Gastric Cancer Treatment

Abstract

A method for treating gastric cancer or gastroesophageal junction cancer in a subject is described. The method can include administering an anti-FGFR2b antibody to the subject. The method can further include administering a chemotherapy regimen to the subject that includes (a) oxaliplatin and capecitabine; or (b) oxaliplatin and S-1.

Description

[Technical field]

[0001] Embodiments herein relate to the use of antibodies against fibroblast growth factor receptor 2 (FGFR2), such as antibodies against FGFR2 isoform FGFR2-IIIb (also called FGFR2b), in the treatment of gastric cancer, such as gastric adenocarcinoma and gastroesophageal junction adenocarcinoma.

[0002] Incorporation by Reference of Electronically Submitted Materials The nucleotide / amino acid sequence listing, which was submitted contemporaneously herewith and is identified below, is incorporated herein by reference in its entirety: "10130-WO01-SEC.xml", a 13,841 byte XML document created on March 27, 2023.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 327,666, filed April 5, 2022, and U.S. Provisional Patent Application No. 63 / 491,969, filed March 24, 2023, the disclosures of which are incorporated by reference in their entireties herein. [Background technology]

[0004] Gastric cancer (GC) is the fifth most common cancer worldwide, with over 1 million new cases worldwide each year (Bray et al., 2018). China, Japan, Latin America, and Eastern Europe have the highest incidence rates (>20 per 100,000 men), while North America, parts of Africa, and Northern Europe have the lowest incidence rates (<10 per 100,000 men). Only 27% of newly diagnosed gastric cancers are localized, advanced cancers have a poor prognosis, treatment remains challenging, with a 5-year overall survival (OS) rate of <5% and little clear benefit in cancer patients with a programmed cell death receptor 1 (PD-L1) combined positive score (CPS) <5 (hazard ratio [HR] = 0.94 [95% CI: 0.78-1.14]). Thus, despite a decline in incidence, gastric cancer remains a significant health burden worldwide with a high mortality rate.

[0005] Fibroblast growth factor receptor 2b (FGFR2b) is present in the majority of gastric cancers (GC) and is a novel therapeutic target that may improve treatment outcomes. Fibroblast growth factor (FGF) family members bind to four known tyrosine kinase receptors, fibroblast growth factor receptors 1-4 (FGFR1-4) and their isoforms, with different FGFs binding to different FGFRs to different degrees (Zhang et al., J. Biol. Chem. 281:15694, 2006). The protein sequence of human FGFR2 is provided, for example, in GenBank Locus AF487553. Each FGFR consists of an extracellular domain (ECD) containing three immunoglobulin (Ig)-like domains (D1, D2, and D3), a single transmembrane helix, and an intracellular catalytic kinase domain (Mohammadi et al., Cytokine Growth Factor Revs, 16:107, 2005). FGFs bind to the receptor primarily through the D2 and D3 domains of the receptor. There is a continuous stretch of acidic amino acids in the linker between D1 and D2, called the "acid box" (AB). The domain containing D1 and AB is thought to be involved in the autoinhibition of the receptor, which is released upon ligand binding.

[0006] FGFRs are characterized by multiple alternative splicing of mRNA, resulting in various isoforms (Ornitz et al., J. Biol. Chem. 271:15292, 1996; for FGFR2 and its isoforms, see also Swiss-Prot P21802 and isoforms P21802-1 to -20). In particular, there are forms that contain all three Ig domains (α isoforms) or only the two Ig domains D2 and D3 without D1 (β isoforms). In FGFR1, FGFR2, and FGFR3, all forms contain the first half of D3, designated IIIa, but two alternative exons are utilized for the second half of D3, resulting in the IIIb and IIIc forms. For FGFR2, these are designated as FGFR2-IIIb and FGFR2-IIIc (or FGFR2b and FGFR2c, respectively), and the corresponding beta forms are designated as FGFR2(beta)IIIb and FGFR2(beta)IIIc. The FGFR2-IIIb form of FGFR2 (also designated K-sam-II) is a receptor with high affinity for both FGF1 and KGF family members (FGF7, FGF10, and FGF22), whereas FGFR2-IIIc (also designated K-sam-I) binds well to both FGF1 and FGF2, but not to KGF family members (Miki et al., Proc. Natl. Acad. Sci. USA 89:246, 1992). In fact, FGFR2-IIIb is the only receptor for KGF family members (Ornitz et al., 1996, supra) and is therefore also referred to as KGFR.

[0007] FGFRs and their isoforms are expressed differently in various tissues. FGFR2-IIIb (as well as the IIIb forms of FGFR1 and FGFR3) are expressed in epithelial tissues, whereas FGFR2-IIIc is expressed in mesenchymal tissues (Duan et al., J. Biol. Chem. 267:16076, 1992; Ornitz et al., 1996, supra). Specific FGF ligands for these receptors have opposite expression patterns. Thus, KGF subfamily members including FGF7 (KGF), FGF10, and FGF22 may be paracrine effectors of epithelial cells, since they bind only to FGFR2-IIIb (Zhang et al., supra) and are expressed in mesenchymal tissues (Ornitz et al., 1996, supra). In contrast, the FGF4 subfamily member FGF4-6 binds to FGFR2-IIIc and is expressed in both epithelial and mesenchymal lineages, and may therefore have autocrine or paracrine functions. Due to the expression patterns of FGFR2 isoforms and their ligands, FGFR2 plays a role in epithelial-mesenchymal interactions (Finch et al., Dev. Dyn. 203:223, 1995), and it is therefore not surprising that knockout of FGFR2-IIIb in mice results in severe fetal damage and lethality (De Moerlooze et al., Development 127:483, 2000). [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Bray et al., 2018 [Non-Patent Document 2] Zhang et al.,J.Biol.Chem.281:15694,2006 [Non-Patent Document 3] Mohammadi et al.,Cytokine Growth Factor Revs,16:107,2005 [Non-Patent Document 4] Ornitz et al.,J.Biol.Chem.271:15292,1996 [Non-Patent Document 5] Miki et al.,Proc.Natl.Acad.Sci.USA 89:246,1992 [Non-Patent Document 6] Duan et al.,J.Biol.Chem.267:16076,1992 [Non-Patent Document 7] Finch et al.,Dev.Dyn.203:223,1995 [Non-Patent Document 8] De Moerlooze et al.,Development 127:483,2000 Summary of the Invention [Means for solving the problem]

[0009] The present disclosure provides a method of treating gastric cancer in a subject, the method comprising administering to the subject an anti-FGFR2b antibody; and administering to the subject a chemotherapy regimen comprising: (a) oxaliplatin and capecitabine; or (b) oxaliplatin and S-1.

[0010] In some embodiments of the above methods, the anti-FGFR2b antibody is administered at a dose of at least 15 mg / kg Q3W.

