Method for treating gastric cancer by combining anti-her2 antibody and chemotherapeutic agent, and use

Abstract

Trastuzumab, a second anti-HER2 antibody and a chemotherapeutic agent are combined to treat HER2-positive advanced gastric cancer. Compared with existing first-line treatment solutions for HER2-positive advanced gastric cancer, the combined treatment method of trastuzumab, the second anti-HER2 antibody and the chemotherapeutic agent (XELOX) prolongs the progression free survival (PFS) and / or the overall survival (OS) of patients.

Description

Method and use of combined anti-HER2 antibody and chemotherapy agent for treating gastric cancer

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application number CN202311527171.5 filed on November 16, 2023, the contents of which are incorporated by reference in their entirety. Technical Field

[0003] The present invention relates to a method and use of a drug combination for treating cancer, and more particularly, to a method and use of a combination of an anti-HER2 antibody, trastuzumab, and a chemotherapeutic agent for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma. Background Art

[0004] Gastric cancer is a common malignant tumor. According to the World Health Organization, in 2015, gastric cancer ranked fourth among the causes of malignant tumor deaths worldwide, with 754,000 deaths. In China, gastric cancer is the second most common malignant tumor with the highest annual incidence. It is also the most common digestive tract malignancy, with a high incidence rate worldwide. Gastric cancer can be divided into adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, and carcinoid tumors, with the vast majority being gastric adenocarcinoma. Gastric cancer has insidious early clinical manifestations. Although rapid advances in gastrointestinal endoscopy have significantly improved the early diagnosis rate of gastric cancer, the overall prognosis remains poor, especially for locally advanced and metastatic gastric cancer. While surgical resection offers the greatest chance of treatment for gastric cancer patients, postoperative recurrence and metastasis are also significant causes of mortality in these patients.

[0005] 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 that binds to the cell membrane and participates in signaling pathways that lead to cell growth and differentiation. It is encoded by the proto-oncogene HER2 / neu. HER2 is generally considered an orphan receptor, and ligands from the epidermal growth factor family cannot activate HER2. However, HER2 can form dimers when ligands bind to ErbB receptors, and HER2 can also form heterodimers with other members of the ErbB (tyrosine kinase receptor) family.

[0006] HER2-positive gastric cancer is a distinct subtype of the disease, requiring different diagnostic and treatment strategies and approaches than HER2-negative gastric cancer. The reported global prevalence of HER2 overexpression in gastric cancer ranges from 7.3% to 20.2%, while the prevalence in Chinese gastric cancer patients is 12% to 13%. Currently, due to varying evaluation criteria used across studies, there is no consensus on the prognostic value of HER2 in gastric cancer.

[0007] Patients with HER2-positive advanced gastric cancer may benefit from trastuzumab. Based on prior nonclinical data and the established clinical benefit of trastuzumab combined with chemotherapy in HER2-positive metastatic breast cancer and adjuvant breast cancer, a randomized phase III study (ToGA) was conducted to evaluate the efficacy and safety of adding trastuzumab to a fluoropyrimidine (capecitabine or 5-FU) plus cisplatin (FP) in the treatment of HER2-positive advanced gastric cancer. The study enrolled 594 patients in 24 countries. Patients were randomized in a 1:1 ratio to receive either FP or FP plus trastuzumab (TFP). The primary endpoint was overall survival (OS). Results demonstrated that TFP was superior to FP alone, with a median overall survival of 13.8 months in the TFP group compared with 11.1 months in the FP group in the intention-to-treat (ITT) population (hazard ratio = 0.74; 95% CI: 0.60, 0.91). The median progression-free survival was 6.7 months in the TFP group and 5.5 months in the FP group (hazard ratio = 0.71; 95% CI: 0.59, 0.85).

[0008] When it comes to the choice of chemotherapy drugs for patients with advanced gastric cancer, a two-drug combination of fluorouracil and platinum drugs is usually recommended in China. Based on patients' better tolerance and actual clinical application in China, the CSCO Gastric Cancer Guidelines recommend oxaliplatin more among platinum drugs. The efficacy of the capecitabine + oxaliplatin (XELOX) regimen has also been confirmed by relevant clinical trials and has received a level I recommendation from the Chinese CSCO Gastric Cancer Guidelines. At the same time, the European ESMO Guidelines and the US NCCN Guidelines also recommend trastuzumab combined with chemotherapy (fluorouracil and platinum drugs) as the first-line treatment for HER2-positive advanced gastric cancer. Immunotherapy has become an important exploration direction for the combined treatment of HER2-positive advanced gastric cancer. Summary of the Invention

[0009] One object of the present invention is to provide a use of trastuzumab in combination with a second antibody and a chemotherapeutic agent in the preparation of a medicament for treating HER2-positive gastric cancer.

[0010] A second object of the present invention is to provide a pharmaceutical kit for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0011] The present invention also provides a method for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma using trastuzumab in combination with a second antibody and a chemotherapeutic agent.

[0012] According to one aspect of the present invention, the present invention provides a method for treating cancer, particularly HER2-positive gastric cancer, using trastuzumab in combination with a second antibody and a chemotherapeutic 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 different binding epitope from trastuzumab, and preferably the second antibody comprises a heavy chain and a light chain:

[0013] The heavy chain comprises a heavy chain variable region comprising HCDR1 (heavy chain complementarity determining region 1) as shown in SEQ ID NO: 1, HCDR2 (heavy chain complementarity determining region 2) as shown in SEQ ID NO: 2, and HCDR3 (heavy chain complementarity determining region 3) as shown in SEQ ID NO: 3; and

[0014] The light chain comprises a light chain variable region comprising LCDR1 (light chain complementary determining region 1) as shown in SEQ ID NO:6, LCDR2 (light chain complementary determining region 2) as shown in SEQ ID NO:7, and LCDR3 (light chain complementary determining region 3) as shown in SEQ ID NO:8.

[0015] In a preferred embodiment of the present invention, the heavy chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:9.

[0016] In a preferred embodiment of the present invention, the heavy chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO: 5, and the light chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO: 10.

[0017] As chemotherapeutic agents used in combination with the two antibodies, various chemotherapeutic agents currently used clinically or recommended by guidelines can be selected. Preferred chemotherapeutic agents are fluorouracils and platinum drugs, used alone or in combination. Preferred fluorouracils are selected from 5-fluorouracil and capecitabine, and platinum drugs are selected from cisplatin and oxaliplatin. More preferably, the chemotherapeutic agents are capecitabine and oxaliplatin. In the most preferred treatment regimen, trastuzumab is used in combination with a second antibody and a chemotherapy regimen of capecitabine + oxaliplatin (XELOX).

[0018] The uses described herein are primarily for the treatment of HER2-positive gastric cancer, particularly advanced HER2-positive gastric cancer. More preferably, they are for the treatment of advanced, unresectable or metastatic HER2-positive gastric cancer, including gastroesophageal junction adenocarcinoma, which has roughly the same or similar diagnostic criteria and clinical manifestations as gastric cancer. In a preferred embodiment of the present invention, the methods and uses of the present invention are used in treatment-naive patients diagnosed with advanced, unresectable or metastatic gastric cancer, i.e., as first-line treatment for such cancers.

[0019] In terms of administration and dosage, the dosage of trastuzumab, the second antibody or its binding fragment is: intravenous administration every 3 weeks, 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; the chemotherapy agent is capecitabine combined with oxaliplatin (XELOX regimen), and the dosage of oxaliplatin is 130 mg / m 2 Dosage: intravenous infusion, administered once every three weeks; capecitabine at 1000 mg / m 2 Dosage: Oral administration, twice a day, every three weeks as one dosing cycle.

[0020] In addition to the above-mentioned combination therapy, immune checkpoint inhibitors, such as anti-PD-1 antibodies and / or anti-PD-L1 antibodies, may also be administered as needed, preferably anti-PD-1 antibodies.

[0021] According to another aspect of the present invention, the combined treatment regimen of the present invention can be administered to the patient individually according to the above regimen, or can be prepared in the form of a drug pack or kit for convenient administration. Therefore, the present invention also provides a kit for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, comprising the following composition:

[0022] Trastuzumab;

[0023] The second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding site from the trastuzumab, comprising a heavy chain and a light chain:

[0024] The heavy chain comprises a heavy chain variable region comprising HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and

[0025] The light chain comprises a light chain variable region comprising LCDR1 as shown in SEQ ID NO: 6, LCDR2 as shown in SEQ ID NO: 7, and LCDR3 as shown in SEQ ID NO: 8; and

[0026] Chemotherapeutic agents.

[0027] In a preferred embodiment of the present invention, the chemotherapeutic agents are capecitabine and oxaliplatin.

[0028] The drug kit of the present invention may further comprise an anti-PD-1 antibody and / or an anti-PD-L1 antibody. Beneficial effects:

[0029] The present invention provides methods and uses of an anti-HER2 antibody combination and a chemotherapeutic agent for treating HER2-positive gastric cancer patients. In particular, the methods and uses are to treat HER2-positive advanced gastric cancer by combining trastuzumab, a second anti-HER2 antibody, and a chemotherapeutic agent. Data from a randomized, double-blind, multicenter, Phase II clinical study of trastuzumab, a second anti-HER2 antibody, and a chemotherapeutic agent (XELOX) in patients with advanced unresectable or metastatic HER2-positive gastric cancer showed that the trastuzumab, a second anti-HER2 antibody, and a chemotherapeutic agent (XELOX) combination therapy prolonged the patient's progression-free survival (PFS) and / or overall survival (OS) compared to the first-line treatment regimen for HER2-positive advanced gastric cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIG1 shows the results of HER2 epitope binding competition analysis of the second anti-HER2 antibody, trastuzumab, and pertuzumab involved in the present invention;

[0031] Where a is the result of epitope binding competition analysis of HER2-Fc protein, trastuzumab and pertuzumab injected sequentially;

[0032] b shows the results of epitope binding competition analysis after sequential injection of HER2-Fc protein, pertuzumab, and trastuzumab;

[0033] In the figure, HER2 represents HER2-Fc protein.

[0034] FIG2 is a study of HER2-mediated endocytosis in gastric cancer cells NCI-N87 (a) and SNU216 (b) treated with a second anti-HER2 antibody according to the present invention in combination with trastuzumab.

[0035] FIG3 is a study of EGFR cell expression levels caused by the combined treatment of gastric cancer cell NCI-N87 cells with the second anti-HER2 antibody of the present invention and trastuzumab;

[0036] a, b, and c are the HER2 expression levels of NCI-N87 cells at different times;

[0037] d, e, and f are the EGFR expression levels of NCI-N87 cells at different times.

[0038] FIG4a is a study on the cell survival rate of gastric cancer cell NCI-N87 treated with the second anti-HER2 antibody of the present invention and trastuzumab in combination;

[0039] FIG4 b is a study on apoptosis of gastric cancer cells NCI-N87 treated with a second anti-HER2 antibody and trastuzumab according to the present invention;

[0040] FIG4 c shows the tumor volume results of the xenogeneic human gastric cancer NCI-N87 model treated with the second anti-HER2 antibody of the present invention and trastuzumab in combination;

[0041] FIG4d and FIG4e show the tumor volume results of the human gastric cancer PDX model treated with the second anti-HER2 antibody of the present invention and trastuzumab in combination.

[0042] FIG5 is a Kaplan-Meier curve (RECIST 1.1) of progression-free survival of subjects in the clinical study involved in the present invention. DETAILED DESCRIPTION

[0043] The present invention is further described in detail below through embodiments, which should not be construed as limiting the present invention.

[0044] I. Definition

[0045] "HER receptor" is a term for a receptor protein tyrosine kinase of the HER receptor family, which includes EGFR, HER2, HER3, and HER4 receptors. A HER receptor generally comprises: a. an extracellular domain that can bind a HER ligand and / or dimerize with another HER receptor molecule; b. a lipophilic transmembrane domain; c. a conserved intracellular tyrosine kinase domain; and d. a carboxy-terminal signaling domain containing several phosphorylated tyrosine residues. The HER receptor can be a "native sequence" HER receptor or an "amino acid sequence variant" thereof. Preferably, the HER receptor is a native sequence human HER receptor.

[0046] "HER dimer" herein refers to a non-covalently associated dimer comprising at least two HER receptors. Such complexes may form when cells expressing two or more HER receptors are exposed to a HER ligand and can be isolated by immunoprecipitation and analyzed by SDS-PAGE, as described, for example, in Sliwkowski et al., J. Biol. Chem. 269(20):14661-14665 (1994). Other proteins, such as cytokine receptor subunits, may be associated with the dimer. Preferably, the HER dimer comprises HER2.

[0047] "HER heterodimer" herein refers to a non-covalently associated heterodimer comprising at least two different HER receptors, such as EGFR-HER2, HER2-HER3 or HER2-HER4 heterodimers.

[0048] "HER antibody" refers to an antibody that binds to a HER receptor. Optionally, the HER antibody further interferes with HER activation or function. Preferably, the HER antibody binds to the HER2 receptor. The HER2 antibodies contemplated herein are trastuzumab and a second anti-HER2 antibody, including CDRs.

[0049] "HER activation" refers to the activation or phosphorylation of any one or more HER receptors. Generally speaking, HER activation results in signal transduction (e.g., phosphorylation of tyrosine residues in a HER receptor or a substrate polypeptide by an intracellular kinase domain of a HER receptor). HER activation can be mediated by a HER ligand that binds to a HER dimer comprising a HER receptor. A HER ligand that binds to a HER dimer can activate the kinase domain of one or more HER receptors in the dimer, thereby leading to phosphorylation of tyrosine residues in one or more HER receptors and / or phosphorylation of tyrosine residues in other substrate polypeptides, such as Akt or MAPK intracellular kinases.

[0050] "Phosphorylation" refers to the addition of one or more phosphate groups to a protein, such as a HER receptor or its substrates.

[0051] An antibody that "inhibits HER dimerization" refers to an antibody that inhibits or interferes with the formation of HER dimers. Preferably, such an antibody binds to HER2 at its heterodimer binding site. The most preferred dimerization-inhibiting antibody herein is trastuzumab or a second anti-HER2 antibody. Other examples of antibodies that inhibit HER dimerization include antibodies that bind to EGFR and inhibit its dimerization with one or more other HER receptors; antibodies that bind to HER3 and inhibit its dimerization with one or more other HER receptors; and antibodies that bind to HER4 and inhibit its dimerization with one or more other HER receptors.

[0052] A "HER2 dimerization inhibitor" is an agent that inhibits the formation of dimers or heterodimers comprising HER2.

[0053] The "heterodimer binding site" on HER2 refers to a region of the HER2 extracellular domain that contacts or forms an interface with a region of the EGFR, HER3, or HER4 extracellular domain when the HER2 dimer forms. This region has been found in domain II of HER2.

[0054] As used herein, "trastuzumab" refers to an antibody comprising a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12 and the CDRs contained therein; it is understood that the term "trastuzumab" herein covers "rhuMb4D5" (e.g., the antibody disclosed in U.S. Patent No. 5,821,337) and biosimilars of trastuzumab drugs.

[0055] "Pertuzumab" refers to an antibody comprising a heavy chain of SEQ ID NO: 13 and a light chain of SEQ ID NO: 14 and the CDRs contained therein; it will be understood that the term "Pertuzumab" herein covers "RhuMAb 2C4" (e.g., disclosed in WO01 / 00245, WO2006 / 007398 and U.S. Patent US2006 / 0034842) and biosimilars of Pertuzumab.

[0056] The term "antibody" is used in the broadest sense herein, specifically covering monoclonal antibodies, polyclonal antibodies, multispecific antibodies and antibody fragments. In some embodiments, the term "antibody" refers to a protein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH). In some antibodies, such as naturally occurring IgG antibodies, the heavy chain constant region comprises a hinge and three domains, CH1, CH2 and CH3. In some antibodies, such as naturally occurring IgG antibodies, each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain (abbreviated herein as CL). The VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, which are arranged in the following order from amino terminus to carboxyl 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 region of an antibody can mediate the binding of an immunoglobulin to 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 a C-terminal lysine. Unless otherwise indicated herein, the amino acids in the variable region are numbered using the Kabat numbering system, while the amino acids in the constant region are numbered using the EU system.

[0057] "Intact antibody" herein refers to an antibody that comprises two antigen binding regions and an Fc region.

[0058] "Antigen-binding fragment" herein refers to any antibody fragment capable of binding to an antigen, including Fab, F(ab'), F(ab')2, Fv, etc. Fab has an antigen-binding site, which is composed of the heavy chain variable domain and light chain variable domain, the light chain constant domain and the first constant domain (CH1) of the heavy chain of the antibody. Fab' is different from Fab in that it has a hinge region containing one or more cysteine ​​residues at the C-terminus of the heavy chain CH1 domain. F(ab')2 antibodies are produced by forming a disulfide bond between the cysteine ​​residues in the Fab' hinge region. Fv is the smallest antibody fragment consisting of the heavy chain variable region and the light chain variable region, and recombinant technologies for preparing Fv fragments are disclosed in PCT WO 88 / 10649, WO 88 / 106630, WO 88 / 07085, WO 88 / 07086 and WO 88 / 09344. In a double chain, the variable regions of the heavy and light chains are linked by non-covalent bonds, while in a single-chain Fv, the variable regions of the heavy and light chains are typically linked by covalent bonds via a peptide linker, or are directly linked to each other at the C-terminus to form a dimer (e.g., a two-chain Fv). Such antibody fragments can be obtained using proteolytic enzymes (e.g., whole antibodies are digested with papain to produce Fab fragments, while pepsin treatment results in the production of F(ab')2 fragments), and such antibody fragments can be prepared by genetic recombination techniques.

