisplatin and oxaliplatin. Claim 89 A combination product in which, in any one of paragraphs 84 to 88, the fluorouracil-based drug is capecitabine. Claim 90 In any one of paragraphs 85 to 89, the platinum-based drug is a combination product in which oxaliplatin is used. Claim 91 In any one of paragraphs 83 to 90, the chemotherapy agent is a combination product of capecitabine and oxaliplatin. Claim 92 A combination product according to any one of claims 83 to 91, wherein the heavy chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:

9. Claim 93 A combination product according to any one of claims 83 to 92, wherein the heavy chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:5, and the light chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:

10. Claim 94 In any one of paragraphs 83 to 93, the combination product further comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody. Claim 95 In any one of paragraphs 83 to 94, the combination product is a combination product further comprising an anti-PD-1 antibody. Claim 96 A kit for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, wherein the kit comprises: trastuzumab; a second antibody—the second antibody being a second anti-HER2 antibody or its antigen-binding fragment having a binding epitope different from that of trastuzumab, comprising a heavy chain variable region including HCDR1 described in SEQ ID NO:1, HCDR2 described in SEQ ID NO:2, and HCDR3 described in SEQ ID NO:3, and a light chain variable region including LCDR1 described in SEQ ID NO:6, LCDR2 described in SEQ ID NO:7, and LCDR3 described in SEQ ID NO:8—; and a kit comprising a chemotherapy agent. Claim 97 In paragraph 96, the above chemotherapy agent is a kit that is a fluorouracil-based drug. Claim 98 In Clause 96, the above chemotherapy agent is a platinum-based drug kit. Claim 99 In any one of claims 96 to 98, the chemotherapy agent is a kit in which a fluorouracil-based drug and a platinum-based drug are combined. Claim 100 In any one of claims 97 to 99, the fluorouracil-based drug is a kit selected from 5-fluorouracil and capecitabine. Claim 101 In any one of claims 98 to 100, the platinum-based drug is a kit selected from cisplatin and oxaliplatin. Claim 102 A kit in which, in any one of claims 97 to 101, the fluorouracil-based drug is capecitabine. Claim 103 Kit, wherein in any one of claims 98 to 102, the platinum-based drug is oxaliplatin. Claim 104 In any one of claims 96 to 103, the chemotherapy agent is a kit in combination of capecitabine and oxaliplatin. Claim 105 Kit, wherein in any one of claims 96 to 104, the cancer is HER2-positive advanced gastric cancer. Claim 106 A kit in which, in any one of claims 96 to 105, the cancer is unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma. Claim 107 A kit according to any one of claims 96 to 106, wherein the heavy chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:

9. Claim 108 A kit according to any one of claims 96 to 107, wherein the heavy chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:5, and the light chain of the second antibody comprises or is composed of the amino acid sequence described in SEQ ID NO:

10. Claim 109 A kit comprising an instruction manual in any one of paragraphs 96 through 108. Claim 110 A kit comprising an anti-PD-1 / PD-L1 antibody in any one of claims 96 to 109. Claim 111 A kit comprising an anti-PD-1 antibody further comprising any one of claims 96 to 110.

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