[0011] In some embodiments of the above methods, the anti-FGFR2b antibody is administered Q3W at a dose of 15-22 mg / kg, or greater than 15 mg / kg to 22 mg / kg inclusive.

[0012] In some embodiments, the method further comprises administering a booster dose of 5-15 mg / kg of anti-FGFR2b antibody 7-10 days after the initial dose of Q3W administration of anti-FGFR2b antibody.

[0013] In some embodiments of the above methods, the booster dose of the anti-FGFR2b antibody is 6 to 9 mg / kg, or 7 to 8 mg / kg.

[0014] In some embodiments of the above methods, the anti-FGFR2b antibody is administered at a dose of at least 20 mg / kg Q3W.

[0015] In some embodiments of the above method, the anti-FGFR2b antibody is administered Q3W at a dose of 20-30 mg / kg, or 22-25 mg / kg, or greater than 22 mg / kg to 30 mg / kg or greater than 22 mg / kg to 25 mg / kg.

[0016] In some embodiments, the method further comprises administering a booster dose of 10-15 mg / kg of anti-FGFR2b antibody 7-10 days after the initial dose of Q3W administration of anti-FGFR2b antibody.

[0017] In some embodiments of the above methods, the booster dose of anti-FGFR2b antibody is 9 to 13 mg / kg, or 10 to 12 mg / kg.

[0018] In some embodiments of the above methods, the anti-FGFR2b antibody is administered intravenously.

[0019] In some embodiments, the method comprises administering oxaliplatin to a patient at least 65 mg / m 2 and capecitabine at a dose of at least 500 mg / m 2 twice daily orally at a dose of

[0020] In some embodiments of the above method, the oxaliplatin is 100 to 150 mg / m 2 was administered intravenously Q3W at a dose of 750–1500 mg / m 2 is administered orally twice daily.

[0021] In some embodiments, the method comprises administering oxaliplatin at least 65 mg / m 2 and S-1 at a dose of at least 20 mg / m 2twice daily orally at a dose of

[0022] In some embodiments of the above method, the oxaliplatin is 100 to 150 mg / m 2 was administered intravenously Q3W at a dose of 30–60 mg / m 2 is administered orally twice daily.

[0023] In some embodiments of the above method, the anti-FGFR2b antibody is administered intravenously at a dose of 15-22 mg / kg Q3W, with a booster dose of 7-12 mg / kg administered 7-10 days after the first dose of anti-FGFR2b antibody Q3W, and the administration of the chemotherapy regimen comprises: (a) oxaliplatin at 100-150 mg / kg Q3W. 2 Administered intravenously Q3W at a dose of 750–1500 mg / m 2 or (b) oxaliplatin at a dose of 10 to 150 mg / m 2 and S-1 was administered intravenously at a dose of 30–60 mg / m 2 The study involves administering the drug orally twice daily at a dose of

[0024] In some embodiments of the above method, the anti-FGFR2b antibody is administered intravenously at a dose of 15-22 mg / kg Q3W, with an additional dose of 7-12 mg / kg administered 7-10 days after the first administration of the Q3W regimen of the anti-FGFR2b antibody, and the administration of the chemotherapy regimen comprises: (a) oxaliplatin at 130 mg / kg; 2 1000 mg / m2 and capecitabine 1000 mg / m2 2 or (b) oxaliplatin at a dose of 130 mg / m 2 and S-1 was administered intravenously at a dose of 40 mg / m 2 The study involves administering the drug orally twice daily at a dose of

[0025] In some embodiments of the above method, the anti-FGFR2b antibody is administered intravenously at a dose of 22-30 mg / kg Q3W, with a booster dose of 10-12 mg / kg administered 7-10 days after the first dose of anti-FGFR2b antibody Q3W, and the administration of the chemotherapy regimen comprises: (a) oxaliplatin at 130 mg / kg; 2 1000 mg / m2 and capecitabine 1000 mg / m2 2 or (b) oxaliplatin at a dose of 130 mg / m 2 and S-1 was administered intravenously at a dose of 40 mg / m 2 The study involves administering the drug orally twice daily at a dose of

[0026] In some embodiments, the method further comprises administering an anti-PD-1 antibody or an anti-PD-L1 antibody to the subject.

[0027] In some embodiments of the above methods, the anti-PD-1 antibody or anti-PD-L1 antibody is administered Q3W.

[0028] In some embodiments of the above methods, the anti-PD-1 antibody comprises nivolumab, pembrolizumab, or cemiplimab, or the anti-PD-L1 antibody comprises atezolizumab, avelumab, or durvalumab.

[0029] In some embodiments, the methods further comprise administering nivolumab to the subject at a dose of at least 300 mg Q3W.

[0030] In some embodiments of the above methods, nivolumab is administered at a dose of 300 mg to 400 mg Q3W.

[0031] In some embodiments of the above methods, nivolumab is administered at a dose of 360 mg Q3W.

[0032] In some embodiments of the above methods, the anti-FGFR2b antibody comprises a heavy chain variable region comprising heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, and HCDR3 of SEQ ID NO: 8; and a light chain variable region comprising light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and LCDR3 of SEQ ID NO: 11.

[0033] In some embodiments of the above methods, the anti-FGFR2b antibody is afucosylated.

[0034] In some embodiments of the above method, the heavy chain variable region of the anti-FGFR2b antibody comprises an amino acid sequence at least 95% identical to SEQ ID NO:4, and the light chain variable region of the anti-FGFR2b antibody comprises an amino acid sequence at least 95% identical to SEQ ID NO:5.

[0035] In some embodiments of the above methods, the heavy chain variable region of the anti-FGFR2b antibody comprises the amino acid sequence of SEQ ID NO:4 and the light chain variable region of the anti-FGFR2b antibody comprises the amino acid sequence of SEQ ID NO:5.

[0036] In some embodiments of the above methods, the anti-FGFR2b antibody comprises a heavy chain of SEQ ID NO:1 and a light chain of SEQ ID NO:2.

[0037] In some embodiments of the above methods, the anti-FGFR2b antibody is bemarituzumab.

[0038] In some embodiments of the above methods, the cells of the gastric cancer overexpress FGFR2b.

[0039] In some embodiments of the above methods, the cells of the gastric cancer overexpress FGFR2b mRNA or protein, or contain an amplification of the FGFR2 gene.

[0040] In some embodiments of the above methods, the cells of the gastric cancer overexpress FGFR2b, as determined by immunohistochemistry (IHC).

[0041] In some embodiments of the above methods, at least 5%, 10%, 15%, or 20% of cells in the gastric cancer express FGFR2b as determined by IHC.

[0042] In some embodiments of the above methods, the gastric cancer cells have an FGFR2b staining intensity of at least 2+ or 3+ as measured by IHC, e.g., at least 5%, 10%, 15%, or 20% of the gastric cancer cells have said FGFR2b staining intensity.