[0059] The term "heavy chain" as used herein refers to both the full-length heavy chain and a portion thereof, which comprises a variable domain (VH) and three constant domains (CH1, CH2, and CH3) comprising an amino acid sequence of a variable region sequence for specific binding to an antigen. The term "light chain" as used herein refers to both the full-length light chain and a portion thereof, which comprises a variable domain (VL) and a constant domain (CL) comprising an amino acid sequence of a variable region sequence for specific binding to an antigen.

[0060] As used herein, the term "CDR (complementarity determining region)" refers to the amino acid sequence of the heavy and light chain hypervariable regions 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 and light chain comprises three CDRs (heavy chain (HCDR1, HCDR2, and HCDR3) and light chain (LCDR1, LCDR2, and LCDR3). CDRs provide contact residues that play an important role in the binding of an antibody to an antigen or epitope.

[0061] "Epitope" or "binding epitope", also known as antigenic determinant, refers to the site on the antigen molecule that can specifically bind to the antibody binding site and determine the antigen specificity.

[0062] As used in the present invention, "immune checkpoint" is a class of immunosuppressive molecules that are mainly expressed on immune cells, can regulate the degree of immune activation, and prevent autoimmunity; for example, they include PD1, CTLA4, LMTK3, LAG3, TIM3, TIGIT, etc. "Immune checkpoint inhibitors" refer to molecules that can reduce, block, inhibit, eliminate or interfere with the interaction between immune checkpoint molecules and their ligands. 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 certain specific embodiments of the present invention, immune checkpoint inhibitors are preferably anti-PD-1 antibodies.

[0063] "PD-1", which stands for programmed death receptor 1, refers to an immunosuppressive receptor that binds to the CD28 family. PD-1 is primarily expressed on the surface of activated T cells in vivo and is capable of binding to two ligands, PD-L1 and PD-L2. The term "PD-1" generally includes human PD-1, its variants, isotypes, or analogs having at least one common epitope. As used herein, anti-PD-1 antibodies can reduce, block, inhibit, eliminate, or interfere with signal transduction by the interaction of PD-1 with PD-L1 and / or PD-L2.

[0064] As used herein, "ADCC or antibody-dependent cell-mediated cytotoxicity" refers to the binding of the Fc fragment of an IgG antibody to effector cells with FcγR, such as NK cells, monocytes-macrophages, neutrophils and other cells, after the IgG antibody specifically binds to the surface antigenic determinants of target cells (such as tumor cells or infected cells) through the Fab fragment, triggering the killing activity of the effector cells and directly killing the target cells. Among them, NK cells are the main cells that mediate ADCC.

[0065] "Cell line-derived xenograft tumor model or CDX" refers to a tumor model constructed by transplanting a heterologous (e.g., human) tumor cell line cultured in vitro into immunodeficient mice. It is currently one of the most common in vivo models for preclinical pharmacodynamic evaluation of anti-tumor drugs.

[0066] "PDX model or patient-derived tumor xenograft model" refers to the transplantation of tumor tissue from tumor patients into severely immunodeficient mice, and the growth of tumor tissue in the mice to form transplanted tumors; this model can retain the growth microenvironment of the parent tumor, and is conducive to better expression of the parent tumor characteristics and maintenance of tumor heterogeneity.

[0067] As used herein, "cancer" or "cancer disease" refers to a physiological condition in mammals characterized by uncontrolled excessive cell proliferation. As used herein, "cancer" refers to a large class of diseases characterized by the uncontrolled growth of abnormal cells in the body. "Cancer" or "cancerous tissue" may include tumors. Uncontrolled cell division may lead to the formation of malignant tumors or cells that invade adjacent tissues and may metastasize to distant sites in the body via the lymphatic system or bloodstream. After metastasis, a distant tumor may be said to be "derived from" a pre-metastasis tumor. For example, a tumor "derived from" a melanoma refers to a tumor caused by a metastatic melanoma. Because a distant tumor is derived from a pre-metastasis tumor, "derived from" a tumor may also include a pre-metastasis tumor, for example, a tumor derived from a melanoma may include a melanoma. In some embodiments, the cancer or tumor comprises a solid tumor. In some embodiments, the cancer or tumor comprises an advanced solid tumor. In some embodiments, the cancer or tumor comprises a solid tumor that has spread. 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., a stage 4 cancer or tumor).

[0068] As used herein, "advanced gastric cancer" refers to cancer that has spread beyond the initial site or organ by local invasion or metastasis. Generally, advanced gastric cancer is determined according to the AJCC / UICC TNM staging rules for gastric cancer, such as tumor invasion of tissues (such as the visceral peritoneum or adjacent structures), regional lymph node metastasis and / or distant metastasis, or CT staging signs.

[0069] "Unresectable" cancer cannot be removed surgically; it is mainly due to tumor reasons, such as severe external invasion of the primary tumor, which cannot be separated from the surrounding normal tissue or surrounds large blood vessels; regional lymph node metastasis is fixed and fused into a mass, or the metastatic lymph nodes are beyond the range of surgical clearance; distant metastasis of the tumor or peritoneal implantation of the tumor, etc.

[0070] "Metastatic" cancer is cancer that has spread from one part of the body (usually the primary site) to another part of the body.

[0071] "HER2-positive" cancer refers to cancer cells that contain higher-than-normal levels of HER2. Typically, HER2-positive cancers have an immunohistochemistry (IHC) score of 2+ or 3+ and / or an in situ hybridization (ISH) amplification ratio of ≥2.0.

[0072] The term "patient" refers to a human subject receiving prophylactic or therapeutic treatment.

[0073] As used herein, the term "subject" refers to a human. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has received at least one prior therapy to treat a cancer or tumor. In some embodiments, the subject has received, then progressed, relapsed, or is intolerant to at least one standard treatment regimen. Various standard of care therapies are known in the art for specific types of cancer or tumors. In some embodiments, at least one standard treatment regimen includes treatment in an advanced or metastatic setting based on the histology of the solid tumor.

[0074] "Treatment" refers to therapeutic treatment and protective or preventative measures to obtain beneficial or desired results (including clinical results). Obtaining beneficial or desired results includes, but is not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, reducing the severity of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), delaying or slowing the progression of the disease, improving the disease state, increasing or improving the quality of life, increasing body weight and / or prolonging survival, etc.

[0075] "Administering" refers to the introduction of a therapeutic drug into a subject (e.g., a subject) using one of a variety of methods and delivery methods or systems known to those skilled in the art. Antibodies can be administered intravenously, intramuscularly, subcutaneously, intraperitoneally, or other parenteral routes. In some embodiments, the drug is administered intravenously, for example, by injection or infusion. Chemotherapeutic agents can be administered intravenously, intramuscularly, subcutaneously, or orally.

[0076] As used herein, the terms "about once a week," "about once every two weeks," "about once every three weeks," or any other similar dosage interval terms refer to approximate numbers. "About once a week" can include every 7 days ± 1 day, i.e., every 6 days to every 8 days. "About once every two weeks" can include every 14 days ± three days, i.e., every 11 days to every 17 days. "About once every three weeks" can include every 21 days ± three days, i.e., every 18 days to every 24 days. For example, similar approximations apply to about once every four weeks, about once every five weeks, about once every six weeks, and about once every twelve weeks. In some embodiments, a dosage interval of about once every six weeks or about once every twelve weeks means that the first dose can be administered on any day of the first week, and the next dose can then be administered on any day of the sixth or twelfth week. In some embodiments, a dosage interval of about once every six weeks or about once every twelve weeks means that the first dose is administered on a specific day (e.g., Monday) of the first week, and the next dose is then administered on the same day (i.e., Monday) of the sixth or twelfth week.

[0077] As used herein, an "effective dose" or "effective amount" refers to an amount that produces a therapeutic effect in an individual upon each administration. This dose may vary due to a variety of factors, such as the purpose of the treatment, the frequency of treatment, the individual's weight and tolerance, the severity of symptoms, the risk of side effects, and the route of administration. Specifically, the term "effective amount" or "effective dose" is defined as an amount sufficient to achieve or at least partially achieve the desired effect. A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent refers to any amount of the drug that, when administered alone or in combination with another therapeutic agent, promotes disease regression, wherein the disease regression is evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods, or prevention of damage or disability caused by the disease. A therapeutically effective amount or dose of a drug includes a "prophylactically effective amount" or "prophylactically effective dose," which is any amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing the disease or at risk of disease recurrence, inhibits the occurrence or recurrence of the disease. The ability of a therapeutic agent to promote disease regression or inhibit disease development or recurrence can be assessed using a variety of methods known to those skilled in the art, such as in human subjects during clinical trials, in animal model systems predictive of the efficacy of the therapeutic agent in humans, or by measuring the activity of the agent in in vitro assays.

[0078] For example, an anticancer agent is a drug that promotes cancer regression in a subject. In some embodiments, a therapeutically effective amount of a drug promotes cancer regression to the extent of eliminating cancer. "Promoting cancer regression" refers to administering an effective amount of a drug alone or in combination with an antineoplastic drug to cause tumor growth or size reduction, tumor necrosis, a decrease in the severity of at least one disease symptom, an increase in the frequency and duration of a symptom-free period, prevention of damage or disability caused by disease distress, or otherwise alleviating the patient's disease symptoms. In addition, the terms "effective" and "effectiveness" for treatment include pharmaceutical efficacy and physiological safety. Pharmaceutical efficacy refers to the ability of a drug to promote the regression of cancer in a patient. Physiological safety refers to the toxicity level or other adverse physiological effects (adverse effects) at the cell, organ and / or organism level caused by the administration of the drug.

[0079] As an example of treating a tumor, a therapeutically effective amount or dose 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% relative to an untreated subject. In some embodiments, a therapeutically effective amount or dose of the drug completely inhibits cell growth or tumor growth, i.e., inhibits cell growth or tumor growth by 100%. The ability of a compound to inhibit tumor growth can be assessed using the assays described below. Alternatively, this property of the composition can be assessed by examining the compound's ability to inhibit cell growth, and this inhibition can be measured in vitro using assays known to those skilled in the art.

[0080] As used herein, the term "weight-based" amount or dosage refers to a dosage calculated based on the patient's weight. For example, if a patient weighing 60 kg requires 15 mg / kg of the second antibody, an appropriate amount of the second antibody (i.e., 900 mg) can be calculated and administered.

[0081] "Chemotherapeutic agent" refers to a chemical compound that can be used to treat cancer. For example, chemotherapeutic agents used for chemotherapy include alkylating agents, ethyleneimines and methylamelamines, aceogenins, colchicines, camptothecins, antibiotics, folic acid analogs, purine analogs, pyrimidine analogs, platinum analogs or platinum-based analogs, etc. The chemotherapeutic agents used in the present invention relate to fluorouracil compounds and platinum-based chemotherapeutic agents, specifically including 5-fluorouracil (5-FU), capecitabine and cisplatin, oxaliplatin. In addition, "XELOX" 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 digestive tract cancers, such as advanced gastric cancer, advanced colon cancer, etc.

[0082] As used herein, "chemotherapy" refers to any chemotherapy method for treating cancer, including the standard regimens of chemotherapy with fluorouracil compounds and platinum-based chemotherapy agents involved in the present invention. In a specific embodiment of the present invention, the chemotherapy agent comprises 5-fluorouracil, capecitabine + cisplatin or oxaliplatin, preferably capecitabine + oxaliplatin.

[0083] "Immunotherapy or immunotherapy" means treating a subject suffering from a disease or at risk of infection or recurrence of a disease by a method that involves inducing, enhancing, suppressing or otherwise altering an immune response.

[0084] As used herein, a "fixed" or "flat" dose refers to a dose that is suitable for a patient regardless of the patient's weight and body surface area.

[0085] A "loading" dose generally includes an initial dose of a therapeutic agent (including trastuzumab, a second anti-HER2 antibody, a chemotherapeutic agent, etc.) administered to a patient, followed by one or more maintenance doses thereof. Generally speaking, a single loading dose is administered; however, 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 dosage is administered more frequently than the maintenance dose, thereby achieving the desired steady-state concentration of the therapeutic agent earlier than with the maintenance dose.

[0086] A "maintenance" dose is herein referred to as one or more doses of a therapeutic agent administered to a patient during treatment. Typically, a maintenance dose is administered at certain treatment intervals, such as about once a week, about once every two weeks, about once every three weeks, or about once every four weeks, preferably once every three weeks.

[0087] "Intravenous (IV)" administration refers to administering the drug (eg, trastuzumab, a second anti-HER2 antibody, or a chemotherapeutic agent) into a patient's vein, such as by infusion.

[0088] "Subcutaneous" administration refers to administering the drug (including trastuzumab, a second anti-HER2 antibody, or a chemotherapeutic agent) under the patient's skin.

[0089] As used herein, "overall survival" or "OS" refers to the survival of a patient for a defined period of time from the time of diagnosis or treatment, such as 1 year, 5 years, etc. For the purposes of the clinical trials described in the Examples, overall survival (OS) is defined as the time from the date of randomization of the patient population to the date of death from any cause.

[0090] "Progression-free survival" or "PFS" means that the patient remains alive without the cancer progressing or getting worse. Progression-free survival (PFS) is defined as the time from randomization of the study population to the first documented progressive disease or unmanageable toxicity or death from any cause, whichever occurs first. Disease progression can be documented by any clinically accepted method.

[0091] "Disease-free survival" or "DFS" refers to the period of time a patient remains alive without cancer recurrence from the start of treatment or from initial diagnosis, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc. In the studies that form the basis of the present invention, DFS was analyzed according to the treatment intent principle, i.e., patients were evaluated based on their assigned therapy. Events used in the DFS analysis typically include local, regional, and distant cancer recurrences, the development of secondary cancers, and death from any cause in patients who did not have a prior event (gastric cancer recurrence or second primary cancer).

[0092] "Invasive disease-free survival" or "iDFS" is the time after adjuvant therapy that a patient is alive and has not had invasive cancer relapse at any site or died of any cause. In other words, iDFS is defined as the time a patient remains alive (survival) without relapse of invasive disease for a period of time after adjuvant therapy, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc., from the start of treatment or from the initial diagnosis. In one embodiment, iDFS is about 1 year or about 3 years from the start of treatment.

[0093] "Prolonging survival" means that the overall or progression-free survival of patients treated according to the present invention is prolonged relative to untreated patients and / or relative to patients treated with one or more approved anti-tumor agents but not treated according to the present invention. In one specific example, "prolonging survival" means that the progression-free survival (PFS) and / or overall survival of cancer patients receiving the combination therapy of the present invention is prolonged relative to patients treated with trastuzumab and chemotherapy alone. In another specific example, "prolonging survival" means that the progression-free survival (PFS) and / or overall survival (OS) of cancer patients receiving the combination therapy of the present invention is prolonged relative to patients treated with antibodies and / or chemotherapeutic agents alone.

[0094] "Objective response" refers to a measurable response, including complete response (CR) or partial response (PR).

[0095] A "complete response" or "CR" means that all signs of cancer disappear in response to treatment. This does not always mean that the cancer is cured.

[0096] A "partial response" or "PR" refers to a reduction in the size of one or more tumors or lesions, or the extent of cancer in the body, in response to treatment.

[0097] As used herein, an "adverse event (AE)" is any unfavorable and generally unintentional, undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment. For example, an adverse event may be associated with activation of the immune system or expansion of immune system cells in response to the treatment.

[0098] As used herein, "safety data" refers to data obtained in controlled clinical trials that show the prevalence and severity of adverse events to facilitate guidance to users on drug safety, including guidance on how to monitor and prevent adverse reactions to a drug.

[0099] "Efficacy data" are data obtained in controlled clinical trials that show that a drug is effective in treating a disease, such as gastric cancer.

[0100] As used herein, "concurrent" use refers to administration during the same treatment cycle, on the same day of treatment with the one or more other drugs, and optionally, at the same time as the one or more other drugs.

[0101] As used herein, "combination use" or "combined use" means that two or more active substances are applied to a patient or subject together in the form of a mixture, simultaneously as a single preparation, or sequentially in any order as a single preparation.

[0102] The term "synergistic action" or "synergistic effect" refers to the simple addition of the effects of two or more active molecules when administered alone.

[0103] The term "about" is used to mean approximately, roughly, roughly, or in the range of... When the term "about" is used in conjunction with a numerical range, it adjusts the range by extending the boundaries above and below the numerical values ​​set forth. In general, the term "about" can adjust a numerical value above or below the stated value by a variance of, for example, 10%, above or below (higher or lower).

[0104] II. Overview

[0105] The present invention provides a use of an anti-HER2 antibody combination and a chemotherapeutic agent for preparing a drug for treating gastric cancer, specifically the use of trastuzumab, a second anti-HER2 antibody or an antigen-binding fragment thereof and a chemotherapeutic agent for preparing a drug for treating HER2-positive gastric cancer, especially HER2-positive advanced gastric cancer, and more preferably, for treating patients diagnosed with advanced unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0106] The present invention also provides a method for treating the above-mentioned diseases, in particular, for treating patients diagnosed with advanced unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, which method comprises administering to the patient a therapeutically effective amount of trastuzumab, a second anti-HER2 antibody or its binding fragment and a chemotherapeutic agent (e.g., a fluorouracil chemotherapeutic agent and a platinum compound).

[0107] In some embodiments of the present invention, the treatment prolongs 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).

[0108] III. Anti-HER2 Antibodies and Chemotherapeutic Agents

[0109] The anti-HER2 antibodies involved in the present invention include trastuzumab and a second anti-HER2 antibody, whose mechanism of action is to inhibit the PI3K / AKT signaling pathway, induce cell cycle arrest, mediate antibody-dependent cell-mediated cytotoxicity (ADCC), inhibit DNA damage repair, inhibit angiogenesis, and induce immune response.

[0110] Trastuzumab

[0111] Trastuzumab includes Herceptin (Trastuzumab) and its biosimilars, wherein the heavy chain of the monoclonal antibody comprises or consists of the amino acid sequence of SEQ ID NO: 11, and the light chain comprises or consists of the amino acid sequence of SEQ ID NO: 12.

[0112] Trastuzumab is used to treat HER2-positive metastatic breast cancer, positive early breast cancer, and metastatic gastric cancer (drug instructions approved by the U.S. Food and Drug Administration, drug instructions annotated by the China National Drug Administration). In the applicable HER2-positive metastatic breast cancer dosing regimen, trastuzumab is used as a single drug to treat metastatic breast cancer that has received one or more chemotherapy regimens, and in combination with paclitaxel or docetaxel, for patients with metastatic breast cancer who have not received chemotherapy, with an initial loading dose of 4 mg / kg, intravenously infused (IV) over 90 minutes, and a maintenance dose of 2 mg / kg; in the applicable dosing regimen for metastatic gastric cancer involved in the present invention, trastuzumab is administered once every three weeks, with an initial loading dose of 8 mg / kg, followed by 6 mg / kg administered once every three weeks, wherein patients with metastatic gastric cancer are treated with trastuzumab until disease progression or unacceptable toxicity.

[0113] Secondary antibody (also called secondary anti-HER2 antibody)

[0114] The second antibody of the present invention, or the second anti-HER2 antibody, is a monoclonal antibody that binds to the HER2 site and is different from trastuzumab. In some embodiments, the second anti-HER2 antibody comprises a heavy chain variable region and a light chain variable region, wherein:

[0115] (a) the heavy chain variable region comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3;

[0116] (b) The light chain variable region comprises LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8.

[0117] In some embodiments, the second anti-HER2 antibody comprises a heavy chain variable region and a light chain variable region, wherein:

[0118] (a) the heavy chain variable region comprises, or consists of, the amino acid sequence of SEQ ID NO: 4;

[0119] (b) the light chain variable region comprises the amino acid sequence of SEQ ID NO: 9, or consists of the amino acid sequence of SEQ ID NO: 9.

[0120] In some embodiments, the second anti-HER2 antibody comprises a heavy chain and a light chain, wherein:

[0121] (a) the heavy chain comprises the amino acid sequence of SEQ ID NO: 5, or consists of the amino acids of SEQ ID NO: 5;

[0122] (b) The light chain comprises the amino acid sequence of SEQ ID NO: 10, or consists of the amino acids of SEQ ID NO: 10.

[0123] In other embodiments of the present invention, a second anti-HER2 antigen-binding fragment is used, which comprises the amino acid sequence defined above, in particular the structural region that binds to the antigen, such as HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, examples of which include Fab, Fab', F(ab')2 and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules and multispecific antibodies formed by other antibody fragments.

[0124] The second anti-HER2 antibody used in the present invention is a humanized IgG1 monoclonal antibody that shares the same HER2 targeting domain as trastuzumab, namely, domain IV of HER2. However, trastuzumab and the second anti-HER2 antibody act on different epitopes, and the second anti-HER2 antibody does not compete with trastuzumab for binding to domain IV of HER2. See Figure 1 for the HER2 epitope binding analysis of the second anti-HER2 antibody, pertuzumab, and trastuzumab. Endocytosis is one of the mechanisms by which antibodies act as tumor therapeutics. Antibody-receptor interactions or complexes can promote the efficient internalization of receptor molecules in cells, leading to the decrease and degradation of cell surface receptors, inhibiting receptor-dependent signaling, and affecting tumor cell growth. In conjunction with the second anti-HER2 antibody and trastuzumab used in the present invention, the applicants discovered that when the second anti-HER2 antibody and trastuzumab act alone on HER2-positive gastric cancer cells, they induce weak HER2 endocytosis on the surface of the gastric cancer cells, thereby causing weak apoptosis and tumor cell growth inhibition. As shown in FIG2 , the second anti-HER2 antibody, trastuzumab, and pertuzumab alone induce weak endocytosis in gastric cancer cells (NCI-N87, SNU216). However, the combined action of the second anti-HER2 antibody and trastuzumab significantly enhances endocytosis in gastric cancer cells, while the combined action of trastuzumab and pertuzumab does not enhance endocytosis in gastric cancer cells. As shown in FIG3 , the combined action of the second anti-HER2 antibody and trastuzumab induces endocytosis in gastric cancer cells, resulting in decreased HER2 and EGFR expression levels in gastric cancer cells, while the combined action of trastuzumab and pertuzumab decreases HER2 expression in gastric cancer cells, but the decrease in EGFR levels is smaller. Therefore, it is reasonable to speculate that although the combination of trastuzumab and pertuzumab can be used for the adjuvant treatment of HER2-positive breast cancer (for example, as recorded in CN110337450, Roche), due to the limitations of different tumor cell characteristics and antibody mechanisms, the combination of trastuzumab and pertuzumab may be difficult to use for the treatment or adjuvant treatment of HER2-positive gastric cancer. Correspondingly, according to the research in the embodiments of the present invention, the combination of trastuzumab and a second anti-HER2 antibody can be used as a new treatment regimen for HER2-positive gastric cancer.

[0125] 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 defined above.

[0126] Fluorouracil compounds and platinum chemotherapy agents

[0127] Fluorouracil compounds

[0128] Fluorouracil compounds are one of the most widely used anti-tumor drugs in clinical practice. They kill cancer cells by preventing the formation of pyrimidine nucleotides and interfering with DNA synthesis. They include 5-FU (5-fluorouracil) and orally available prodrugs such as capecitabine and tegafur. They are mainly used clinically to treat breast cancer, gastrointestinal cancer, ovarian cancer, and primary bronchopulmonary adenocarcinoma.

[0129] Some embodiments of the present invention involve the use of 5-FU or capecitabine. In a more preferred embodiment, capecitabine is used in the uses and methods of the present invention.

[0130] Platinum-based chemotherapy agents

[0131] Platinum-based chemotherapeutics are also widely used anti-tumor drugs. They can cause DNA crosslinks as monoadducts, interstrand crosslinks, intrastrand crosslinks, or DNA-protein crosslinks. They act on the adjacent N-7 position of guanine to form 1,2 intrastrand 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 in cancer cells. Platinum-based chemotherapeutics include cisplatin, carboplatin, oxaliplatin, and satraplatin.

[0132] Some embodiments of the present invention involve the use of cisplatin or oxaliplatin. In a more preferred embodiment, oxaliplatin is used in the uses and methods of the present invention.

[0133] IV. Methods of Treatment and Use

[0134] The present invention relates to the use of trastuzumab, a second anti-HER2 antibody or a binding fragment thereof and a chemotherapeutic agent in combination for preparing a drug for treating HER2-positive gastric cancer, in particular for treating patients diagnosed with advanced unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0135] On the other hand, the present invention also relates to a method for treating HER2-positive gastric cancer, in particular a method for treating a patient diagnosed with advanced unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, comprising administering to the patient a therapeutically effective amount of trastuzumab, a second anti-HER2 antibody or its binding fragment and a chemotherapeutic agent. In some embodiments, the treatment of the present invention prolongs 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).

[0136] The present invention specifically relates to treatment options for advanced gastric cancer, particularly advanced, unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma. Advanced gastric cancer, as described herein, can be determined according to the AJCC / UICC TNM criteria, for example, based on the progression of tumor invasion of surrounding tissues, regional lymph node metastasis or distant metastasis, and CT staging signs. HER2 testing is used in patients with advanced gastric cancer treated by the present invention. For example, HER2 positivity was defined in the KEYNOTE 811 study as being based on immunohistochemistry (IHC) 3+ or immunohistochemistry (IHC) 2+ positive and in situ hybridization (ISH) positive. In some embodiments of the present invention, HER2-positive cancer is based on HER2 expression levels of immunohistochemistry (IHC) 3+ or 2+ and ISH positive. HER2 immunohistochemistry (IHC) and in situ hybridization (ISH) testing are performed in accordance with the guidelines for HER2 testing in gastric cancer. Commercial assays approved by the FDA or the China National Medical Products Administration (NMPA) for IHC and ISH testing can be used.

[0137] In some embodiments of the present invention, the use or method comprises the combination of trastuzumab, a second anti-HER2 antibody or binding fragment thereof, and a chemotherapeutic agent. In some embodiments, the second anti-HER2 antibody or binding fragment thereof is as defined above. The chemotherapeutic agent is a combination of a fluorouracil compound and a platinum chemotherapeutic agent. In some specific embodiments, the fluorouracil compound is 5-fluorouracil or capecitabine. In some specific embodiments, the platinum compound is cisplatin or oxaliplatin. In some preferred embodiments, the chemotherapeutic agent is a combination of 5-fluorouracil and oxaliplatin.

[0138] Specifically, in one aspect, the present invention provides a method for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma in a patient, comprising administering to the patient a therapeutically effective amount of:

[0139] (1) Trastuzumab;

[0140] (2) a second antibody, wherein the second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding epitope from 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 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises LCDR1 as shown in SEQ ID NO: 6, LCDR2 as shown in SEQ ID NO: 7, and LCDR3 as shown in SEQ ID NO: 8;

[0141] (3) Chemotherapeutic agents.

[0142] In a further embodiment, the chemotherapeutic agent is a fluorouracil-based drug. In a further embodiment, the chemotherapeutic agent is a platinum-based drug.

[0143] In a further embodiment, the chemotherapeutic agent is a combination of a fluorouracil-based drug and a platinum-based drug.

[0144] In a further embodiment, the fluorouracil drug is selected from 5-fluorouracil and capecitabine.

[0145] In a further embodiment, the platinum drug is selected from cisplatin and oxaliplatin. In a further embodiment, the fluorouracil drug is capecitabine. In a further embodiment, the platinum drug is oxaliplatin. In a further embodiment, the chemotherapeutic agent is a combination of capecitabine and oxaliplatin.

[0146] In a further embodiment, the cancer is HER2-positive advanced gastric cancer.

[0147] In a further embodiment, the cancer is unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0148] In a further embodiment, the heavy chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:9.

[0149] In a further embodiment, the heavy chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:5, and the light chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:10.

[0150] In a further embodiment, trastuzumab is administered at a body weight-based dose of about 0.1 mg / kg to about 10 mg / kg.

[0151] In further embodiments, trastuzumab is administered at a dose 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, 0.9 mg / kg to about 10 mg / kg.

[0014] In some embodiments, the present invention provides a weight-based dose of about 1 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.

[0152] In further embodiments, trastuzumab is administered at a weight-based 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.

[0153] In a further embodiment, trastuzumab is administered at an initial loading dose of about 8 mg / kg, followed by a dose of about 6 mg / kg, based on body weight.

[0154] In further embodiments, trastuzumab is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

[0155] In a further embodiment, trastuzumab is administered intravenously.

[0156] In a further embodiment, the second antibody is administered at 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 2.5mg / kg to about 25mg / kg, about 3mg / kg to about 25mg / kg, about 4mg / kg to about 25mg / kg, about 5mg / kg to about 25mg / kg, about 6mg / kg to about 25mg / kg, about 7mg / kg to about 25mg / kg, about 8mg / kg to about 25mg / kg, about 9mg / kg to about 25mg / kg, about 10mg / kg to about 25mg / kg, about 11mg / kg to about 25mg / kg, about 12mg / kg to about 25mg / kg, about 13mg / kg to about 25mg / kg, about 14mg / kg to about 25mg / kg. 5mg / kg, about 15mg / kg to about 25mg / kg, about 16mg / kg to about 25mg / kg, about 17mg / kg to about 25mg / kg, about 18mg / kg to about 25mg / kg, about 19mg / kg to about 25mg / kg, about 20mg / kg to about 25mg / kg, about 21mg / kg to about 25mg / kg, about 22mg / kg to about 25mg / kg, about 23mg / kg to about 25mg / kg, about 24mg / kg to about 25mg / kg, about 0.1mg / kg to about 20mg / kg, about 0.3mg / kg to about 2 0mg / kg, 0.9mg / kg to about 20mg / kg, about 1mg / kg to about 20mg / kg, about 2.5mg / kg to about 20mg / kg, about 3mg / kg to about 20mg / kg, about 4mg / kg to about 20mg / kg, about 5mg / kg to about 20mg / kg, about 6mg / kg to about 20mg / kg, about 7mg / kg to about 20mg / kg, about 8mg / kg to about 20mg / kg, about 9mg / kg to about 20mg / kg, about 10mg / kg to about 20mg / kg, about 11mg / kg to about 20mg / kg, about 1 2 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 20 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 to 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 based on body weight.

[0157] In a further embodiment, the second antibody is administered at a weight-based 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, 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, about 28 mg / kg, about 29 mg / kg or about 30 mg / kg.

[0158] In further embodiments, the second antibody is administered at a body weight-based dose of about 25 mg / kg or 15 mg / kg.

[0159] In further embodiments, the second antibody is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

[0160] In a further embodiment, the second antibody is administered intravenously.

[0161] In a further embodiment, oxaliplatin is administered at a dose of about 10 to about 150 mg / m 2 , about 20 to about 150 mg / m 2 , about 30 to about 150 mg / m 2 , about 40 to about 150 mg / m 2 , about 50 to about 150 mg / m 2 , about 60 to about 150 mg / m 2, about 70 to about 150 mg / m 2 , about 75 to about 150 mg / m 2 , about 80 to about 150 mg / m 2 , about 85 to about 150 mg / m 2 , about 90 to about 150 mg / m 2 , about 95 to about 150 mg / m 2 , about 100 to about 150 mg / m 2 , about 105 to about 150 mg / m 2 , about 110 to about 150 mg / m 2 , about 115 to about 150 mg / m 2 , about 120 to about 150 mg / m 2 , about 125 to about 150 mg / m 2 , about 130 to about 150 mg / m 2 , about 135 to about 150 mg / m 2 , about 140 to about 150 mg / m 2 , about 145 to about 150 mg / m 2 , about 10 to about 140 mg / m 2 , about 20 to about 140 mg / m 2 , about 30 to about 140 mg / m 2 , about 40 to about 140 mg / m 2 , about 50 to about 140 mg / m 2 , about 60 to about 140 mg / m 2 , about 70 to about 140 mg / m 2 , about 75 to about 140 mg / m 2 , about 80 to about 140 mg / m 2 , about 85 to about 140 mg / m 2 , about 90 to about 140 mg / m 2 , about 95 to about 140 mg / m 2 , about 100 to about 140 mg / m 2 , about 105 to about 140 mg / m 2 , about 110 to about 140 mg / m 2 , about 115 to about 140 mg / m 2 , about 120 to about 140 mg / m 2 , about 125 to about 140 mg / m 2 , about 130 to about 140 mg / m 2 , about 135 to about 140 mg / m 2 , about 10 to about 130 mg / m 2 , about 20 to about 130 mg / m2 , about 30 to about 130 mg / m 2 , about 40 to about 130 mg / m 2 , about 50 to about 130 mg / m 2 , about 60 to about 130 mg / m 2 , about 70 to about 130 mg / m 2 , about 75 to about 130 mg / m 2 , about 80 to about 130 mg / m 2 , about 85 to about 130 mg / m 2 , about 90 to about 130 mg / m 2 , about 95 to about 130 mg / m 2 , about 100 to about 130 mg / m 2 , about 105 to about 130 mg / m 2 , about 110 to about 130 mg / m 2 , about 115 to about 130 mg / m 2 , about 120 to about 130 mg / m 2 , about 125 to about 130 mg / m 2 Dosage administration based on body surface area.

[0162] In a further embodiment, oxaliplatin is administered at about 10 mg / m 2 , about 20 mg / m 2 , about 30 mg / m 2 , about 40 mg / m 2 , about 50 mg / m 2 , about 60mg / m 2 , about 70 mg / m 2 , about 75 mg / m 2 , about 80mg / m 2 , about 85 mg / m 2 , about 90 mg / m 2 , about 95mg / m 2 , about 100 mg / m 2 , about 105 mg / m 2 , about 110 mg / m 2 , about 115 mg / m 2 , about 120 mg / m 2 , about 125 mg / m 2 , about 130mg / m 2 , about 135 mg / m 2 , about 140 mg / m 2 , about 145 mg / m 2 or about 150 mg / m 2 Dosage administration based on body surface area.

[0163] In a further embodiment, oxaliplatin is administered at about 130 mg / m 2 Dosage administration based on body surface area.

[0164] In further embodiments, oxaliplatin is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

[0165] In a further embodiment, oxaliplatin is administered intravenously.

[0166] In a further embodiment, capecitabine is administered at a dose of about 100 to about 1200 mg / m 2 , about 200 to about 1200 mg / m 2 , about 300 to about 1200 mg / m 2 , about 400 to about 1200 mg / m 2 , about 500 to about 1200 mg / m 2 , about 600 to about 1200 mg / m 2 , about 650 to about 1200 mg / m 2 , about 700 to about 1200 mg / m 2 , about 750 to about 1200 mg / m 2 , about 800 to about 1200 mg / m 2 , about 850 to about 1200 mg / m 2 , about 900 to about 1200 mg / m 2 , about 950 to about 1200 mg / m 2 , about 1000 to about 1200 mg / m 2 , about 1050 to about 1200 mg / m 2 , about 1100 to about 1200 mg / m 2 , about 1150 to about 1200 mg / m 2 , about 100 to about 1100 mg / m 2 , about 200 to about 1100 mg / m 2 , about 300 to about 1100 mg / m 2 , about 400 to about 1100 mg / m 2 , about 500 to about 1100 mg / m 2 , about 600 to about 1100 mg / m 2 , about 650 to about 1100 mg / m 2 , about 700 to about 1100 mg / m 2 , about 750 to about 1100 mg / m 2 , about 800 to about 1100 mg / m2 , about 850 to about 1100 mg / m 2 , about 900 to about 1100 mg / m 2 , about 950 to about 1100 mg / m 2 , about 1000 to about 1100 mg / m 2 , about 100 to about 1000 mg / m 2 , about 200 to about 1000 mg / m 2 , about 300 to about 1000 mg / m 2 , about 400 to about 1000 mg / m 2 , about 500 to about 1000 mg / m 2 , about 600 to about 1000 mg / m 2 , about 650 to about 1000 mg / m 2 , about 700 to about 1000 mg / m 2 , about 750 to about 1000 mg / m 2 , about 800 to about 1000 mg / m 2 , about 850 to about 1000 mg / m 2 , about 900 to about 1000 mg / m 2 or about 950 to about 1000 mg / m 2 Dosage administration based on body surface area.