[0043] In some embodiments of the above methods, the subject's gastric cancer overexpresses FGFR2b as determined by an FGFR2b staining intensity of at least 2+, or 3+ in any cell of the gastric cancer sample, as measured by IHC.

[0044] In some embodiments of the above methods, the subject's gastric cancer overexpresses FGFR2b as determined by an FGFR2b staining intensity of at least 2+, or 3+ in at least 10% of cells in the gastric cancer sample, as measured by IHC.

[0045] In some embodiments of the above methods, the gastric cancer comprises gastric cancer or gastroesophageal junction cancer.

[0046] In some embodiments of the above methods, the chemotherapy regimen comprises (a) oxaliplatin and capecitabine. [Brief description of the drawings]

[0047] [Figure 1] FIG. 1 is an illustration of a method for treating gastric cancer. [Figure 2A] Figures 2A-B are diagrams of amino acid sequences: Figure 2A shows the amino acid sequence of an anti-FGFR2b antibody of some embodiments; Figure 2B shows the amino acid sequence of FGFR2 of some embodiments. [Figure 2B] Figures 2A-B are diagrams of amino acid sequences: Figure 2A shows the amino acid sequence of an anti-FGFR2b antibody of some embodiments; Figure 2B shows the amino acid sequence of FGFR2 of some embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] Provided herein is a method for treating gastric cancer in a subject. Gastric cancer cells can overexpress the FGFR2 isoform FGFR2-IIIb (also known as FGFR2b). The method can include administering an anti-FGFR2b antibody, such as bemarituzumab, to the subject. The method can further include administering a chemotherapy regimen, such as oxaliplatin and capecitabine (CAPOX) or oxaliplatin and S-1 (SOX). The anti-FGFR2b antibody can be administered with CAPOX or SOX in the same composition, or in separate compositions (sequentially or simultaneously). It is contemplated herein that the dosing of anti-FGFR2b antibody monotherapy can be aligned with CAPOX and SOX regimens, typically once every three weeks (Q3W). For example, the anti-FGFR2b antibody may be administered to the subject Q3W at a dose of at least 15 mg / kg, e.g., 15-22 mg / kg, more than 15 mg / kg to 22 mg / kg or less, 20-30 mg / kg, 22-25 mg / kg, more than 22 mg / kg to 30 mg / kg or less, or more than 22 mg / kg to 25 mg / kg or less. For example, the anti-FGFR2b antibody may be administered to the subject Q3W at a dose of at least 15 mg / kg or at least 20 mg / kg. In some embodiments, the method further comprises administering to the subject an additional dose of about 5-15 mg / kg of the anti-FGFR2b antibody 7-10 days after the first dose of the Q3W administration of the anti-FGFR2b antibody. For example, the additional dose of anti-FGFR2b antibody can be about 10-15 mg / kg (e.g., 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, or 15 mg / kg) administered 7-10 days after the first administration of Q3W administration of anti-FGFR2b antibody. For example, anti-FGFR2b antibody can be administered Q3W to a subject at a dose of at least 15 mg / kg (e.g., 15-22 mg / kg) in the first administration, and an additional dose of 5-15 mg / kg (e.g., 6-9 mg / kg, 7-8 mg / kg, 9-13 mg / kg, or 10-12 mg / kg) of anti-FGFR2b antibody can be administered 7-10 days after the first administration of anti-FGFR2b antibody.

[0049] The administration schedule of the anti-FGFR2b antibody can be synchronized with the administration schedule of oxaliplatin and capecitabine (CAPOX) or oxaliplatin and S-1 (SOX) to minimize the number of administration sessions for a subject.

[0050] Fibroblast growth factor receptor 2b (FGFR2b) is present in the majority of gastric cancers. Although results vary widely based on the assay used and tumor stage, up to 61% of gastric cancer patients have been reported to have tumors that overexpress FGFR2b (Ahn et al., 2016; Tokunaga et al., 2016; Han et al., 2015). Fibroblast growth factor receptor (FGFR) signaling plays an important role in cell proliferation and survival (Katoh and Katoh, 2006).

[0051] A recent study evaluating the pathological and prognostic significance of FGFR2 overexpression in gastric cancer patients, including 4294 patients from 10 studies, found that gastric cancers overexpressing FGFR2 were associated with significantly poorer survival compared with tumors with low FGFR2 expression (HR = 1.40, 95% CI: 1.25-1.58; p < 0.00001) ( Kim et al., 2019 ), suggesting that inhibition of FGFR2b may be an important therapeutic target ( Jung et al., 2012 ; Matsumoto et al., 2012 ).

[0052] Chemotherapy for advanced gastric cancer extends survival and improves symptoms (Waddell et al., 2014; Kang et al., 2009; Okines et al., 2009; Al-Batran et al., 2008; Wagner et al., 2006). Platinum-fluoropyrimidine combinations have become frequently used combinations (Kang et al., 2009) and have been confirmed to be superior to monotherapy and best supportive care in a recent meta-analysis (Wagner et al., 2006). Although there is no single standard, globally accepted first-line reference chemotherapy regimen for advanced gastric cancer, the combination of a fluoropyrimidine (5-FU, capecitabine or S-1) and a platinum agent (cisplatin or oxaliplatin) is the accepted standard of care in both Western and Asian countries (Kang et al., 2009; Okines et al., 2009; Al-Batran et al., 2008; Keam et al., 2008; Wagner et al., 2006).

[0053] Anti-FGFR2b antibody As used herein, "antigen binding protein" has its normal and customary meaning as would be understood by one of skill in the art in light of the present disclosure. It refers to a protein that specifically binds to a particular antigen. The term encompasses intact antibodies, as well as derivatives, variants, fragments, and mutants thereof. Antigen binding proteins also include bivalent and multivalent constructs, as well as bispecific and multispecific constructs, as well as domain antibodies, scFvs, and both membrane-bound and soluble receptors. In some embodiments, the antigen binding protein comprises, consists essentially of, or consists of an antibody. In any of the methods described herein, an anti-FGFR2b antigen binding protein can be administered to a subject. By way of example, the antigen binding protein can comprise or consist of an antibody, such as bemarituzumab.

[0054] An antibody is an example of an antigen-binding protein. As used herein, "antibody" has its normal, customary meaning as would be understood by one of skill in the art in light of the present disclosure. It refers to any isotype of immunoglobulin that specifically binds to a target antigen, including, for example, chimeric antibodies, humanized antibodies, fully human antibodies, and monoclonal antibodies. Thus, "antibody" is a subgenus of antigen-binding proteins. For example, a human or humanized antibody can be of any isotype, such as IgG (including IgG1, IgG2, IgG3, and IgG4 subtypes), IgA (including IgA1 and IgA2 subtypes), IgM, and IgE. A human IgG antibody generally comprises two full-length heavy chains and two full-length light chains. An antibody may be derived from only a single source or may be "chimeric," i.e., different portions of the antibody may be derived from two or more different antibodies from the same or different species. Of course, once an antibody is obtained from a source, the antibody may be subjected to further manipulation, for example to enhance stability and folding. Thus, it will be understood that a "human" antibody can be derived from a source and may have been further engineered, for example in the Fc region. An engineered antibody may still be referred to as a type of human antibody. Similarly, unless otherwise specified, variants of human antibodies, such as those that have undergone affinity maturation, will also be understood to be "human antibodies." In some embodiments, the antigen binding protein comprises, consists essentially of, or consists of a human monoclonal antibody, a humanized monoclonal antibody, or a chimeric monoclonal antibody.

[0055] A "heavy chain" of an antigen binding protein (e.g., an antibody) comprises a variable region ("VH") and three constant regions: CH1, CH2, and CH3. A "light chain" of an antigen binding protein (e.g., an antibody) comprises a variable region ("VL") and a constant region ("CL"). Human light chains include kappa and lambda chains.

[0056] "Antigen-binding region" refers to a protein or a portion of a protein that specifically binds to a particular antigen. For example, that portion of an antigen-binding protein that contains amino acid residues that interact with an antigen and confer its specificity and affinity for the antigen to the antigen is referred to as the "antigen-binding region". An antigen-binding region typically includes one or more "complementary binding regions" ("CDRs") of an antibody. A "CDR" is an amino acid sequence that contributes to the specificity and affinity of antigen binding. Antigen-binding regions of antibody heavy and light chains generally exhibit the same overall structure, including relatively conserved framework regions (FRs) linked by three CDRs. The CDRs of the two chains of each heavy / light chain pair are typically aligned by the framework regions to form a structure that specifically binds to a particular epitope of a target protein. From the N-terminus to the C-terminus, both naturally occurring light and heavy chain variable regions typically have these elements in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. A numbering system has been devised to assign numbers to the amino acids that occupy each position in these domains. This numbering system is defined in Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, National Institutes of Health, Bethesda, Md.), or Chothia & Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:878-883. In some embodiments, the CDRs of an antigen binding protein are defined according to the Kabat or Chothia definition.

[0057] Antigen binding proteins against FGFR2b, such as antibodies, can be used in the methods described herein. The antibodies can specifically bind to FGFR2b. In some embodiment methods, the anti-FGFR2b antigen binding protein binds to FGFR2b with higher affinity than to FGFR2-IIIc. For example, the anti-FGFR2b antibody cannot detectably bind to FGFR-IIIc. In some embodiment methods, the anti-FGFR2b antigen binding protein (e.g., an antibody) binds to FGFR2b and blocks or inhibits signal transduction through the FGFR2b receptor. For example, binding of the anti-FGFR2b antigen binding protein (e.g., an antibody) to FGFR2b can inhibit phosphorylation of FGFR2 or downstream MAP kinase of FGFR2. In some embodiment methods, the anti-FGFR2b antigen binding protein (e.g., an antibody), upon binding to FGFR2b, inhibits binding between FGFR2b and its FGF ligands, such as FGF1 and / or FGF2.

[0058] Binding of antigen binding proteins (e.g., antibodies) to FGFR2b and inhibition of binding between FGFR2b and FGF can be assessed by ELISA assays, e.g., as described in U.S. Pat. No. 8,101,723, or chip-based assays, e.g., as described in Example 2 of WO 2015 / 017600. In some embodiments, the antibodies induce ADCC activity, and in some embodiments have enhanced ADCC activity, e.g., as described in WO 2015 / 017600. ADCC activity can be determined, e.g., as described in Example 3 of WO 2015 / 07600. In some embodiments, the antibodies can inhibit human tumor growth in mouse models, e.g., as shown in Example 1 of WO 2017 / 091577. In some embodiments, the anti-FGFR2-IIIb antibody can increase the number of one or more of PD-L1 positive cells, NK cells, CD3+ T cells, CD4+ T cells, CD8+ T cells, and macrophages in tumor tissue of a mouse tumor model compared to a control, for example as described in Example 2 of International Application WO 2017 / 091577.

[0059] Any of the anti-FGFR2b antibodies described herein may be afucosylated. For example, the antibody may be an IgG1 or IgG3 antibody lacking fucose at Asn297. As used herein, an "afucosylated" antibody or an "antibody lacking fucose" refers to an IgG1 or IgG3 isotype antibody lacking fucose in its constant region glycosylation. Glycosylation of human IgG1 or IgG3 occurs at Asn297 (N297; EU numbering of Fc region residues) as a core fucosylated biantennary complex oligosaccharide glycosylation terminating with up to two Gal residues. In some embodiments, an afucosylated antibody lacks fucose at Asn297. These structures are designated G0, G1 (α1,6 or α1,3) or G2 glycan residues depending on the amount of terminal Gal residues. See, for example, Raju, TS, BioProcess Int. 1:44-53 (2003). CHO-type glycosylation of antibody Fc is described, for example, in Routier, FH, Glycoconjugate J. 14:201-207 (1997). It will be understood that compositions containing monoclonal antibodies are often heterogeneous. As a practical matter, the method comprising administering an afucosylated anti-FGFR2 antibody described herein may further comprise administering an antibody molecule that is not afucosylated. In a population of antibodies, an antibody is considered to be afucosylated if less than 5% of the population comprises fucose at Asn297. For example, in some embodiments, more than 95% of the anti-FGFR2b antibody molecules administered to a subject are afucosylated. For example, in some embodiments, at least 96%, 97%, or 99% of the anti-FGFR2b antibody molecules administered to a subject may be afucosylated. Additional antibodies that may be used in embodiments herein include those described in U.S. Patent Application Publication No. 2015 / 0050273, which describes certain afucosylated anti-FGFR2b antibodies and is incorporated by reference in its entirety.

[0060] In some embodiments, the afucosylated anti-FGFR2b antibody mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in the presence of human effector cells more effectively than an antibody having the same amino acid sequence that includes fucose. Generally, ADCC activity can be determined using the in vitro ADCC assays disclosed in US Patent Publication No. 2015 / 0050273, although other assays or methods for determining ADCC activity, such as in animal models, are also contemplated.