[0167] In a further embodiment, capecitabine is administered at about 100 mg / m 2 , about 200mg / m 2 , about 300mg / m 2 , about 400mg / m 2 , about 500mg / m 2 , about 600mg / m 2 , about 650mg / m 2 , about 700mg / m 2 , about 750mg / m 2 , about 800mg / m 2 , about 850mg / m 2 , about 900mg / m 2 , about 950mg / m 2 , about 1000mg / m 2 , about 1050 mg / m 2 , about 1100mg / m 2 , about 1150mg / m 2 or about 1200 mg / m 2 Dosage administration based on body surface area.

[0168] In a further embodiment, capecitabine is administered at about 1000 mg / m 2 Dosage administration based on body surface area.

[0169] In further embodiments, capecitabine is administered once daily, twice daily, or three times daily.

[0170] In a further embodiment, capecitabine is administered orally.

[0171] 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 administered at a dose of about 130 mg / kg based on body weight. 2 The body surface area based dose was administered, and capecitabine was administered at approximately 1000 mg / m 2 Dosage administration based on body surface area.

[0172] In a further embodiment, the second antibody is administered to the patient prior to administration of trastuzumab.

[0173] In a further embodiment, the second antibody is administered to the patient after administration of trastuzumab.

[0174] In a further embodiment, trastuzumab and the second antibody are administered simultaneously.

[0175] In a further embodiment, the method further comprises administering an immune checkpoint inhibitor.

[0176] In a further embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0177] In a further embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0178] In another aspect, the present invention also provides a combination therapy for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma in a patient, the treatment comprising administering to the patient a combination therapy comprising:

[0179] (1) Trastuzumab;

[0180] (2) a second antibody, wherein the second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding epitope from 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 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises LCDR1 as shown in SEQ ID NO: 6, LCDR2 as shown in SEQ ID NO: 7, and LCDR3 as shown in SEQ ID NO: 8;

[0181] (3) Chemotherapeutic agents.

[0182] In a further embodiment, the chemotherapeutic agent is a fluorouracil-based drug. In a further embodiment, the chemotherapeutic agent is a platinum-based drug.

[0183] In a further embodiment, the chemotherapeutic agent is a combination of a fluorouracil-based drug and a platinum-based drug.

[0184] In a further embodiment, the fluorouracil drug is selected from 5-fluorouracil and capecitabine.

[0185] In a further embodiment, the platinum drug is selected from cisplatin and oxaliplatin. In a further embodiment, the fluorouracil drug is capecitabine. In a further embodiment, the platinum drug is oxaliplatin. In a further embodiment, the chemotherapeutic agent is a combination of capecitabine and oxaliplatin.

[0186] In a further embodiment, the cancer is HER2-positive advanced gastric cancer.

[0187] In a further embodiment, the cancer is unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0188] In a further embodiment, the heavy chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:9.

[0189] In a further embodiment, the heavy chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:5, and the light chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:10.

[0190] In a further embodiment, trastuzumab is administered at a body weight-based dose of about 0.1 mg / kg to about 10 mg / kg.

[0191] In further embodiments, trastuzumab is administered at a dose 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, 0.9 mg / kg to about 10 mg / kg.

[0014] In some embodiments, the present invention provides a weight-based dose of about 1 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.

[0192] In further embodiments, trastuzumab is administered at a weight-based 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.

[0193] In a further embodiment, trastuzumab is administered at an initial loading dose of about 8 mg / kg, followed by a dose of about 6 mg / kg, based on body weight.

[0194] In further embodiments, trastuzumab is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

[0195] In a further embodiment, trastuzumab is administered intravenously.

[0196] In a further embodiment, the second antibody is administered at 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 2.5mg / kg to about 25mg / kg, about 3mg / kg to about 25mg / kg, about 4mg / kg to about 25mg / kg, about 5mg / kg to about 25mg / kg, about 6mg / kg to about 25mg / kg, about 7mg / kg to about 25mg / kg, about 8mg / kg to about 25mg / kg, about 9mg / kg to about 25mg / kg, about 10mg / kg to about 25mg / kg, about 11mg / kg to about 25mg / kg, about 12mg / kg to about 25mg / kg, about 13mg / kg to about 25mg / kg, about 14mg / kg to about 25mg / kg. 5mg / kg, about 15mg / kg to about 25mg / kg, about 16mg / kg to about 25mg / kg, about 17mg / kg to about 25mg / kg, about 18mg / kg to about 25mg / kg, about 19mg / kg to about 25mg / kg, about 20mg / kg to about 25mg / kg, about 21mg / kg to about 25mg / kg, about 22mg / kg to about 25mg / kg, about 23mg / kg to about 25mg / kg, about 24mg / kg to about 25mg / kg, about 0.1mg / kg to about 20mg / kg, about 0.3mg / kg to about 2 0mg / kg, 0.9mg / kg to about 20mg / kg, about 1mg / kg to about 20mg / kg, about 2.5mg / kg to about 20mg / kg, about 3mg / kg to about 20mg / kg, about 4mg / kg to about 20mg / kg, about 5mg / kg to about 20mg / kg, about 6mg / kg to about 20mg / kg, about 7mg / kg to about 20mg / kg, about 8mg / kg to about 20mg / kg, about 9mg / kg to about 20mg / kg, about 10mg / kg to about 20mg / kg, about 11mg / kg to about 20mg / kg, about 1 2 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 20 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 to 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 based on body weight.

[0197] In a further embodiment, the second antibody is administered at a weight-based 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, 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, about 28 mg / kg, about 29 mg / kg or about 30 mg / kg.

[0198] In further embodiments, the second antibody is administered at a body weight-based dose of about 25 mg / kg or 15 mg / kg.

[0199] In further embodiments, the second antibody is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

[0200] In a further embodiment, the second antibody is administered intravenously.

[0201] In a further embodiment, oxaliplatin is administered at a dose of about 10 to about 150 mg / m 2 , about 20 to about 150 mg / m 2 , about 30 to about 150 mg / m 2 , about 40 to about 150 mg / m 2 , about 50 to about 150 mg / m 2 , about 60 to about 150 mg / m 2, about 70 to about 150 mg / m 2 , about 75 to about 150 mg / m 2 , about 80 to about 150 mg / m 2 , about 85 to about 150 mg / m 2 , about 90 to about 150 mg / m 2 , about 95 to about 150 mg / m 2 , about 100 to about 150 mg / m 2 , about 105 to about 150 mg / m 2 , about 110 to about 150 mg / m 2 , about 115 to about 150 mg / m 2 , about 120 to about 150 mg / m 2 , about 125 to about 150 mg / m 2 , about 130 to about 150 mg / m 2 , about 135 to about 150 mg / m 2 , about 140 to about 150 mg / m 2 , about 145 to about 150 mg / m 2 , about 10 to about 140 mg / m 2 , about 20 to about 140 mg / m 2 , about 30 to about 140 mg / m 2 , about 40 to about 140 mg / m 2 , about 50 to about 140 mg / m 2 , about 60 to about 140 mg / m 2 , about 70 to about 140 mg / m 2 , about 75 to about 140 mg / m 2 , about 80 to about 140 mg / m 2 , about 85 to about 140 mg / m 2 , about 90 to about 140 mg / m 2 , about 95 to about 140 mg / m 2 , about 100 to about 140 mg / m 2 , about 105 to about 140 mg / m 2 , about 110 to about 140 mg / m 2 , about 115 to about 140 mg / m 2 , about 120 to about 140 mg / m 2 , about 125 to about 140 mg / m 2 , about 130 to about 140 mg / m 2 , about 135 to about 140 mg / m 2 , about 10 to about 130 mg / m 2 , about 20 to about 130 mg / m2 , about 30 to about 130 mg / m 2 , about 40 to about 130 mg / m 2 , about 50 to about 130 mg / m 2 , about 60 to about 130 mg / m 2 , about 70 to about 130 mg / m 2 , about 75 to about 130 mg / m 2 , about 80 to about 130 mg / m 2 , about 85 to about 130 mg / m 2 , about 90 to about 130 mg / m 2 , about 95 to about 130 mg / m 2 , about 100 to about 130 mg / m 2 , about 105 to about 130 mg / m 2 , about 110 to about 130 mg / m 2 , about 115 to about 130 mg / m 2 , about 120 to about 130 mg / m 2 , about 125 to about 130 mg / m 2 Dosage administration based on body surface area.

[0202] In a further embodiment, oxaliplatin is administered at about 10 mg / m 2 , about 20 mg / m 2 , about 30 mg / m 2 , about 40 mg / m 2 , about 50 mg / m 2 , about 60mg / m 2 , about 70 mg / m 2 , about 75 mg / m 2 , about 80mg / m 2 , about 85 mg / m 2 , about 90 mg / m 2 , about 95mg / m 2 , about 100 mg / m 2 , about 105 mg / m 2 , about 110 mg / m 2 , about 115 mg / m 2 , about 120 mg / m 2 , about 125 mg / m 2 , about 130mg / m 2 , about 135 mg / m 2 , about 140 mg / m 2 , about 145 mg / m 2 or about 150 mg / m 2 Dosage administration based on body surface area.

[0203] In a further embodiment, oxaliplatin is administered at about 130 mg / m 2 Dosage administration based on body surface area.

[0204] In further embodiments, oxaliplatin is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

[0205] In a further embodiment, oxaliplatin is administered intravenously.

[0206] In a further embodiment, capecitabine is administered at a dose of about 100 to about 1200 mg / m 2 , about 200 to about 1200 mg / m 2 , about 300 to about 1200 mg / m 2 , about 400 to about 1200 mg / m 2 , about 500 to about 1200 mg / m 2 , about 600 to about 1200 mg / m 2 , about 650 to about 1200 mg / m 2 , about 700 to about 1200 mg / m 2 , about 750 to about 1200 mg / m 2 , about 800 to about 1200 mg / m 2 , about 850 to about 1200 mg / m 2 , about 900 to about 1200 mg / m 2 , about 950 to about 1200 mg / m 2 , about 1000 to about 1200 mg / m 2 , about 1050 to about 1200 mg / m 2 , about 1100 to about 1200 mg / m 2 , about 1150 to about 1200 mg / m 2 , about 100 to about 1100 mg / m 2 , about 200 to about 1100 mg / m 2 , about 300 to about 1100 mg / m 2 , about 400 to about 1100 mg / m 2 , about 500 to about 1100 mg / m 2 , about 600 to about 1100 mg / m 2 , about 650 to about 1100 mg / m 2 , about 700 to about 1100 mg / m 2 , about 750 to about 1100 mg / m 2 , about 800 to about 1100 mg / m2 , about 850 to about 1100 mg / m 2 , about 900 to about 1100 mg / m 2 , about 950 to about 1100 mg / m 2 , about 1000 to about 1100 mg / m 2 , about 100 to about 1000 mg / m 2 , about 200 to about 1000 mg / m 2 , about 300 to about 1000 mg / m 2 , about 400 to about 1000 mg / m 2 , about 500 to about 1000 mg / m 2 , about 600 to about 1000 mg / m 2 , about 650 to about 1000 mg / m 2 , about 700 to about 1000 mg / m 2 , about 750 to about 1000 mg / m 2 , about 800 to about 1000 mg / m 2 , about 850 to about 1000 mg / m 2 , about 900 to about 1000 mg / m 2 or about 950 to about 1000 mg / m 2 Dosage administration based on body surface area.

[0207] In a further embodiment, capecitabine is administered at about 100 mg / m 2 , about 200mg / m 2 , about 300mg / m 2 , about 400mg / m 2 , about 500mg / m 2 , about 600mg / m 2 , about 650mg / m 2 , about 700mg / m 2 , about 750mg / m 2 , about 800mg / m 2 , about 850mg / m 2 , about 900mg / m 2 , about 950mg / m 2 , about 1000mg / m 2 , about 1050 mg / m 2 , about 1100mg / m 2 , about 1150mg / m 2 or about 1200 mg / m 2 Dosage administration based on body surface area.

[0208] In a further embodiment, capecitabine is administered at about 1000 mg / m 2 Dosage administration based on body surface area.

[0209] In further embodiments, capecitabine is administered once daily, twice daily, or three times daily.

[0210] In a further embodiment, capecitabine is administered orally.

[0211] 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 administered at a dose of about 130 mg / kg based on body weight. 2 The body surface area based dose was administered, and capecitabine was administered at approximately 1000 mg / m 2 Dosage administration based on body surface area.

[0212] In a further embodiment, the second antibody is administered to the patient prior to administration of trastuzumab.

[0213] In a further embodiment, the second antibody is administered to the patient after administration of trastuzumab.

[0214] In a further embodiment, trastuzumab and the second antibody are administered simultaneously.

[0215] In a further embodiment, the method further comprises administering an immune checkpoint inhibitor.

[0216] In a further embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0217] In a further embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0218] In yet another aspect, the present invention also provides use of a second antibody in the preparation of a medicament for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma in a patient, wherein the treatment comprises administering to the patient a combination therapy comprising:

[0219] (1) Trastuzumab;

[0220] (2) a second antibody, wherein the second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding epitope from 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 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises LCDR1 as shown in SEQ ID NO: 6, LCDR2 as shown in SEQ ID NO: 7, and LCDR3 as shown in SEQ ID NO: 8;

[0221] (3) Chemotherapeutic agents.

[0222] In an alternative aspect, the present invention also provides the use of a second antibody, trastuzumab, and a chemotherapeutic agent in the preparation of a medicament for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma in a patient, the treatment comprising administering to the patient a combination therapy comprising:

[0223] (1) Trastuzumab;

[0224] (2) a second antibody, wherein the second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding epitope from 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 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises LCDR1 as shown in SEQ ID NO: 6, LCDR2 as shown in SEQ ID NO: 7, and LCDR3 as shown in SEQ ID NO: 8;

[0225] (3) Chemotherapeutic agents.

[0226] In a further embodiment, the chemotherapeutic agent is a fluorouracil-based drug. In a further embodiment, the chemotherapeutic agent is a platinum-based drug.

[0227] In a further embodiment, the chemotherapeutic agent is a combination of a fluorouracil-based drug and a platinum-based drug.

[0228] In a further embodiment, the fluorouracil drug is selected from 5-fluorouracil and capecitabine.

[0229] In a further embodiment, the platinum drug is selected from cisplatin and oxaliplatin. In a further embodiment, the fluorouracil drug is capecitabine. In a further embodiment, the platinum drug is oxaliplatin. In a further embodiment, the chemotherapeutic agent is a combination of capecitabine and oxaliplatin.

[0230] In a further embodiment, the cancer is HER2-positive advanced gastric cancer.

[0231] In a further embodiment, the cancer is unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0232] In a further embodiment, the heavy chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:9.

[0233] In a further embodiment, the heavy chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:5, and the light chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:10.

[0234] In a further embodiment, trastuzumab is administered at a body weight-based dose of about 0.1 mg / kg to about 10 mg / kg.

[0235] In further embodiments, trastuzumab is administered at a dose 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, 0.9 mg / kg to about 10 mg / kg.

[0014] In some embodiments, the present invention provides a weight-based dose of about 1 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.

[0236] In further embodiments, trastuzumab is administered at a weight-based 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.

[0237] In a further embodiment, trastuzumab is administered at an initial loading dose of about 8 mg / kg, followed by a dose of about 6 mg / kg, based on body weight.

[0238] In further embodiments, trastuzumab is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

[0239] In a further embodiment, trastuzumab is administered intravenously.

[0240] In a further embodiment, the second antibody is administered at 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 2.5mg / kg to about 25mg / kg, about 3mg / kg to about 25mg / kg, about 4mg / kg to about 25mg / kg, about 5mg / kg to about 25mg / kg, about 6mg / kg to about 25mg / kg, about 7mg / kg to about 25mg / kg, about 8mg / kg to about 25mg / kg, about 9mg / kg to about 25mg / kg, about 10mg / kg to about 25mg / kg, about 11mg / kg to about 25mg / kg, about 12mg / kg to about 25mg / kg, about 13mg / kg to about 25mg / kg, about 14mg / kg to about 25mg / kg. 5mg / kg, about 15mg / kg to about 25mg / kg, about 16mg / kg to about 25mg / kg, about 17mg / kg to about 25mg / kg, about 18mg / kg to about 25mg / kg, about 19mg / kg to about 25mg / kg, about 20mg / kg to about 25mg / kg, about 21mg / kg to about 25mg / kg, about 22mg / kg to about 25mg / kg, about 23mg / kg to about 25mg / kg, about 24mg / kg to about 25mg / kg, about 0.1mg / kg to about 20mg / kg, about 0.3mg / kg to about 2 0mg / kg, 0.9mg / kg to about 20mg / kg, about 1mg / kg to about 20mg / kg, about 2.5mg / kg to about 20mg / kg, about 3mg / kg to about 20mg / kg, about 4mg / kg to about 20mg / kg, about 5mg / kg to about 20mg / kg, about 6mg / kg to about 20mg / kg, about 7mg / kg to about 20mg / kg, about 8mg / kg to about 20mg / kg, about 9mg / kg to about 20mg / kg, about 10mg / kg to about 20mg / kg, about 11mg / kg to about 20mg / kg, about 1 2 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 20 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 to 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 based on body weight.

[0241] In a further embodiment, the second antibody is administered at a weight-based 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, 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, about 28 mg / kg, about 29 mg / kg or about 30 mg / kg.

[0242] In further embodiments, the second antibody is administered at a body weight-based dose of about 25 mg / kg or 15 mg / kg.

[0243] In further embodiments, the second antibody is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

[0244] In a further embodiment, the second antibody is administered intravenously.

[0245] In a further embodiment, oxaliplatin is administered at a dose of about 10 to about 150 mg / m 2 , about 20 to about 150 mg / m 2 , about 30 to about 150 mg / m 2 , about 40 to about 150 mg / m 2 , about 50 to about 150 mg / m 2 , about 60 to about 150 mg / m 2, about 70 to about 150 mg / m 2 , about 75 to about 150 mg / m 2 , about 80 to about 150 mg / m 2 , about 85 to about 150 mg / m 2 , about 90 to about 150 mg / m 2 , about 95 to about 150 mg / m 2 , about 100 to about 150 mg / m 2 , about 105 to about 150 mg / m 2 , about 110 to about 150 mg / m 2 , about 115 to about 150 mg / m 2 , about 120 to about 150 mg / m 2 , about 125 to about 150 mg / m 2 , about 130 to about 150 mg / m 2 , about 135 to about 150 mg / m 2 , about 140 to about 150 mg / m 2 , about 145 to about 150 mg / m 2 , about 10 to about 140 mg / m 2 , about 20 to about 140 mg / m 2 , about 30 to about 140 mg / m 2 , about 40 to about 140 mg / m 2 , about 50 to about 140 mg / m 2 , about 60 to about 140 mg / m 2 , about 70 to about 140 mg / m 2 , about 75 to about 140 mg / m 2 , about 80 to about 140 mg / m 2 , about 85 to about 140 mg / m 2 , about 90 to about 140 mg / m 2 , about 95 to about 140 mg / m 2 , about 100 to about 140 mg / m 2 , about 105 to about 140 mg / m 2 , about 110 to about 140 mg / m 2 , about 115 to about 140 mg / m 2 , about 120 to about 140 mg / m 2 , about 125 to about 140 mg / m 2 , about 130 to about 140 mg / m 2 , about 135 to about 140 mg / m 2 , about 10 to about 130 mg / m 2 , about 20 to about 130 mg / m2 , about 30 to about 130 mg / m 2 , about 40 to about 130 mg / m 2 , about 50 to about 130 mg / m 2 , about 60 to about 130 mg / m 2 , about 70 to about 130 mg / m 2 , about 75 to about 130 mg / m 2 , about 80 to about 130 mg / m 2 , about 85 to about 130 mg / m 2 , about 90 to about 130 mg / m 2 , about 95 to about 130 mg / m 2 , about 100 to about 130 mg / m 2 , about 105 to about 130 mg / m 2 , about 110 to about 130 mg / m 2 , about 115 to about 130 mg / m 2 , about 120 to about 130 mg / m 2 , about 125 to about 130 mg / m 2 Dosage administration based on body surface area.

[0246] In a further embodiment, oxaliplatin is administered at about 10 mg / m 2 , about 20 mg / m 2 , about 30 mg / m 2 , about 40 mg / m 2 , about 50 mg / m 2 , about 60mg / m 2 , about 70 mg / m 2 , about 75 mg / m 2 , about 80mg / m 2 , about 85 mg / m 2 , about 90 mg / m 2 , about 95mg / m 2 , about 100 mg / m 2 , about 105 mg / m 2 , about 110 mg / m 2 , about 115 mg / m 2 , about 120 mg / m 2 , about 125 mg / m 2 , about 130mg / m 2 , about 135 mg / m 2 , about 140 mg / m 2 , about 145 mg / m 2 or about 150 mg / m 2 Dosage administration based on body surface area.

[0247] In a further embodiment, oxaliplatin is administered at about 130 mg / m 2 Dosage administration based on body surface area.

[0248] In further embodiments, oxaliplatin is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

[0249] In a further embodiment, oxaliplatin is administered intravenously.

[0250] In a further embodiment, capecitabine is administered at a dose of about 100 to about 1200 mg / m 2 , about 200 to about 1200 mg / m 2 , about 300 to about 1200 mg / m 2 , about 400 to about 1200 mg / m 2 , about 500 to about 1200 mg / m 2 , about 600 to about 1200 mg / m 2 , about 650 to about 1200 mg / m 2 , about 700 to about 1200 mg / m 2 , about 750 to about 1200 mg / m 2 , about 800 to about 1200 mg / m 2 , about 850 to about 1200 mg / m 2 , about 900 to about 1200 mg / m 2 , about 950 to about 1200 mg / m 2 , about 1000 to about 1200 mg / m 2 , about 1050 to about 1200 mg / m 2 , about 1100 to about 1200 mg / m 2 , about 1150 to about 1200 mg / m 2 , about 100 to about 1100 mg / m 2 , about 200 to about 1100 mg / m 2 , about 300 to about 1100 mg / m 2 , about 400 to about 1100 mg / m 2 , about 500 to about 1100 mg / m 2 , about 600 to about 1100 mg / m 2 , about 650 to about 1100 mg / m 2 , about 700 to about 1100 mg / m 2 , about 750 to about 1100 mg / m 2 , about 800 to about 1100 mg / m2 , about 850 to about 1100 mg / m 2 , about 900 to about 1100 mg / m 2 , about 950 to about 1100 mg / m 2 , about 1000 to about 1100 mg / m 2 , about 100 to about 1000 mg / m 2 , about 200 to about 1000 mg / m 2 , about 300 to about 1000 mg / m 2 , about 400 to about 1000 mg / m 2 , about 500 to about 1000 mg / m 2 , about 600 to about 1000 mg / m 2 , about 650 to about 1000 mg / m 2 , about 700 to about 1000 mg / m 2 , about 750 to about 1000 mg / m 2 , about 800 to about 1000 mg / m 2 , about 850 to about 1000 mg / m 2 , about 900 to about 1000 mg / m 2 or about 950 to about 1000 mg / m 2 Dosage administration based on body surface area.

[0251] In a further embodiment, capecitabine is administered at about 100 mg / m 2 , about 200mg / m 2 , about 300mg / m 2 , about 400mg / m 2 , about 500mg / m 2 , about 600mg / m 2 , about 650mg / m 2 , about 700mg / m 2 , about 750mg / m 2 , about 800mg / m 2 , about 850mg / m 2 , about 900mg / m 2 , about 950mg / m 2 , about 1000mg / m 2 , about 1050 mg / m 2 , about 1100mg / m 2 , about 1150mg / m 2 or about 1200 mg / m 2 Dosage administration based on body surface area.

[0252] In a further embodiment, capecitabine is administered at about 1000 mg / m 2 Dosage administration based on body surface area.

[0253] In further embodiments, capecitabine is administered once daily, twice daily, or three times daily.

[0254] In a further embodiment, capecitabine is administered orally.

[0255] 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 administered at a dose of about 130 mg / kg based on body weight. 2 The body surface area based dose was administered, and capecitabine was administered at approximately 1000 mg / m 2 Dosage administration based on body surface area.

[0256] In a further embodiment, the second antibody is administered to the patient prior to administration of trastuzumab.

[0257] In a further embodiment, the second antibody is administered to the patient after administration of trastuzumab.

[0258] In a further embodiment, trastuzumab and the second antibody are administered simultaneously.

[0259] In further embodiments, the treatment further comprises administering an immune checkpoint inhibitor.

[0260] In a further embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0261] In a further embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0262] In some embodiments of the present invention, the patient is untreated, including, for example, not having undergone any systemic anti-tumor treatment for advanced unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, or although having received adjuvant therapy in the past, the last treatment was completed ≥6 months from the first administration of the treatment regimen of the present invention, or since having received anti-tumor traditional Chinese medicine or Chinese patent medicine treatment, the last treatment was completed before the random grouping of the study involved in the present invention.

[0263] In some embodiments of the present invention, the trastuzumab, the second anti-HER2 antibody, or a binding fragment thereof is administered intravenously every 3 weeks.

[0264] In some embodiments, the second anti-HER2 antibody is administered at a dose of about 25 mg / kg.

[0265] In some embodiments, the second anti-HER2 antibody is administered at a dose of about 15 mg / kg.

[0266] In some embodiments, trastuzumab is administered at an initial loading dose of about 8 mg / kg, followed by administration of about 6 mg / kg every 3 weeks.

[0267] In some embodiments of the invention, the chemotherapeutic agent is a combination of capecitabine and oxaliplatin.

[0268] In some embodiments, oxaliplatin is administered at a dose of about 130 mg / m 2 Dosage: Intravenous infusion, administered once every three weeks; typically, intravenous infusion over 2-6 hours, administered on the first day of each cycle; and in some cases, such as those with a body surface area greater than 2.0 m 2 When using the drug, researchers can calculate the dosage based on clinical practice.

[0269] In some embodiments, capecitabine is administered at about 1000 mg / m 2 Dosage: Oral administration, twice daily, with one dosing cycle of three weeks; generally, administration is performed on the first to fourteenth day of each cycle; and in some cases, researchers calculate the dosage based on clinical practice, for example, when the theoretical dose exceeds 1500 mg, the dose of capecitabine is selected to be approximately 1500 mg.

[0270] Immune checkpoint inhibitors are also an important part of treatment options for advanced gastric cancer. For example, in the Phase III KEYNOTE-811 study of HER2-positive gastric cancer, the combination of pembrolizumab and trastuzumab significantly improved the response rate compared to the combination of trastuzumab and chemotherapy. The FDA has approved pembrolizumab in combination with trastuzumab, fluorouracil, and platinum chemotherapy as a first-line treatment for patients with advanced, unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma. The combination therapy of trastuzumab, a second anti-HER2 antibody, and chemotherapy, as described in the present invention, can also be combined with immune checkpoint inhibitors to improve the response rate. In some embodiments of the present invention, in the uses or treatment regimens involved in the present invention, immune checkpoint inhibitors can be administered simultaneously or at intervals, preferably anti-PD-1 antibodies or anti-PD-L1 antibodies, preferably anti-PD-1 antibodies, such as nivolumab, pembrolizumab (pembrolizumab), sintilimab, tislelizumab, carrelizumab, toripalimab, slulizumab, etc.

[0271] V. Pharmaceutical Combinations / Pharmaceutical Compositions

[0272] The present invention provides a drug combination involving the combined use of trastuzumab and the above-mentioned second anti-HER2 antibody, which specifically comprises trastuzumab and the second anti-HER2 antibody or a binding fragment thereof.

[0273] The present invention also provides a pharmaceutical composition, for example, a pharmaceutical composition for treating gastric cancer, comprising trastuzumab and the above-mentioned second anti-HER2 antibody and a pharmaceutically acceptable carrier.

[0274] In some embodiments, the pharmaceutical composition of the present invention is in the form of a liquid preparation or a lyophilized powder, typically in the form of a liquid preparation. The preparation comprises an antibody (trastuzumab, a second anti-HER2 antibody), a surfactant (e.g., polysorbate 20, 80), a buffer (histidine buffer, acetate buffer, citrate buffer, or a mixture of the two buffers), a stabilizer (e.g., sugars, alcohols, salts, amino acids, etc.), and an appropriate pH value.

[0275] In one aspect, the present invention also provides a combination product comprising:

[0276] Trastuzumab;

[0277] The second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding site from the trastuzumab, comprising:

[0278] a heavy chain variable region comprising HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and

[0279] a light chain variable region comprising LCDR1 as set forth in SEQ ID NO:6, LCDR2 as set forth in SEQ ID NO:7, and LCDR3 as set forth in SEQ ID NO:8; and

[0280] Chemotherapeutic agents.

[0281] In a further embodiment, the chemotherapeutic agent is a fluorouracil-based drug. In a further embodiment, the chemotherapeutic agent is a platinum-based drug.

[0282] In a further embodiment, the chemotherapeutic agent is a combination of a fluorouracil-based drug and a platinum-based drug.

[0283] In a further embodiment, the fluorouracil is selected from 5-fluorouracil and capecitabine. In a further embodiment, the platinum is selected from cisplatin and oxaliplatin. In a further embodiment, the fluorouracil is capecitabine. In a further embodiment, the platinum is oxaliplatin. In a further embodiment, the chemotherapeutic agent is a combination of capecitabine and oxaliplatin.

[0284] In a further embodiment, the heavy chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:9.

[0285] In a further embodiment, the heavy chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:5, and the light chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:10.

[0286] In a further embodiment, the combination product further comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0287] In a further embodiment, the combination product further comprises an anti-PD-1 antibody.

[0288] VI.Medicine Box

[0289] The present invention also relates to a kit for treating gastric cancer, which typically includes an antibody, a chemotherapeutic agent, and / or a label and instructions for intended use. Specifically, the present invention relates to a kit for treating gastric cancer, particularly advanced, unresectable or metastatic HER2-positive gastric cancer, comprising at least one cycle of trastuzumab, a second anti-HER2 antibody, and a chemotherapeutic agent. In some exemplary embodiments, the trastuzumab, the second anti-HER2 antibody, and / or the chemotherapeutic agent are packaged in a unit dosage form. The second anti-HER2 antibody is as defined above. In a preferred embodiment of the present invention, the chemotherapeutic agent contained in the kit is a fluorouracil compound and a platinum drug, for example, the fluorouracil compound is 5-fluorouracil or capecitabine, and the platinum drug is cisplatin or oxaliplatin. In a more preferred embodiment, the kit contains trastuzumab, a second anti-HER2 antibody, and capecitabine or oxaliplatin.

[0290] Specifically, in one aspect, the present invention further provides a drug kit for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, the drug kit comprising:

[0291] Trastuzumab;

[0292] The second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding site from the trastuzumab, comprising:

[0293] a heavy chain variable region comprising HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and

[0294] a light chain variable region comprising LCDR1 as set forth in SEQ ID NO:6, LCDR2 as set forth in SEQ ID NO:7, and LCDR3 as set forth in SEQ ID NO:8; and

[0295] Chemotherapeutic agents.

[0296] In a further embodiment, the chemotherapeutic agent is a fluorouracil.

[0297] In a further embodiment, the chemotherapeutic agent is a platinum drug.

[0298] In a further embodiment, the chemotherapeutic agent is a combination of a fluorouracil-based drug and a platinum-based drug.

[0299] In a further embodiment, the fluorouracil drug is selected from 5-fluorouracil and capecitabine.

[0300] In a further embodiment, the platinum drug is selected from cisplatin and oxaliplatin.

[0301] In a further embodiment, the fluorouracil drug is capecitabine.

[0302] In a further embodiment, the platinum drug is oxaliplatin.

[0303] In a further embodiment, the chemotherapeutic agent is a combination of capecitabine and oxaliplatin.

[0304] In a further embodiment, the cancer is HER2-positive advanced gastric cancer.

[0305] In a further embodiment, the cancer is unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

[0306] In a further embodiment, the heavy chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:9.

[0307] In a further embodiment, the heavy chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:5, and the light chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:10.

[0308] In a further embodiment, the kit further comprises instructions for use.

[0309] In a further embodiment, the kit further comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0310] In a further embodiment, the kit further comprises an anti-PD-1 antibody.

[0311] The sequence information involved in the present invention is summarized in Table 1.

[0312] Table 1 Sequence Listing

[0313] Table 2 Abbreviations

[0314] Drug source: Trastuzumab (or biosimilar): from Fuhong Hanlin, its trade name is Hanquyou.

[0315] The second anti-HER2 antibody was prepared according to the method of Chinese patent application No. 201480024152.3, wherein the antibody numbered hz1E11-133 was the reference antibody;

[0316] Pertuzumab: prepared according to the methods described in WO01 / 00245 and WO2006 / 007398. Commercially available drugs or biosimilars approved for clinical research may also be used.

[0317] Chemotherapeutic agents:

[0318] Capecitabine and oxaliplatin, Qilu Pharmaceutical;

[0319] Cells used in the experiments: Gastric cancer cell line NCI-N87 was purchased from the National Cancer Institute (NCI); SNU216 was purchased from CoBioer.

[0320] The HER2-Fc protein used in Example 1 was obtained from Sino Biological (PA, USA), product number 10004-H02H, LC10JA1203.

[0321] The invention is illustrated by the following non-limiting examples.

[0322] Example 1. HER2 epitope studies of trastuzumab and a second anti-HER2 antibody

[0323] Analysis of epitope binding competition between trastuzumab, a secondary anti-HER2 antibody, and pertuzumab. The secondary anti-HER2 antibody was immobilized on a Biacore CM5 sensor chip using approximately 1000 RU of amine coupling, followed by the addition of (a) HER2-Fc protein, trastuzumab, and pertuzumab, and (b) HER2-Fc protein, pertuzumab, and trastuzumab.

[0324] Referring to the HER2 epitope affinity study shown in Figure 1, the second anti-HER2 antibody has no competitive binding with either trastuzumab or pertuzumab, and the second anti-HER2 antibody has different binding sites from trastuzumab. Although the second anti-HER2 antibody also binds to HER2 subdomain IV, it does not compete with trastuzumab.