[0061] An example of the sequence of an anti-FGFR2b antibody of some embodiments is shown in Figure 2A. In some embodiments, the anti-FGFR2b antibody comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) selected from (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, (d) LCDR1 of SEQ ID NO: 9, (e) LCDR2 of SEQ ID NO: 10, and (f) LCDR3 of SEQ ID NO: 11. The anti-FGFR2b may comprise a heavy chain comprising a heavy chain variable region comprising HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, and HCDR3 of SEQ ID NO: 8, and may further comprise a light chain comprising a light chain variable region comprising LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9. In some embodiments, the heavy chain variable region is at least 90% identical to SEQ ID NO: 4, and the light chain variable region is at least 90% identical to SEQ ID NO: 5. In some embodiment methods, the heavy chain variable region is at least 95% identical to SEQ ID NO:4 and the light chain variable region is at least 95% identical to SEQ ID NO:5. In some embodiments, the heavy chain variable region comprises SEQ ID NO:4 and the light chain variable region comprises SEQ ID NO:5. In some embodiment methods, the heavy chain comprises SEQ ID NO:2 and the light chain comprises SEQ ID NO:3. Any of the anti-FGFR2 antibodies described herein may be afucosylated. For example, the antibody may be an IgG1 or IgG3 antibody lacking fucose at Asn297. In some embodiments, the anti-FGFR2b antibody is bemarituzumab.

[0062] In some embodiments, the anti-FGFR2b antibody comprises a heavy chain variable region comprising SEQ ID NO: 4 and a light chain variable region comprising SEQ ID NO: 5. In some embodiments, it is further contemplated that the anti-FGFR2b antibody comprises one or more substitutions, insertions or deletions compared to SEQ ID NO: 4 and / or SEQ ID NO: 5 and continues to bind to FGFR2b. For example, the anti-FGFR2b antibody comprises one or more substitutions, insertions or deletions compared to SEQ ID NO: 4 and / or SEQ ID NO: 5 and may bind to FGFR2b with an affinity that is one or more orders of magnitude lower than the affinity of a reference anti-FGFR2b antibody comprising a heavy chain variable region comprising SEQ ID NO: 4 and a light chain variable region comprising SEQ ID NO: 5, as measured by surface plasmon resonance. In some embodiment methods, the anti-FGFR2b antibody comprises a heavy chain variable region that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4 and a light chain variable region that is at least 90% identical to SEQ ID NO: 5. In some embodiments, the anti-FGFR2b antibody comprises a heavy chain variable region at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4 and a light chain variable region at least 91% identical to SEQ ID NO: 5. In some embodiments, the anti-FGFR2b antibody comprises a heavy chain variable region at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4 and a light chain variable region at least 95% identical to SEQ ID NO: 5. In some embodiments, the anti-FGFR2b antibody comprises a heavy chain variable region at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4 and a light chain variable region at least 97% identical to SEQ ID NO: 5. In some embodiment methods, the anti-FGFR2b antibody comprises a heavy chain variable region at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4 and a light chain variable region of SEQ ID NO: 5. In some embodiment methods, the anti-FGFR2b antibody comprises a heavy chain variable region at least 90% identical to SEQ ID NO: 4 and a light chain variable region at least 90% identical to SEQ ID NO: 5.In some embodiments, the heavy chain variable region is at least 95% identical to SEQ ID NO: 4, and the light chain variable region is at least 95% identical to SEQ ID NO: 5. In some embodiments, a total of 1 to 10 amino acids are substituted, inserted and / or deleted in SEQ ID NO: 4. The substitution, insertion or deletion may occur in the region outside the CDR (i.e., in the FR). In some embodiments, a total of 1 to 10, 1 to 5 or 1 to 3 amino acids are substituted, inserted and / or deleted in SEQ ID NO: 5. The substitution, insertion or deletion may occur in the region outside the CDR (i.e., in the FR). In some embodiments, a total of 1 to 10, 1 to 5 or 1 to 3 amino acids are substituted, inserted and / or deleted in SEQ ID NO: 4. The substitution, insertion or deletion may occur in the region outside the CDR (i.e., in the FR). In some embodiments, up to 10, up to 5, or up to 3 amino acids are substituted, inserted, and / or deleted in SEQ ID NO:5, and up to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO:4. The substitutions, insertions, or deletions may occur in regions outside the CDRs (i.e., in the FRs). In some embodiments, up to 10, up to 5, or up to 3 amino acids are substituted, inserted, and / or deleted in SEQ ID NO:5, and up to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO:4. The substitutions, insertions, or deletions may occur in regions outside the CDRs (i.e., in the FRs). In some embodiments, up to 10, up to 5, or up to 3 amino acids are substituted, inserted, and / or deleted in SEQ ID NO:5, and up to 3 amino acids are substituted, inserted, and / or deleted in SEQ ID NO:4. The substitutions, insertions, or deletions may occur in regions outside the CDRs (i.e., in the FRs). In some embodiments, a total of 1-10, 1-5, or 1-3 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 4. Any of the anti-FGFR2 antibodies described herein may be afucosylated. For example, the antibody may be an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0063] Further examples of anti-FGFR2b antibodies are the HuGAL-FR21, GAL-FR22 and GAL-FR23 antibodies described in U.S. Pat. No. 8,101,723B2, which are incorporated herein by reference in their entirety. Figures 13 and 14 of U.S. Pat. No. 8,101,723B2 show the amino acid sequences of the variable region and full-length mature antibody chain of HuGAL-FR21, which are incorporated herein by reference in their entirety. The heavy chain variable region sequence of antibody HuGAL-FR21 is underlined in Figure 13 of U.S. Pat. No. 8,101,723B2, which are specifically incorporated herein by reference. For example, the light and heavy chain variable regions of GAL-FR22 are provided in Patent No. 8,101,723B2 as SEQ ID NOs: 7 and 8, while the Kabat CDRs and the light and heavy chain variable regions are also provided in FIG. 16 of that patent, which is incorporated herein by reference. Hybridomas producing GAL-FR21, GAL-FR22 and GAL-FR23 have been deposited with the American Type Culture Collection, PO Box 1549, Manassas VA, USA, 20108 under ATCC numbers 9586, 9587 and 9408 on November 6, 2008, November 6 and August 12, 2008, respectively. Thus, in some embodiments, the FGFR2 antibody is an antibody that comprises the amino acid sequence of an antibody obtained from one of these three hybridoma lines.

[0064] Bemarituzumab is an afucosylated humanized monoclonal antibody targeting FGF receptor isoform 2b (FGFR2b) with a dual mechanism of fibroblast growth factor (FGF) binding inhibition and antibody-dependent cellular cytotoxicity. The anti-FGFR2b antibody of any of the methods described herein can be bemarituzumab. Bemarituzumab comprises a heavy chain of SEQ ID NO:2 and a light chain of SEQ ID NO:3. In some embodiment methods, the anti-FGFR2 antibody comprises a heavy chain of SEQ ID NO:2 and a light chain of SEQ ID NO:3 and is afucosylated. In some embodiment methods, the anti-FGFR2b antibody is bemarituzumab. In some embodiment methods, the anti-FGFR2b antibody comprises HCDR1-3 and LCDR1-3 of bemarituzumab. Bemarituzumab can be produced in a Chinese hamster ovary cell line lacking the FUT8 gene, such that the produced antibody is glycosylated but lacks core fucose in the polysaccharide portion of the antibody. The absence of core fucose may result in higher affinity for the Fc receptor FcγRIIIa compared to fucosylated molecules, potentially enhancing immune cell-mediated tumor cell killing.