[0325] Example 2. Study on HER2-mediated endocytosis and EGFR cell surface expression levels in gastric cancer cells NCI-N87 and SNU216 treated with trastuzumab and a second anti-HER2 antibody

[0326] Endocytosis capacity study

[0327] pHrodo Green staining was used to observe the temporal gradient of HER2 antibody internalization in gastric cancer cell lines NCI-N87 and SNU216 treated with trastuzumab, a second anti-HER2 antibody, pertuzumab, and their combination. HER2 internalization assay was performed using pHrodo iFL Green STP esteramine reactive dye (P35369, Invitrogen). 5 Gastric cancer cells (100 cells / well) were seeded into 96-well plates (CLS3799, Corning) and then incubated with trastuzumab, anti-HER2 antibody, pertuzumab, trastuzumab + pertuzumab, or trastuzumab + anti-HER2 antibody (10 μg / mL) on ice for 1 hour. After a brief wash with wash buffer to remove unbound antibody, one group of cells was frozen on ice to terminate internalization, and the remaining cells were placed in a 37°C incubator and continued to be cultured. After antibody incubation, the cells were fixed with fixation buffer (420801, biolgend) for 30 minutes. Finally, all stained cells were washed with staining buffer and analyzed using a CytoFLEX LX flow cytometer (Beckman Coulter, USA).

[0328] As shown in Figure 2, trastuzumab plus pertuzumab demonstrated limited HER2 internalization in the gastric cancer cell lines NCI-N87 and SNU216, while trastuzumab plus an anti-HER2 antibody induced stronger HER2 internalization in both NCI-N87 and SNU216. The combination of anti-HER2 antibodies and trastuzumab binds simultaneously to HER2 subdomain IV, while trastuzumab and pertuzumab bind to both subdomain IV and subdomain II. Therefore, antibody binding to different subdomains results in different receptor internalization rates, demonstrating the unique synergistic effect of the anti-HER2 antibody and trastuzumab combination.

[0329] Study on EGFR cell expression level

[0330] EGFR and HER2 protein expression levels were detected using BV421 anti-human EGF receptor (749755, BD Biosciences) and AF647 anti-human CD340 (erbB2 / HER-2) (324412, biolgend). All stained cells were analyzed using a CytoFLEX LX flow cytometer (Beckman Coulter, USA). Data were analyzed using FlowJo software.

[0331] As shown in Figure 3 , in NCI-N87 gastric cancer cells, combined treatment with anti-HER2 antibodies and trastuzumab not only reduced the expression of HER2 (a, b, c in Figure 3 ), but also reduced the expression of cell surface EGFR (d, e, f in Figure 3 ), indicating that EGFR is internalized together with HER2 in the form of a HER2 / EGFR heterodimer. While combined treatment with pertuzumab and trastuzumab can reduce the expression of HER2, the extent of reduction in cell surface EGFR expression is limited.

[0332] Example 3. Study on the synergistic effect of trastuzumab and a second anti-HER2 antibody in the treatment of HER2-positive gastric cancer

[0333] The synergistic antitumor effect of trastuzumab and a second anti-HER2 antibody was investigated by measuring the survival rate of gastric cancer cell NCI-N87 cells and the PDX model of HER2-positive gastric cancer.

[0334] After 72 hours of 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, the cell viability of gastric cancer cells NCI-N87 was measured; The assay system assesses apoptosis by measuring the activity of caspase 3 / 7 in NCI-N87 gastric cancer cells. The xenograft human gastric cancer NCI-N87 model and human gastric cancer PDX models were treated with antibodies at the indicated doses. All data are presented as mean ± SEM. P values ​​were calculated using the Student's t-test. **p < 0.01, *p < 0.05.

[0335] In vitro proliferation experimental study

[0336] Cell proliferation was detected using the CellTiter-Glo Luminescent Cell Viability Kit (G7571, Promega). 4 Cells were incubated overnight at 37°C in 96-well plates (CLS3799, Corning). Cells were treated with IgG1, trastuzumab, a secondary anti-HER2 antibody, pertuzumab, or trastuzumab / secondary anti-HER2 antibody or trastuzumab / pertuzumab. Luminescence was measured at T = 0 h. After 72 h of incubation, luminescence was measured at T = 72 h using Spark (Tecan, Switzerland). Cell viability was calculated as follows: Cell viability = (T72 - T0) / (T72(c) - T0) × 100%, where T = treatment and c = control.

[0337] Cell apoptosis detection

[0338] use Apoptosis was assessed by measuring the activity of caspases 3 / 7 in NCI-N87 cells using the G8093 Assay (Promega) system. Approximately 1.5 × 10 4 Cells were seeded in 96-well plates (CLS3799, Corning) and cultured overnight. The culture medium was replaced with 100 μL of drug-containing medium and treated for 24 hours. After incubation at room temperature for 30 minutes, 100 μL of Caspase-Glo 3 / 7 reagent was added. Incubate in the dark for 30 minutes, gently shaken, and then detected using Spark (Tecan, Switzerland).

[0339] Animal tumor model research

[0340] In the xenogeneic human gastric cancer NCI-N87 model, BALB / cn nude female mice were subcutaneously implanted with 5×10 6 NCI-N87 cells. When the average tumor volume of mice reaches about 120-150mm 3At the time of treatment, mice were randomized into groups and then given the following treatments. Secondary anti-HER2 antibody or control agent was injected intraperitoneally at 10 mg / kg twice a week for 28 consecutive days, with 8 mice in each group. In the PDX model, tumor xenografts were generated from patient gastric cancer tissue and transplanted subcutaneously into the right back of each NCG mouse. Trastuzumab, trastuzumab / secondary anti-HER2 antibody, and trastuzumab / pertuzumab were treated at different doses in the PDX model, with n=5 mice per group, and the doses were administered twice a week for 52-60 consecutive days. Tumor volume and body weight were measured twice a week.

[0341] As shown in Figure 4a, in a study of the in vitro growth inhibition of the NCI-N87 gastric cancer cell line using either a second anti-HER2 antibody or trastuzumab alone or in combination, the combination of trastuzumab and a second anti-HER2 antibody significantly enhanced the anti-proliferative activity of either antibody alone and demonstrated superior cell proliferation efficacy compared to the combination of trastuzumab and pertuzumab. As shown in Figure 4b, the combination of a second anti-HER2 antibody and trastuzumab induced apoptosis in NCI-N87 gastric cancer cells, as assessed by caspase 3 / 7 activity. However, treatment with trastuzumab, a second anti-HER2 antibody, or pertuzumab alone, or with the combination of trastuzumab and pertuzumab, did not significantly induce apoptosis. As shown in Figure 4c, in a study of the NCI-N87 xenograft gastric cancer model, trastuzumab combined with a second anti-HER2 antibody significantly inhibited tumor size in the model. Referring to the treated PDX model studies shown in Figures 4d and 4e, trastuzumab combined with a second anti-HER2 antibody was able to inhibit tumor size.

[0342] In the above-mentioned studies on human gastric cancer cell lines, xenogeneic human gastric cancer NCI-N87 model, and PDX model, the combination of trastuzumab and a second anti-HER2 antibody had a strong anti-tumor effect (gastric cancer cells), inhibited tumor growth, and promoted tumor regression. The combination of the second anti-HER2 antibody and trastuzumab also showed an enhanced anti-tumor effect, reflecting the unique synergistic effect of the combination of trastuzumab and a second anti-HER2 antibody. This is partly because the anti-HER2 antibody and trastuzumab can induce apoptosis of gastric cancer cells. However, this effect did not appear in studies of gastric cancer cells treated with trastuzumab, a second anti-HER2 antibody, or pertuzumab alone, or with the combination of trastuzumab and pertuzumab.

[0343] Example 4. Clinical Study of Trastuzumab, a Second Anti-HER2 Antibody, and a Chemotherapeutic Agent in Combination Therapy for Patients Diagnosed with Advanced Unresectable or Metastatic HER2-Positive Gastric Cancer or Gastroesophageal Junction Adenocarcinoma

[0344] This study is a randomized, double-blind, multicenter, Phase II clinical study designed to evaluate the clinical efficacy and safety of trastuzumab + a second anti-HER2 antibody + chemotherapy in the treatment of patients with advanced unresectable or metastatic gastric cancer compared with placebo and trastuzumab + chemotherapy as the first-line treatment.

[0345] Study Design

[0346] This randomized, double-blind study enrolled approximately 53 patients diagnosed with advanced, unresectable, or metastatic gastric cancer (untreated) and randomly assigned to one of three groups in a 1:1:1 ratio.

[0347] Group A (experimental group): second anti-HER2 antibody (25 mg / kg) + trastuzumab + chemotherapy agent (XELOX);

[0348] Group B (experimental group): second anti-HER2 antibody (15 mg / kg) + trastuzumab + chemotherapy agent (XELOX);

[0349] Group C (standard treatment group): placebo (some subjects in the unblinded and open-label groups did not use placebo) + trastuzumab + chemotherapy (XELOX).

[0350] The randomization procedure used a central randomization system and interactive web response system (IWRS), with randomization stratified according to the HER2 expression level (3+ or 2+) confirmed by immunohistochemistry (IHC / FISH) method, and random codes were generated in a 1:1:1 ratio.

[0351] The dosage is as follows:

[0352] Second anti-HER2 antibody: 25 mg / kg or 15 mg / kg intravenous infusion (IV) every three weeks, given on the first day of each cycle.

[0353] Placebo: Refer to the second anti-HER2 antibody administration method (the dosage varies according to the stage).

[0354] Trastuzumab: The initial loading dose is 8 mg / kg, followed by 6 mg / kg administered once every three weeks on the first day of each cycle; the first infusion time should be more than 90 minutes (including 90 minutes), and repeated at 6 mg / kg.

[0355] Oxaliplatin: 130 mg / m 2 , intravenous infusion for 2-6 hours (to be used after the end of trastuzumab infusion), once every three weeks, on the first day of each cycle, for a maximum of 8 cycles; if the body surface area exceeds 2.0 m 2 Researchers can use 2.0m 2 Calculate the dosage to be administered.

[0356] Capecitabine: 1000 mg / m 2 , orally, twice a day, with one dosing cycle of three weeks, and administration from the first to the fourteenth day of each cycle; if the calculated theoretical dose exceeds 1500 mg, the researcher can choose a capecitabine dose of 1500 mg, orally, twice a day based on clinical practice.

[0357] Tumor assessments were continued until investigator-assessed progression according to RECIST v1.1, treatment was continued until loss of clinical benefit, intolerable toxicity occurred, patient or study decision to discontinue treatment (abnormal termination of treatment), death of the subject receiving trial treatment, withdrawal of informed consent, pregnancy, non-compliance with protocol or procedural requirements, or administrative reasons (whichever occurred first).

[0358] patient

[0359] Patients were treatment-naive and diagnosed with advanced unresectable or metastatic gastric cancer and met the criteria for participation in this study.

[0360] Inclusion criteria

[0361] 1) Volunteer to participate in the clinical study; fully understand and be informed of this study and sign the Informed Consent Form (ICF); be willing to follow and be able to complete all trial procedures;

[0362] 2) regardless of gender, aged ≥18 and ≤80 years at the time of signing the ICF;

[0363] 3) Patients with HER2-positive locally advanced / metastatic gastric cancer or gastroesophageal junction adenocarcinoma confirmed by histopathological examination and incurable by surgery, and with histological examination confirming that the primary tumor is adenocarcinoma;

[0364] 4) Patients who have not received systemic anti-tumor treatment for locally advanced / metastatic gastric cancer or gastroesophageal junction adenocarcinoma;

[0365] 5) For subjects who have received neoadjuvant / adjuvant therapy in the past, the last treatment must be ≥ 6 months from the first medication of this study;

[0366] 6) For subjects who have received anti-tumor Chinese medicine or Chinese patent medicine in the past, the last treatment should be completed before randomization;

[0367] 7) Previous treatment-related AEs have recovered to NCI-CTCAE ≤ grade 1 (except for alopecia);

[0368] 8) According to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), the patient must have at least one measurable lesion as assessed by central imaging. The measurable lesion should not have received local treatment such as radiotherapy (lesions located within the previously radiotherapy area can also be selected as target lesions if they have been confirmed to have progressed). The target lesion cannot be solely a bone metastasis.

[0369] 9) Patients must provide tumor tissue for HER2 expression testing and confirm that the tumor is HER2-positive, i.e.:

[0370] a. HER2 positive at least 3+ (+++) or

[0371] b. HER2-positive at least 2+(++) as determined by immunohistochemistry (IHC) and positive by fluorescence in situ hybridization (FISH);

[0372] 10) ECOG within 7 days before randomization: 0-1;

[0373] 11) Expected survival period ≥ 6 months;

[0374] 12) Hepatitis B surface antigen (HBsAg) (-) and hepatitis B core antibody (HBcAb) (-). If HBsAg (+) or HBcAb (+), the hepatitis B virus deoxyribonucleic acid (HBV-DNA) must be <2500 copies / mL or 500 IU / mL or within the normal range of our center.

[0375] 13) HCV antibody (-); if HCV antibody (+), HCV RNA testing must be negative for enrollment. Subjects with hepatitis B and C co-infection (positive HBsAg or HBcAb testing, and positive HCV antibody testing) must be excluded.

[0376] 14) The main organ functions are normal, that is, they meet the following criteria (within 14 days before the first medication of this study, they have not received blood transfusion, albumin, recombinant human thrombopoietin or colony stimulating factor (CSF) treatment):

[0377] Table 3. Major organ function standards

[0378] 15) Female subjects of childbearing potential must have a negative blood pregnancy test within 7 days before randomization. Female subjects of childbearing potential, and male subjects whose partners are women of childbearing age, must use at least one medically approved contraceptive method (such as intrauterine device, birth control pills, or condoms) during the study treatment and for at least 6 months after the last use of the second anti-HER2 antibody / trastuzumab / placebo and chemotherapy.

[0379] Exclusion criteria

[0380] Patients who meet any of the following exclusion criteria will not be eligible for this study:

[0381] 1) Patients with other malignant tumors within 2 years before the first use of the study drug. Patients with cured localized tumors, such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, prostate carcinoma in situ, cervical carcinoma in situ, breast carcinoma in situ, and thyroid cancer, are eligible for inclusion;

[0382] 2) Disease progression within 6 months after completing neoadjuvant or adjuvant chemotherapy (or both) or radiotherapy for gastric adenocarcinoma or gastroesophageal junction adenocarcinoma;

[0383] 3) Have received any HER2-targeted therapy or treatment targeting immune checkpoints (such as PD-1, PD-L1, CTLA-4);

[0384] 4) Previous use of doxorubicin with a concentration > 360 mg / m 2 (or equivalent); Note: Equivalent drugs include epirubicin >720mg / m 2 , mitoxantrone>120 mg / m 2 Idarubicin >90 mg / m 2 , more than 360mg / m 2 Doxorubicin equivalents of liposomal doxorubicin or other anthracyclines. If more than one anthracycline is used, the cumulative dose should not exceed 360 mg / m 2 doxorubicin equivalents;

[0385] 5) Pleural effusion, pericardial effusion, or ascites requiring frequent drainage that cannot be controlled after appropriate intervention;

[0386] 6) Active gastrointestinal bleeding requiring blood transfusion or invasive intervention;

[0387] 7) presence of central nervous system (CNS) or leptomeningeal metastasis;

[0388] 8) Cerebrovascular accident, myocardial infarction, unstable angina, or poorly controlled arrhythmia (including QTc interval ≥450ms for men and ≥470ms for women) occurred within six months before the first use of the drug (QTc interval was calculated using the Fridericia formula);

[0389] 9) According to the New York Heart Association (NYHA) standard, grade III or IV heart failure, or cardiac ultrasound examination: LVEF (left ventricular ejection fraction) <55%;

[0390] 10) Suffering from active pulmonary tuberculosis;

[0391] 11) Patients with a history or current history of interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe lung function impairment, etc., which may interfere with the detection and treatment of suspected drug-related pulmonary toxicity;

[0392] 12) Received treatment with live attenuated vaccines within 28 days before randomization, except for inactivated virus vaccines for seasonal influenza or novel coronavirus pneumonia;

[0393] 13) Baseline chest imaging examinations indicate active lung inflammation accompanied by clinically relevant symptoms or signs;

[0394] 14) Patients who need to receive systemic corticosteroids (>10 mg / day prednisone effective dose) or other immunosuppressive drugs within 14 days before randomization or during the study. However, the following conditions are allowed to be enrolled: In the absence of active autoimmune diseases, patients are allowed to use topical or inhaled steroids, or adrenal hormone replacement therapy with a dose of ≤10 mg / day prednisone effective dose;

[0395] 15) Major surgery within 28 days before the first use of the study drug. The definition of major surgery in this study is: at least 3 weeks of recovery time is required after the surgery before the study treatment can be performed;

[0396] 16) Received radical radiotherapy within 3 months before starting study treatment; palliative radiotherapy for bone diseases and superficial lesions is allowed and has been completed 14 days before the first dose; radiotherapy covering more than 30% of the bone marrow area within 28 days before the first dose is not allowed;

[0397] 17) Currently participating in other clinical studies, or planning to start treatment in this study less than 14 days after the end of the previous clinical study;

[0398] 18) Known history of severe allergy to any monoclonal antibody or study drug excipients;

[0399] 19) There is evidence of intra-abdominal gas that cannot be explained by puncture or recent surgery;

[0400] 20) Known history of psychotropic substance abuse or drug use;

[0401] 21) Pregnant or breastfeeding women;

[0402] 22) The researcher determines that the subject has other factors that may force him / her to terminate the study, such as other serious diseases (including mental illness) requiring combined treatment, serious abnormalities in laboratory test values, family or social factors that may affect the subject's safety or the collection of trial data.

[0403] result

[0404] The primary efficacy endpoints of this study were progression-free survival (PFS) and objective response rate (ORR). PFS was defined as the time (in months) from randomization to the first documented disease progression or death (whichever occurred first), as assessed according to RECIST v1.1 (IRRC) criteria. For subjects who had not experienced disease progression or death at the time of analysis, the date of their last objective tumor assessment was used as the censored date for PFS. The objective response rate (ORR) was defined as the proportion of subjects achieving a best response of CR or PR, as assessed according to RECIST v1.1 (investigator and IRRC) criteria. The objective response rate for each group was analyzed descriptively, with corresponding 95% confidence intervals (CIs). Median progression-free survival was estimated using the Kaplan-Meier method, and Kaplan-Meier curves were plotted. Stratified Cox proportional hazards models were used to estimate the hazard ratios (HRs) for PFS, along with their 95% CIs. The stratified log-rank test was used to compare PFS between groups. The difference in ORR between the two groups was tested using the stratified Cochran-Mantel-Haenszel (CMH) method to estimate the odds ratio and its 95% confidence interval.

[0405] The secondary efficacy endpoint of this study was overall survival. Progression-free survival and objective response rate, assessed by the investigator according to RECIST v1.1, were statistically analyzed using the same methods as the primary efficacy endpoint. Duration of response was defined as the time from the date of first achievement of a CR or PR (whichever was recorded first) to the date of first documented disease progression or death (whichever occurred first). Duration of response (DOR) was assessed separately for subjects with an objective response as assessed by the investigator and the IRRC. Medians were estimated using the Kaplan-Meier method, and Kaplan-Meier curves were constructed.

[0406] Efficacy

[0407] A total of 53 patients were randomized and included in this study: 18 in Group A, 17 in Group B, and 18 in Group C. The median progression-free survival (PFS) for these 53 patients, as assessed by imaging, was as follows: PFS for Group A was 15.1 months (95% confidence interval, 6.8 months to not evaluable), not yet reached for Group B (95% confidence interval, 9.9 months to not evaluable), and 8.2 months for Group C (95% confidence interval, 9.9 months to not evaluable). At the time of this analysis, 12 patients (28.3%) had died, and overall survival data were not yet mature; median overall survival had not been reached in any group. KM curves for progression-free survival are shown in Figure 5 , and efficacy data are summarized in Table 4 .

[0408] Table 4. Summary of efficacy data

[0409] As shown in Table 4, the median progression-free survival of Group A was 15.11 months and the median sustained remission time was 12.4 months, the median progression-free survival and median sustained remission time of Group B were not reached, the median progression-free survival of Group C was 8.21 months and the median sustained remission time was 6.8 months, that is, the combination of trastuzumab + a second anti-HER2 antibody + chemotherapy (Group A, Group B) can significantly prolong the patient's median progression-free survival and median sustained remission time compared with the combination of trastuzumab + chemotherapy. The median hazard ratio for progression-free survival was 0.5 (95% CI, 0.17-1.27, P = 0.1272) in group A, and the median hazard ratio for progression-free survival in group B was 0.1 (95% CI, 0.04-0.52, P = 0.0007). At the same time, the median hazard ratio for sustained remission time was 0.6 (95% CI, 0.20-1.62, P = 0.2848) in group A, and the median hazard ratio for sustained remission time in group B was 0.1 (95% CI, 0.02-0.50, P = 0.0006), which favored the combination group of trastuzumab + second anti-HER2 antibody + chemotherapy agent.

[0410] The objective response rates of both trial groups (Group A and Group B) were significantly higher than those of the control group (Group C). The 36-week objective response rates of Group A and Group B were 44.4% and 64.7%, respectively, and the 48-week objective response rates of Group A and Group B were 38.9% and 58.8%, respectively.

[0411] In the treatment of patients with HER2-positive advanced gastric cancer in this study, the combination of a second anti-HER2 antibody and standard treatment (trastuzumab + XELOX) showed significant and lasting remission, enabling these patients to achieve significantly prolonged progression-free survival.

[0412] Security

[0413] In a Phase 1 clinical trial of a second anti-HER2 antibody, as of April 22, 2022, a total of 11 subjects had been enrolled and received at least one dose of the anti-HER2 antibody, and 11 subjects were included in the safety analysis set. Trial results showed that the second anti-HER2 antibody was well tolerated across all dose groups. No dose-related toxicities were observed, and no adverse events during treatment that led to interruption of study drug infusion, dose reduction, or reduction in study drug infusion rate occurred. Adverse events that occurred during the trial included decreased lymphocyte count, decreased white blood cell count, and hypokalemia.

[0414] In this study, as of July 30, 2023, a total of 53 subjects were enrolled and received at least one dose of trastuzumab + a second anti-HER2 antibody + chemotherapy, and 53 subjects were included in the safety analysis set. The most common adverse events (TEAEs) occurring during the trial were decreased platelet count (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%), decreased neutrophil count (72.2% vs 64.7% vs 55.6%), and decreased white blood cell count (72.2% vs 52.9% vs 61.1%). During the trial, grade 3 or higher adverse events occurred in 13 patients (72.2%) in Group A, 7 (41.2%) in Group B, and 8 (44.4%) in Group C. The most common adverse events were decreased platelet count and decreased neutrophil count. The efficacy data for the subjects are summarized in Table 5.

[0415] Table 5. Summary of safety data

[0416] In the experimental groups of this study, the safety data of the experimental groups (Group A and Group B), especially Group B, were basically consistent with those of the standard treatment group (Group C, trastuzumab + XELOX). No subject in the experimental group experienced adverse events of death related to the second anti-HER2 antibody, reflecting good safety and tolerability.

[0417] Summarize

[0418] Trastuzumab combined with chemotherapy, the first-line standard of care for HER2-positive advanced gastric cancer, has a median overall survival of 13.8 months and a median progression-free survival of 6.7 months. In this study, the combination of a second anti-HER2 antibody and standard of care (trastuzumab + chemotherapy) demonstrated significant efficacy advantages over current standard of care. The high-dose group (Group A) achieved a median progression-free survival of 15.1 months, exceeding the historical registration-based median overall survival. The low-dose group (Group B) had not yet achieved median progression-free survival but is expected to exceed that of Group A. Compared with the standard of care group (Group C), the hazard ratio was 0.71 (95% confidence interval: 0.04, 0.52), with a p-value of 0.0007. Therefore, the combination therapy of a second anti-HER2 antibody, trastuzumab, and chemotherapy presented in the present invention demonstrated significant efficacy advantages over standard of care while also exhibiting favorable safety and tolerability.

[0419] It should be understood that after reading the above content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma in a patient, comprising administering to the patient a therapeutically effective amount of: (1) Trastuzumab; (2) a second antibody, wherein the second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding epitope from 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 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:2, and HCDR3 as shown in SEQ ID NO:3; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises LCDR1 as shown in SEQ ID NO:6, LCDR2 as shown in SEQ ID NO:7, and LCDR3 as shown in SEQ ID NO:8; (3) Chemotherapeutic agents.

2. The method of claim 1, wherein the chemotherapeutic agent is a fluorouracil drug.

3. The method of claim 1, wherein the chemotherapeutic agent is a platinum drug.

4. The method according to any one of claims 1 to 3, wherein the chemotherapeutic agent is a combination of a fluorouracil-based drug and a platinum-based drug.

5. The method according to any one of claims 2 to 4, wherein the fluorouracil drug is selected from 5-fluorouracil and capecitabine.

6. The method according to any one of claims 3-4, wherein the platinum drug is selected from cisplatin and oxaliplatin.

7. The method according to any one of claims 2 to 6, wherein the fluorouracil drug is capecitabine.

8. The method according to any one of claims 3 to 6, wherein the platinum drug is oxaliplatin.

9. The method of any one of claims 1-8, wherein the chemotherapeutic agent is a combination of capecitabine and oxaliplatin.

10. The method of any one of claims 1-9, wherein the cancer is HER2-positive advanced gastric cancer.

11. The method of any one of claims 1-10, wherein the cancer is unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

12. The method according to any one of claims 1 to 11, wherein the heavy chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO: 4, and the light chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:

9.

13. The method according to any one of claims 1 to 12, wherein the heavy chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:5, and the light chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:

10.

14. The method of any one of claims 1-13, wherein trastuzumab is administered at a body weight-based dose of about 0.1 mg / kg to about 10 mg / kg.

15. The method of any one of claims 1-14, wherein trastuzumab is administered at 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 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 of body weight based dosage administration.

16. The method of any one of claims 1-15, wherein trastuzumab is administered at a weight-based 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.

17. The method of any one of claims 1-16, wherein trastuzumab is administered at an initial loading dose of about 8 mg / kg, followed by a dose of about 6 mg / kg, based on body weight.

18. The method of any one of claims 1-17, wherein trastuzumab is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

19. The method of any one of claims 1-18, wherein trastuzumab is administered intravenously.

20. The method of any one of claims 1-19, wherein the second antibody is administered at 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 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 / kg, about 25mg / kg to about 30mg / kg, about 26mg / kg to about 30mg / kg, about 27mg / kg to about 30mg / kg, about 28mg / kg to about 30mg / kg, about 29mg / kg to about 30mg / kg, about 0.1mg / kg to about 25mg / kg, about 0.3mg / kg to about 25mg / kg, 0.9mg / kg to about 25mg / kg, about 1mg / kg to about 25mg / kg, about 2.5mg / kg to about 25mg / kg, about 3mg / kg to about 25mg / kg, about 4mg / kg to about 25mg / kg, about 5mg / kg to about 25mg / kg, about 6mg / kg to about 25mg / kg, about 7mg / kg to about 25mg / kg, about 8mg / kg to about 25mg / kg, about 9mg / kg to about 25mg / kg, about 10mg / kg to about 25mg / kg, about 11mg / kg to about 25mg / kg, about 12mg / kg to about 25mg / kg, about 13mg / kg to about 25mg / kg, about 14mg / kg to about 25mg / kg 5mg / kg, about 15mg / kg to about 25mg / kg, about 16mg / kg to about 25mg / kg, about 17mg / kg to about 25mg / kg, about 18mg / kg to about 25mg / kg, about 19mg / kg to about 25mg / kg, about 20mg / kg to about 25mg / kg, about 21mg / kg to about 25mg / kg, about 22mg / kg to about 25mg / kg, about 23mg / kg to about 25mg / kg, about 24mg / kg to about 25mg / kg, about 0.1mg / kg to about 20mg / kg, about 0.3mg / kg to about 2 0mg / kg, 0.9mg / kg to about 20mg / kg, about 1mg / kg to about 20mg / kg, about 2.5mg / kg to about 20mg / kg, about 3mg / kg to about 20mg / kg, about 4mg / kg to about 20mg / kg, about 5mg / kg to about 20mg / kg, about 6mg / kg to about 20mg / kg, about 7mg / kg to about 20mg / kg, about 8mg / kg to about 20mg / kg, about 9mg / kg to about 20mg / kg, about 10mg / kg to about 20mg / kg, about 11mg / kg to about 20mg / kg, about 1 2mg / kg to about 20mg / kg, about 13mg / kg to about 20mg / kg, about 14mg / kg to about 20mg / kg, about 15mg / kg to about 20mg / kg, about 16mg / kg to about 20mg / kg, about 17mg / kg to about 20mg / kg, about 18mg / kg to about 20mg / kg, about 19mg / kg to about 20mg / kg, about 0.1mg / kg to about 15mg / kg, about 0.3mg / kg to about 15mg / kg, 0.9mg / kg to about 15mg / kg, about 1mg / kg to about 15mg / 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 to 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 of body weight based dosage administration. .

21. The method of any one of claims 1-20, wherein the second antibody is administered at 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. / 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, about 28 mg / kg, about 29 mg / kg or about 30 mg / kg of body weight based dosage.

22. The method of any one of claims 1-21, wherein the second antibody is administered at a body weight-based dose of about 25 mg / kg or 15 mg / kg.

23. The method of any one of claims 1-22, wherein the second antibody is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

24. The method of any one of claims 1-23, wherein the second antibody is administered intravenously.

25. The method of any one of claims 6-24, wherein oxaliplatin is administered at about 10 to about 150 mg / m 2 , about 20 to about 150 mg / m 2 , about 30 to about 150 mg / m 2 , about 40 to about 150 mg / m 2 , about 50 to about 150 mg / m 2 , about 60 to about 150 mg / m 2 , about 70 to about 150 mg / m 2 , about 75 to about 150 mg / m 2 , about 80 to about 150 mg / m 2 , about 85 to about 150 mg / m 2 , about 90 to about 150 mg / m 2 , about 95 to about 150 mg / m 2 , about 100 to about 150 mg / m 2 , about 105 to about 150 mg / m 2 , about 110 to about 150 mg / m 2 , about 115 to about 150 mg / m 2 , about 120 to about 150 mg / m 2 , about 125 to about 150 mg / m 2 , about 130 to about 150 mg / m 2 , about 135 to about 150 mg / m 2 , about 140 to about 150 mg / m 2 , about 145 to about 150 mg / m 2 , about 10 to about 140 mg / m 2 , about 20 to about 140 mg / m 2 , about 30 to about 140 mg / m 2 , about 40 to about 140 mg / m 2 , about 50 to about 140 mg / m 2 , about 60 to about 140 mg / m 2 , about 70 to about 140 mg / m 2 , about 75 to about 140 mg / m 2 , about 80 to about 140 mg / m 2 , about 85 to about 140 mg / m 2 , about 90 to about 140 mg / m 2 , about 95 to about 140 mg / m 2 , about 100 to about 140 mg / m 2 , about 105 to about 140 mg / m 2 , about 110 to about 140 mg / m 2 , about 115 to about 140 mg / m 2 , about 120 to about 140 mg / m 2 , about 125 to about 140 mg / m 2 , about 130 to about 140 mg / m 2 , about 135 to about 140 mg / m 2 , about 10 to about 130 mg / m 2 , about 20 to about 130 mg / m 2 , about 30 to about 130 mg / m 2 , about 40 to about 130 mg / m 2 , about 50 to about 130 mg / m 2 , about 60 to about 130 mg / m 2 , about 70 to about 130 mg / m 2 , about 75 to about 130 mg / m 2 , about 80 to about 130 mg / m 2 , about 85 to about 130 mg / m 2 , about 90 to about 130 mg / m 2 , about 95 to about 130 mg / m 2 , about 100 to about 130 mg / m 2 , about 105 to about 130 mg / m 2 , about 110 to about 130 mg / m 2 , about 115 to about 130 mg / m 2 , about 120 to about 130 mg / m 2 , about 125 to about 130 mg / m 2 Dosing based on body surface area.

26. The method of any one of claims 6-25, wherein oxaliplatin is administered at about 10 mg / m 2 , about 20 mg / m 2 , about 30mg / m 2 , about 40 mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 75 mg / m 2 , about 80mg / m 2 , about 85mg / m 2 , about 90mg / m 2 , about 95mg / m 2 , about 100 mg / m 2 , about 105 mg / m 2 , about 110 mg / m 2 , about 115 mg / m 2 , about 120mg / m 2 , about 125 mg / m 2 , about 130mg / m 2 , about 135mg / m 2 , about 140mg / m 2 , about 145mg / m 2 or about 150 mg / m 2 Dosing based on body surface area.

27. The method of any one of claims 6-26, wherein oxaliplatin is administered at about 130 mg / m 2 Dosing based on body surface area.

28. The method of any one of claims 6-27, wherein oxaliplatin is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

29. The method of any one of claims 6-28, wherein oxaliplatin is administered intravenously.

30. The method of any one of claims 7-29, wherein capecitabine is administered at about 100 to about 1200 mg / m 2 , about 200 to about 1200 mg / m 2 , about 300 to about 1200 mg / m 2 , about 400 to about 1200 mg / m 2 , about 500 to about 1200 mg / m 2 , about 600 to about 1200 mg / m 2 , about 650 to about 1200 mg / m 2 , about 700 to about 1200 mg / m 2 , about 750 to about 1200 mg / m 2 , about 800 to about 1200 mg / m 2 , about 850 to about 1200 mg / m 2 , about 900 to about 1200 mg / m 2 , about 950 to about 1200 mg / m 2 , about 1000 to about 1200 mg / m 2 , about 1050 to about 1200 mg / m 2 , about 1100 to about 1200 mg / m 2 , about 1150 to about 1200 mg / m 2 , about 100 to about 1100 mg / m 2 , about 200 to about 1100 mg / m 2 , about 300 to about 1100 mg / m 2 , about 400 to about 1100 mg / m 2 , about 500 to about 1100 mg / m 2 , about 600 to about 1100 mg / m 2 , about 650 to about 1100 mg / m 2 , about 700 to about 1100 mg / m 2 , about 750 to about 1100 mg / m 2 , about 800 to about 1100 mg / m 2 , about 850 to about 1100 mg / m 2 , about 900 to about 1100 mg / m 2 , about 950 to about 1100 mg / m 2 , about 1000 to about 1100 mg / m 2 , about 100 to about 1000 mg / m 2 , about 200 to about 1000 mg / m 2 , about 300 to about 1000 mg / m 2 , about 400 to about 1000 mg / m 2 , about 500 to about 1000 mg / m 2 , about 600 to about 1000 mg / m 2 , about 650 to about 1000 mg / m 2 , about 700 to about 1000 mg / m 2 , about 750 to about 1000 mg / m 2 , about 800 to about 1000 mg / m 2 , about 850 to about 1000 mg / m 2 , about 900 to about 1000 mg / m 2 or about 950 to about 1000 mg / m 2 Dosing based on body surface area.

31. The method of any one of claims 7-30, wherein capecitabine is administered at about 100 mg / m 2 , about 200 mg / m 2 , about 300mg / m 2 , about 400mg / m 2 , about 500mg / m 2 , about 600mg / m 2 , about 650mg / m 2 , about 700mg / m 2 , about 750mg / m 2 , about 800mg / m 2 , about 850mg / m 2 , about 900mg / m 2 , about 950mg / m 2 , about 1000mg / m 2 , about 1050mg / m 2 , about 1100mg / m 2 , about 1150mg / m 2 or about 1200 mg / m 2 Dosing based on body surface area.

32. The method of any one of claims 7-31, wherein capecitabine is administered at about 1000 mg / m 2 Dosing based on body surface area.