[0065] Bemarituzumab inhibits FGF ligand-stimulated FGFR2b phosphorylation and cell proliferation in cell cultures of gastric and breast cancer cell lines that overexpress FGFR2b. Bemarituzumab also inhibits tumor growth in gastric and breast xenograft models that overexpress FGFR2b. Without being limited by theory, it is believed that the mechanism of action of bemarituzumab may include blocking ligand binding and downstream signaling, reducing the expression of FGFR2b driver proteins, and / or enhancing ADCC. Furthermore, without being limited by theory, it is believed that bemarituzumab is specific for the FGFR2b receptor and therefore does not interfere with the signaling of other FGF / FGFRs, such as FGFR2c. In contrast to FGFR tyrosine kinase inhibitors (TKIs), bemarituzumab does not inhibit FGF23 signaling. FGF23 is a ligand involved in calcium / phosphate metabolism and therefore treatment with bemarituzumab is not associated with FGFR TKI-associated hyperphosphatemia (Catenacci et al., 2020; Dienstmann et al., 2014; Sequist et al., 2014; Andre et al., 2013; Brown et al., 2005).

[0066] Bemarituzumab monotherapy has been investigated in a Phase 1 dose-finding study (FPA144-001) and in combination with mFOLFOX6 chemotherapy for FGFR2b-positive gastric cancer in the FIGHT study. Bemarituzumab efficacy correlated with the degree of FGFR2b overexpression by immunohistochemistry (IHC) in gastric cancer and demonstrated a manageable safety profile in combination with mFOLFOX6. Genomic and IHC data suggest that rates of FGFR2b overexpression may also be significant in other carcinomas.

[0067] Bemarituzumab inhibits phosphorylation of FGFR2b, downregulating the receptor and inhibiting downstream signaling. The effect on downstream signaling was measured by examining phosphorylation of a protein that is directly phosphorylated by the FGFR2 protein, FGFR substrate-2 (FRS2). Each of these mechanisms has been explored in vitro and in vivo and, without being limited by theory, is likely to contribute to the antitumor activity of bemarituzumab. In FGFR2b-overexpressing human tumor xenograft models, bemarituzumab shows dose-related antitumor activity, with regressions and complete responses at well-tolerated doses.

[0068] Bemarituzumab demonstrated consistent pharmacokinetic (PK) behavior following intravenous (IV) administration in rats and cynomolgus monkeys, and the observed PK characteristics were consistent across all studies. Half-life was dose-dependent, ranging from 0.8 days at the lowest dose (1–1.5 mg / kg) tested in cynomolgus monkeys to at least 8 days at the highest dose (100–150 mg / kg). Bemarituzumab demonstrated dose-dependent nonlinear PK, characterized by rapid clearance at the terminal phase of the plasma concentration-time profile and a greater than dose-proportional increase in exposure (area under the concentration-time curve [AUC]) with increasing dose. Target-mediated clearance was saturable and characterized by a dose-proportional increase in exposure at doses above this level when administered at weekly intervals. PK studies supporting the toxicokinetic studies demonstrated a dose-dependent increase in exposure (AUC), supporting the reliability of these studies for assessing toxicity. Studies of pre- and postnatal development have shown significant reproductive and developmental toxicity in embryo-fetal development at all doses (5-100 mg / kg / dose). Therefore, in some embodiments, it is contemplated that subjects treated with bemarituzumab will not be pregnant.

[0069] Bemarituzumab has demonstrated an acceptable safety profile. Identified risks when used in combination with mFOLFOX6 include corneal toxicity, injection-related reactions, gastrointestinal toxicity (stomatitis and mucosal inflammation), nail toxicity, and increased AST and ALT. Corneal events are very common with bemarituzumab, with the most common adverse event being dry eye. Nearly all events are not serious, but events that can lead to reduced vision, such as grade 3 ulcerative keratitis and punctate keratitis, have been observed. The majority of corneal events typically resolve with interruption or discontinuation of treatment and standard care interventions for corneal events. Therefore, in some embodiments, it is contemplated that subjects treated with bemarituzumab will be further treated with an ocular lubricant. Ocular lubricants can be administered prophylactically to reduce the risk of corneal events.

[0070] In some methods described herein, bemarituzumab may be provided in a pharmaceutical composition that comprises, or consists essentially of, an aqueous solution at pH 6.0 comprising 20 mg / mL bemarituzumab, L-histidine, sucrose, and polysorbate 20. For example, the solution may comprise, consist essentially of, or consist of 20 mg / mL bemarituzumab, 20 mM L-histidine, 270 nM sucrose, and 0.01% (w / v) polysorbate 20 at pH 6.0.

[0071] Anti-FGFR2b antibodies, such as bemarituzumab, may be administered intravenously using the methods described herein.

[0072] CAPOX CAPOX (also known as XELOX) is a chemotherapy regimen containing capecitabine and oxaliplatin, which is indicated for the treatment of advanced stage colorectal cancer. The most common (≧30%) side effects of capecitabine include diarrhea, hand-foot syndrome, nausea, vomiting, abdominal pain, fatigue / weakness, and hyperbilirubinemia. Other side effects, including serious side effects, have been reported (Capecitabine (XELODA®) Prescribing Information, 2021). The most common (≧40%) side effects of oxaliplatin include peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increased transaminases and alkaline phosphatases, diarrhea, vomiting, fatigue, and stomatitis.

[0073] Oxaliplatin can be administered intravenously as described herein, and capecitabine can be administered orally.

[0074] SOX SOX is a chemotherapy regimen that includes tegafur / gimeracil / oteracil (S-1) and oxaliplatin. S-1 combines tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. Tegafur is a metabolically activated prodrug of 5-FU, and 5-chloro-2,4-dihydropyridine (CDHP) and potassium oxonate (Oxo) are modulators, where CDHP inhibits 5-FU degradation and Oxo suppresses the activation of 5-FU in the gastrointestinal (GI) tract by inhibiting its activation in mucosal cells (Shirasaka, 2008).

[0075] S-1 has been shown to be non-inferiorly effective to 5-FU monotherapy in previously untreated metastatic gastric cancer, and SOX has been shown to have an improved safety profile and comparable efficacy to S-1 and cisplatin (Boku et al., 2009; Yamada et al., 2014). The most common side effects of S-1 in combination with oxaliplatin include leukopenia (40% or greater), neutropenia, anemia, thrombocytopenia, AST and ALT elevations, diarrhea, nausea, fatigue, and sensory neuropathy.

[0076] Oxaliplatin can be administered intravenously as described herein, and S-1 can be administered orally.

[0077] PD-1 / PD-L1 antibody In some embodiments, the method of the present disclosure further comprises administering an anti-PD-1 antibody or an anti-PD-L1 antibody to a subject. The PD-1 / PD-L1 axis is involved in suppressing T cell immune responses in cancer. Antagonists of this pathway have been clinically validated in many solid tumor indications. Monoclonal antibodies targeting the PD-1 pathway have been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma. Exemplary anti-PD-1 antibodies include, but are not limited to, nivolumab, pembrolizumab, and cemiplimab. Exemplary anti-PD-L1 antibodies include, but are not limited to, atezolizumab, avelumab, and durvalumab.

[0078] Nivolumab, a PD-1 antibody that blocks interaction with PD-L1, has recently been approved in the United States in combination with fluoropyrimidine and platinum-containing chemotherapy. Nivolumab (also known as "OPDIVO®") is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively inhibits interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking downregulation of antitumor T cell function (U.S. Pat. No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56).

[0079] Treatment of stomach cancer A method comprising administering an anti-FGFR2b antibody Described herein are methods of treating gastric cancer, such as gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, in a subject. The methods can include administering an anti-FGFR2b antibody to the subject Q3W at a dose of at least 15 mg / kg. The methods can further include administering an additional dose of 5-15 mg / kg of anti-FGFR2b antibody 7-10 days after the first dose of the Q3W administration of anti-FGFR2b antibody. The additional dose can be referred to as an "intervening" dose. In some of the methods, the anti-FGFR2b antibody is administered to the subject Q3W at a dose of greater than 15 mg / kg to 22 mg / kg or less (e.g., 15-22 mg / kg). In some of the methods, the anti-FGFR2b antibody is administered to the subject at a dose of about 15 mg / kg, about 17 mg / kg, about 20 mg / kg, about 22 mg / kg, about 25 mg / kg, or about 30 mg / kg, e.g., any two ranges of these recited values, e.g., 15-17 mg / kg, 17-20 mg / kg, 17-22 mg / kg, 17-25 mg / kg, 20-22 mg / kg, 20-25 mg / kg, 22-25 mg / kg, 20-30 mg / kg, greater than 22 mg / kg to 30 mg / kg or less, or greater than 22 mg / kg to 25 mg / kg or less, Q3W. In some of the methods, the anti-FGFR2b antibody is administered to the subject at a dose of 15 mg / kg, Q3W. According to some methods described herein, the additional dose or "intervening" dose can be 5-15 mg / kg (e.g., 10-15 mg / kg) and can be administered 7-10 days after the first dose of the Q3W administration of anti-FGFR2b antibody. According to some methods described herein, the additional dose or "intervening" dose can be 6-9 mg / kg, 7-8 mg / kg, 9-13 mg / kg, or 10-12 mg / kg and can be administered 7-10 days after the first dose of the Q3W administration of anti-FGFR2b antibody. By way of example, the additional dose or "intervening" dose can be about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11 mg / kg, about 11.5 mg / kg, or about 12 mg / kg, 7 to 10 days after the first dose of Q3W administration of anti-FGFR2b antibody. In any of the methods described herein, the anti-FGFR2b antibody can be bemarituzumab.

[0080] A method of treating gastric cancer in a subject, according to some embodiments, is shown in Figure 1. The method may include administering an anti-FGFR2b antibody to the subject Q3W at a dose of at least 15 mg / kg or at least about 20 mg / kg, e.g., 15-22 mg / kg, 15-20 mg / kg, 15-17 mg / kg, 17-20 mg / kg, 17-22 mg / kg, 17-25 mg / kg, 20-22 mg / kg, 20-25 mg / kg, 22-25 mg / kg, 25-30 mg / kg, 20-30 mg / kg, about 15 mg / kg, about 17 mg / kg, about 20 mg / kg, about 22 mg / kg, about 25 mg / kg, or about 30 mg / kg. The method may further include administering to the subject an additional dose of 5 to 15 mg / kg or 10 to 15 mg / kg, for example, 8 mg / kg, 7 to 7.5 mg / kg, 7.5 to 8 mg / kg, 7.5 to 9 mg / kg, 7.5 to 10 mg / kg, 7 to 9 mg / kg, 7 to 10 mg / kg, 10 to 12 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, or about 11 mg / kg of anti-FGFR2b antibody 7 to 10 days after the initial administration of the anti-FGFR2b antibody.

[0081] In some embodiments, the method may include administering an anti-FGFR2b antibody to a subject at a dose of about 15 mg / kg Q3W, followed by a booster dose of 7.5 mg / kg of anti-FGFR2b antibody 7-10 days after the first administration of the anti-FGFR2b antibody. For example, the method may include administering an anti-FGFR2b antibody to a subject at a dose of about 15 mg / kg Q3W, followed by a booster dose of about 7.5 mg / kg of anti-FGFR2b antibody 8 days after the first administration of the anti-FGFR2b antibody. In other embodiments, the method may include administering an anti-FGFR2b antibody to a subject at a dose of about 22 mg / kg Q3W, followed by a booster dose of 11 mg / kg of anti-FGFR2b antibody 7-10 days after the first administration of the anti-FGFR2b antibody. For example, the method may include administering an anti-FGFR2b antibody to a subject at a dose of about 22 mg / kg Q3W, followed by administering a booster dose of about 11 mg / kg of anti-FGFR2b antibody 8 days after the first administration of the anti-FGFR2b antibody.

[0082] Methods Comprising Administering Anti-FGFR2b Antibody and CAPOX (Oxaliplatin and Capecitabine) or SOX (Oxaliplatin and S-1) In some embodiments, the methods described herein may further comprise administering oxaliplatin and capecitabine (CAPOX) to the subject. In other embodiments, the methods may further comprise administering oxaliplatin and S-1 (SOX). In any of the methods described herein, the anti-FGFR2b antibody may be bemarituzumab.