33. The method of any one of claims 7-32, wherein capecitabine is administered once daily, twice daily, or three times daily.

34. The method of any one of claims 7-33, wherein capecitabine is administered orally.

35. The method of any one of claims 1-34, 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, the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight, and oxaliplatin is administered at a dose of about 130 mg / kg based on body weight. 2 The dose based on body surface area is administered, and capecitabine is administered at about 1000 mg / m 2 Dosing based on body surface area.

36. The method of any one of claims 1-35, wherein the second antibody is administered to the patient prior to administration of trastuzumab.

37. The method of any one of claims 1-36, wherein the second antibody is administered to the patient after administration of trastuzumab.

38. The method of any one of claims 1-37, wherein trastuzumab and the second antibody are administered simultaneously.

39. The method of any one of claims 1-38, wherein the method further comprises administering an immune checkpoint inhibitor.

40. The method of claim 39, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

41. The method of claim 39 or 40, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

42. A combination therapy for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma in a patient, the treatment comprising administering to the patient a combination therapy comprising: (1) Trastuzumab; (2) a second antibody, wherein the second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding epitope from 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 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:2, and HCDR3 as shown in SEQ ID NO:3; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises LCDR1 as shown in SEQ ID NO:6, LCDR2 as shown in SEQ ID NO:7, and LCDR3 as shown in SEQ ID NO:8; (3) Chemotherapeutic agents.

43. The combination therapy of claim 42, wherein the chemotherapeutic agent is a fluorouracil.

44. The combination therapy of claim 42, wherein the chemotherapeutic agent is a platinum drug.

45. The combination therapy of any one of claims 42-44, wherein the chemotherapeutic agent is a combination of a fluorouracil-based drug and a platinum-based drug.

46. ​​The combination therapy according to any one of claims 43-45, wherein the fluorouracil drug is selected from 5-fluorouracil and capecitabine.

47. The combination therapy according to any one of claims 44-46, wherein the platinum drug is selected from cisplatin and oxaliplatin.

48. The combination therapy of any one of claims 43-47, wherein the fluorouracil is capecitabine.

49. The combination therapy of any one of claims 44-47, wherein the platinum drug is oxaliplatin.

50. The combination therapy of any one of claims 42-49, wherein the chemotherapeutic agent is a combination of capecitabine and oxaliplatin.

51. The combination therapy of any one of claims 42-50, wherein the cancer is HER2-positive advanced gastric cancer.

52. The combination therapy of any one of claims 42-51, wherein the cancer is unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

53. The combination therapy according to any one of claims 42-52, wherein the heavy chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:

9.

54. The combination therapy according to any one of claims 42-53, wherein the heavy chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:5, and the light chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:

10.

55. The combination therapy of any one of claims 42-54, wherein trastuzumab is administered at a body weight-based dose of about 0.1 mg / kg to about 10 mg / kg.

56. The combination therapy of any one of claims 42-55, wherein trastuzumab is administered at 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 kg, 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 of body weight based dosage administration.

57. The combination therapy of any one of claims 42-56, wherein trastuzumab is administered at a weight-based 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.

58. The combination therapy of any one of claims 42-57, wherein trastuzumab is administered at an initial loading dose of about 8 mg / kg, followed by a dose of about 6 mg / kg, based on body weight.

59. The combination therapy of any one of claims 42-58, wherein trastuzumab is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

60. The combination therapy of any one of claims 42-59, wherein trastuzumab is administered intravenously.

61. The combination therapy of any one of claims 42-60, wherein the second antibody is administered at 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 / kg to about 30mg / kg, about 16mg / kg to about 30mg / kg, about 17mg / kg to about 30mg / kg, about 18mg / kg to about 30mg / kg, about 19mg / kg to about 30mg / kg, about 20mg / kg to about 30mg / kg, about 21mg / kg to about 30mg / kg, about 22mg / kg to about 30mg / kg, about 23mg / kg to about 30mg / kg, about 24mg / kg to about 30m g / 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 2.5mg / kg to about 25mg / kg, about 3mg / kg to about 25mg / kg, about 4mg / kg to about 25mg / kg, about 5mg / kg to about 25mg / kg, about 6mg / kg to about 25mg / kg, about 7mg / kg to about 25mg / kg, about 8mg / kg to about 25mg / kg, about 9mg / kg to about 25mg / kg, about 10mg / kg to about 25mg / kg, about 11mg / kg to about 25mg / kg, about 12mg / kg to about 25mg / kg, about 13mg / kg to about 25mg / kg, about 14mg / kg to about 25mg / kg 5mg / kg, about 15mg / kg to about 25mg / kg, about 16mg / kg to about 25mg / kg, about 17mg / kg to about 25mg / kg, about 18mg / kg to about 25mg / kg, about 19mg / kg to about 25mg / kg, about 20mg / kg to about 25mg / kg, about 21mg / kg to about 25mg / kg, about 22mg / kg to about 25mg / kg, about 23mg / kg to about 25mg / kg, about 24mg / kg to about 25mg / kg, about 0.1mg / kg to about 20mg / kg, about 0.3mg / kg to about 2 0mg / kg, 0.9mg / kg to about 20mg / kg, about 1mg / kg to about 20mg / kg, about 2.5mg / kg to about 20mg / kg, about 3mg / kg to about 20mg / kg, about 4mg / kg to about 20mg / kg, about 5mg / kg to about 20mg / kg, about 6mg / kg to about 20mg / kg, about 7mg / kg to about 20mg / kg, about 8mg / kg to about 20mg / kg, about 9mg / kg to about 20mg / kg, about 10mg / kg to about 20mg / kg, about 11mg / kg to about 20mg / kg, about 1 2mg / kg to about 20mg / kg, about 13mg / kg to about 20mg / kg, about 14mg / kg to about 20mg / kg, about 15mg / kg to about 20mg / kg, about 16mg / kg to about 20mg / kg, about 17mg / kg to about 20mg / kg, about 18mg / kg to about 20mg / kg, about 19mg / kg to about 20mg / kg, about 0.1mg / kg to about 15mg / kg, about 0.3mg / kg to about 15mg / kg, 0.9mg / kg to about 15mg / kg, about 1mg / kg to about 15mg / 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 to 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 of body weight based dosage administration. .

62. The combination therapy of any one of claims 42-61, wherein the second antibody is administered at 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. g / 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, about 28 mg / kg, about 29 mg / kg or about 30 mg / kg of body weight based dosage.

63. The combination therapy of any one of claims 42-62, wherein the second antibody is administered at a body weight-based dose of about 25 mg / kg or 15 mg / kg.

64. The combination therapy of any one of claims 42-63, wherein the second antibody is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more.

65. The combination therapy of any one of claims 42-64, wherein the second antibody is administered intravenously.

66. The combination therapy according to any one of claims 47-65, wherein oxaliplatin is administered at about 10 to about 150 mg / m 2 , about 20 to about 150 mg / m 2 , about 30 to about 150 mg / m 2 , about 40 to about 150 mg / m 2 , about 50 to about 150 mg / m 2 , about 60 to about 150 mg / m 2 , about 70 to about 150 mg / m 2 , about 75 to about 150 mg / m 2 , about 80 to about 150 mg / m 2 , about 85 to about 150 mg / m 2 , about 90 to about 150 mg / m 2 , about 95 to about 150 mg / m 2 , about 100 to about 150 mg / m 2 , about 105 to about 150 mg / m 2 , about 110 to about 150 mg / m 2 , about 115 to about 150 mg / m 2 , about 120 to about 150 mg / m 2 , about 125 to about 150 mg / m 2 , about 130 to about 150 mg / m 2 , about 135 to about 150 mg / m 2 , about 140 to about 150 mg / m 2 , about 145 to about 150 mg / m 2 , about 10 to about 140 mg / m 2 , about 20 to about 140 mg / m 2 , about 30 to about 140 mg / m 2 , about 40 to about 140 mg / m 2 , about 50 to about 140 mg / m 2 , about 60 to about 140 mg / m 2 , about 70 to about 140 mg / m 2 , about 75 to about 140 mg / m 2 , about 80 to about 140 mg / m 2 , about 85 to about 140 mg / m 2 , about 90 to about 140 mg / m 2 , about 95 to about 140 mg / m 2 , about 100 to about 140 mg / m 2 , about 105 to about 140 mg / m 2 , about 110 to about 140 mg / m 2 , about 115 to about 140 mg / m 2 , about 120 to about 140 mg / m 2 , about 125 to about 140 mg / m 2 , about 130 to about 140 mg / m 2 , about 135 to about 140 mg / m 2 , about 10 to about 130 mg / m 2 , about 20 to about 130 mg / m 2 , about 30 to about 130 mg / m 2 , about 40 to about 130 mg / m 2 , about 50 to about 130 mg / m 2 , about 60 to about 130 mg / m 2 , about 70 to about 130 mg / m 2 , about 75 to about 130 mg / m 2 , about 80 to about 130 mg / m 2 , about 85 to about 130 mg / m 2 , about 90 to about 130 mg / m 2 , about 95 to about 130 mg / m 2 , about 100 to about 130 mg / m 2 , about 105 to about 130 mg / m 2 , about 110 to about 130 mg / m 2 , about 115 to about 130 mg / m 2 , about 120 to about 130 mg / m 2 , about 125 to about 130 mg / m 2 Dosing based on body surface area.

67. The combination therapy according to any one of claims 47-66, wherein oxaliplatin is administered at about 10 mg / m 2 , about 20 mg / m 2 , about 30mg / m 2 , about 40 mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 75 mg / m 2 , about 80mg / m 2 , about 85mg / m 2 , about 90mg / m 2 , about 95mg / m 2 , about 100 mg / m 2 , about 105 mg / m 2 , about 110 mg / m 2 , about 115 mg / m 2 , about 120mg / m 2 , about 125 mg / m 2 , about 130mg / m 2 , about 135mg / m 2 , about 140mg / m 2 , about 145mg / m 2 or about 150 mg / m 2 Dosing based on body surface area.

68. The combination therapy according to any one of claims 47-67, wherein oxaliplatin is administered at about 130 mg / m 2 Dosing based on body surface area.

69. The combination therapy of any one of claims 47-68, wherein oxaliplatin is administered about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, about once every 3-6 months, or more frequently.

70. The combination therapy according to any one of claims 47-69, wherein oxaliplatin is administered intravenously.

71. The combination therapy according to any one of claims 48-70, wherein capecitabine is administered at about 100 to about 1200 mg / m 2 , about 200 to about 1200 mg / m 2 , about 300 to about 1200 mg / m 2 , about 400 to about 1200 mg / m 2 , about 500 to about 1200 mg / m 2 , about 600 to about 1200 mg / m 2 , about 650 to about 1200 mg / m 2 , about 700 to about 1200 mg / m 2 , about 750 to about 1200 mg / m 2 , about 800 to about 1200 mg / m 2 , about 850 to about 1200 mg / m 2 , about 900 to about 1200 mg / m 2 , about 950 to about 1200 mg / m 2 , about 1000 to about 1200 mg / m 2 , about 1050 to about 1200 mg / m 2 , about 1100 to about 1200 mg / m 2 , about 1150 to about 1200 mg / m 2 , about 100 to about 1100 mg / m 2 , about 200 to about 1100 mg / m 2 , about 300 to about 1100 mg / m 2 , about 400 to about 1100 mg / m 2 , about 500 to about 1100 mg / m 2 , about 600 to about 1100 mg / m 2 , about 650 to about 1100 mg / m 2 , about 700 to about 1100 mg / m 2 , about 750 to about 1100 mg / m 2 , about 800 to about 1100 mg / m 2 , about 850 to about 1100 mg / m 2 , about 900 to about 1100 mg / m 2 , about 950 to about 1100 mg / m 2 , about 1000 to about 1100 mg / m 2 , about 100 to about 1000 mg / m 2 , about 200 to about 1000 mg / m 2 , about 300 to about 1000 mg / m 2 , about 400 to about 1000 mg / m 2 , about 500 to about 1000 mg / m 2 , about 600 to about 1000 mg / m 2 , about 650 to about 1000 mg / m 2 , about 700 to about 1000 mg / m 2 , about 750 to about 1000 mg / m 2 , about 800 to about 1000 mg / m 2 , about 850 to about 1000 mg / m 2 , about 900 to about 1000 mg / m 2 or about 950 to about 1000 mg / m 2 Dosing based on body surface area.

72. The combination therapy according to any one of claims 48-71, wherein capecitabine is administered at about 100 mg / m 2 , about 200 mg / m 2 , about 300mg / m 2 , about 400mg / m 2 , about 500mg / m 2 , about 600mg / m 2 , about 650mg / m 2 , about 700mg / m 2 , about 750mg / m 2 , about 800mg / m 2 , about 850mg / m 2 , about 900mg / m 2 , about 950mg / m 2 , about 1000mg / m 2 , about 1050mg / m 2 , about 1100mg / m 2 , about 1150mg / m 2 or about 1200 mg / m 2 Dosing based on body surface area.

73. The combination therapy according to any one of claims 48-72, wherein capecitabine is administered at about 1000 mg / m 2 Dosing based on body surface area.

74. The combination therapy of any one of claims 48-73, wherein capecitabine is administered once daily, twice daily, or three times daily.

75. The combination therapy according to any one of claims 48-74, wherein capecitabine is administered orally.

76. The combination therapy of any one of claims 42-75, 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, the second antibody is administered at a dose of about 25 mg / kg or 15 mg / kg based on body weight, and oxaliplatin is administered at a dose of about 130 mg / kg based on body weight. 2 The dose based on body surface area is administered, and capecitabine is administered at about 1000 mg / m 2 Dosing based on body surface area.

77. The combination therapy of any one of claims 42-76, wherein the second antibody is administered to the patient prior to administration of trastuzumab.

78. The combination therapy of any one of claims 42-77, wherein the second antibody is administered to the patient after administration of trastuzumab.

79. The combination therapy of any one of claims 42-78, wherein trastuzumab and the second antibody are administered simultaneously.

80. The combination therapy of any one of claims 42-79, wherein the method further comprises administering an immune checkpoint inhibitor.

81. The combination therapy of claim 80, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

82. The combination therapy of claim 80 or 81, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

83. A combination product comprising: Trastuzumab; The second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding site from the trastuzumab, comprising: a heavy chain variable region comprising HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and a light chain variable region comprising LCDR1 as shown in SEQ ID NO:6, LCDR2 as shown in SEQ ID NO:7, and LCDR3 as shown in SEQ ID NO:8; and Chemotherapeutic agents.

84. The combination product of claim 83, wherein the chemotherapeutic agent is a fluorouracil.

85. The combination product of claim 83, wherein the chemotherapeutic agent is a platinum drug.

86. A combination product according to any one of claims 83-85, wherein the chemotherapeutic agent is a combination of a fluorouracil-based drug and a platinum-based drug.

87. A combination product according to any one of claims 84-86, wherein the fluorouracil drug is selected from 5-fluorouracil and capecitabine.

88. A combination product according to any one of claims 85-87, wherein the platinum drug is selected from cisplatin and oxaliplatin.

89. A combination product according to any one of claims 84-88, wherein the fluorouracil drug is capecitabine.

90. A combination product according to any one of claims 85-89, wherein the platinum drug is oxaliplatin.

91. A combination product according to any one of claims 83-90, wherein the chemotherapeutic agent is a combination of capecitabine and oxaliplatin.

92. A combination product according to any one of claims 83-91, wherein the heavy chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:

9.

93. The combination product according to any one of claims 83-92, wherein the heavy chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:5, and the light chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:

10.

94. The combination product according to any one of claims 83-93, wherein the combination product further comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

95. The combination product according to any one of claims 83-94, wherein the combination product further comprises an anti-PD-1 antibody.

96. A pharmaceutical kit for treating HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma, the pharmaceutical kit comprising: Trastuzumab; The second antibody is a second anti-HER2 antibody or an antigen-binding fragment thereof having a different binding site from the trastuzumab, comprising: a heavy chain variable region comprising HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and a light chain variable region comprising LCDR1 as shown in SEQ ID NO:6, LCDR2 as shown in SEQ ID NO:7, and LCDR3 as shown in SEQ ID NO:8; and Chemotherapeutic agents.

97. The kit of claim 96, wherein the chemotherapeutic agent is a fluorouracil.

98. The kit of claim 96, wherein the chemotherapeutic agent is a platinum-based drug.

99. The kit of any one of claims 96-98, wherein the chemotherapeutic agent is a combination of a fluorouracil-based drug and a platinum-based drug.

100. The kit of any one of claims 97-99, wherein the fluorouracil drug is selected from 5-fluorouracil and capecitabine.

101. The kit of any one of claims 98-100, wherein the platinum drug is selected from cisplatin and oxaliplatin.

102. The kit of any one of claims 97-101, wherein the fluorouracil is capecitabine.

103. The kit of any one of claims 98-102, wherein the platinum drug is oxaliplatin.

104. The kit of any one of claims 96-103, wherein the chemotherapeutic agent is a combination of capecitabine and oxaliplatin.

105. The kit of any one of claims 96-104, wherein the cancer is HER2-positive advanced gastric cancer.

106. The kit of any one of claims 96-105, wherein the cancer is unresectable or metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

107. The kit according to any one of claims 96-106, wherein the heavy chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:4, and the light chain variable region of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:

9.

108. The kit according to any one of claims 96-107, wherein the heavy chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:5, and the light chain of the second antibody comprises or consists of the amino acid sequence shown in SEQ ID NO:

10.

109. The kit of any one of claims 96-108, further comprising instructions for use.

110. The kit of any one of claims 96-109, further comprising an anti-PD-1 / PD-L1 antibody.

111. The kit of any one of claims 96-110, further comprising an anti-PD-1 antibody.