[0083] A method of treating gastric cancer in a subject, according to some embodiments, is shown in Figure 1. The method may include administering to the subject a first administration of an anti-FGFR2b antibody at a dose of at least 15 mg / kg, e.g., at least 20 mg / kg, at least 22 mg / kg, 25 mg / kg, 20-25 mg / kg, 20-30 mg / kg, or 25-30 mg / kg. The anti-FGFR2b antibody may be administered intravenously. The method may include administering CAPOX to the subject Q3W, e.g., oxaliplatin at a dose of at least 65 mg / m 2 Q3W at a dose of 65 mg / m 2 ~150mg / m 2 Q3W) and capecitabine at a dose of at least 500 mg / m 2 (e.g., 500 mg / m 2 ~1500mg / m 2 ) twice daily. For example, oxaliplatin may be administered orally at a dose of about 100-150 mg / m 2 (For example, 100-120 mg / m 2 , 120-130mg / m 2 , 130-140mg / m 2 , or 140 to 150 mg / m 2 ) may be administered intravenously Q3W at a dose of about 750-1500 mg / m 2 (For example, 750-800 mg / m 2 , 800-900mg / m 2 , 900-1000mg / m 2, 1000-1100mg / m 2 , 1100-1200mg / m 2 , 1200-1300mg / m 2 , 1300-1400mg / m 2 , or 1400 to 1500 mg / m 2 ) may be orally administered twice daily. The method may optionally further comprise administering to the subject an additional dose of 5-15 mg / kg or 10-15 mg / kg, e.g., 8 mg / kg, 7-7.5 mg / kg, 7.5-8 mg / kg, 7.5-9 mg / kg, 7.5-10 mg / kg, 7-9 mg / kg, 7-10 mg / kg, 10-12 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, or about 11 mg / kg of the anti-FGFR2b antibody 7-10 days after the initial administration of the anti-FGFR2b antibody. For example, the method includes administering an anti-FGFR2b antibody intravenously at a dose of 15-22 mg / kg Q3W, followed by an additional dose of 7-12 mg / kg of anti-FGFR2b antibody 7-10 days after the first dose of anti-FGFR2b antibody Q3W, and administering oxaliplatin at a dose of 100-150 mg / m 2 , e.g. 130 mg / m 2 Q3W, and capecitabine was administered intravenously at a dose of 750-1500 mg / m 2 , e.g. 1000 mg / m 2 In some embodiments, the method includes administering an anti-FGFR2b antibody intravenously at a dose of 22-30 mg / kg Q3W, with a booster dose of 10-12 mg / kg of anti-FGFR2b antibody administered 7-10 days after the first dose of anti-FGFR2b antibody Q3W, and administering oxaliplatin at 130 mg / m 2 Q3W, and capecitabine at 1000 mg / m 2 The dose may include twice daily oral administration of oxaliplatin at a dose of 100 mg / kg / day or 100 mg / kg / day or 100 mg / kg / day. Optionally, the oxaliplatin and the anti-FGFR2b antibody may be administered Q3W simultaneously, e.g., in a single composition, or in separate compositions. By way of example, the anti-FGFR2b antibody may be bemarituzumab.

[0084] In other embodiments, the method of treating gastric cancer may include administering to the subject a first administration of an anti-FGFR2b antibody at a dose of at least 15 mg / kg, e.g., at least 20 mg / kg, at least 22 mg / kg, 25 mg / kg, 20-25 mg / kg, 20-30 mg / kg, or 25-30 mg / kg. The anti-FGFR2b antibody may be administered intravenously. The method may include administering SOX to the subject Q3W, e.g., oxaliplatin at a dose of at least 65 mg / m 2 Q3W at a dose of 65 mg / m 2 ~150mg / m 2 Q3W) and administer S-1 at a dose of at least 20 mg / m 2 (e.g., 20 mg / m 2 ~60mg / m 2 ) orally twice daily. By way of example, oxaliplatin may be administered at a dose of about 100-150 mg / m 2 (For example, 100-120 mg / m 2 , 120-130mg / m 2 , 130-140mg / m 2 , or 140 to 150 mg / m 2 ) may be administered intravenously Q3W, with S-1 at a dose of about 30-60 mg / m 2 (For example, 30 mg / m 2 , 35 mg / m 2 , 40 mg / m 2 , 45 mg / m 2 , 50 mg / m 2 , 55 mg / m 2 , 60 mg / m 2or a range defined by any two of the foregoing values, may be orally administered twice daily. The method may optionally further comprise administering to the subject, 7-10 days after the initial administration of the anti-FGFR2b antibody, an additional dose of 5-15 mg / kg or 10-15 mg / kg, e.g., 8 mg / kg, 7-7.5 mg / kg, 7.5-8 mg / kg, 7.5-9 mg / kg, 7.5-10 mg / kg, 7-9 mg / kg, 7-10 mg / kg, 10-12 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, or about 11 mg / kg of the anti-FGFR2b antibody. For example, the method includes administering an anti-FGFR2b antibody intravenously at a dose of 15-22 mg / kg Q3W, followed by a booster dose of 7-12 mg / kg 7-10 days after the first dose of anti-FGFR2b antibody Q3W, and administering oxaliplatin at a dose of 10-150 mg / m 2 , e.g. 130 mg / m 2 Q3W, and S-1 was administered intravenously at a dose of 30-60 mg / m 2 , e.g. 40 mg / m 2 In some embodiments, the method includes administering an anti-FGFR2b antibody intravenously at a dose of 22-30 mg / kg Q3W, with a booster dose of 10-12 mg / kg administered 7-10 days after the first dose of anti-FGFR2b antibody Q3W, and administering oxaliplatin at 130 mg / m 2 Q3W, and S-1 was administered intravenously at a dose of 40 mg / m 2 The dose may include twice daily oral administration of oxaliplatin at a dose of 100 mg / kg / day or 100 mg / kg / day or 100 mg / kg / day. Optionally, the oxaliplatin and the anti-FGFR2b antibody may be administered Q3W simultaneously, e.g., in a single composition, or in separate compositions. By way of example, the anti-FGFR2b antibody may be bemarituzumab.

[0085] A method comprising administering an anti-FGFR2b antibody, CAPOX or SOX, and an anti-PD-1 or anti-PD-L1 antibody. As shown in FIG. 1, the method of treating gastric cancer described herein may include administering to a subject an anti-FGFR2b antibody, CAPOX or SOX, and optionally an anti-PD-1 or anti-PD-L1 antibody. The anti-PD-1 antibody or anti-PD-L1 antibody may be any such antibody known in the art or disclosed herein. In some embodiments, the method includes administering an anti-PD-1 antibody. The anti-PD-1 antibody may be nivolumab. For example, the method of treating gastric cancer may include administering to a subject an anti-FGFR2b antibody, the following chemotherapy regimen: (a) oxaliplatin and capecitabine (CAPOX) or (b) oxaliplatin and S-1 (SOX), and nivolumab. In some embodiments, the method comprises administering an anti-FGFR2b antibody at a dose of at least 15 mg / kg Q3W, administering an additional dose of 5-15 mg / kg of anti-FGFR2b antibody 7-10 days after the first dose of the Q3W administration of anti-FGFR2b antibody, and administering oxaliplatin at a dose of at least 65 mg / m 2 Q3W, intravenously at a dose of at least 500 mg / m 2 In another embodiment, the method includes administering an anti-FGFR2b antibody at a dose of at least 20 mg / kg Q3W, administering a booster dose of the anti-FGFR2b antibody at 10-15 mg / kg 7-10 days after the first dose of the Q3W administration of the anti-FGFR2b antibody, and administering oxaliplatin at a dose of at least 65 mg / m 2 Q3W, intravenously at a dose of at least 500 mg / m 2 In some embodiments, the method includes administering an anti-FGFR2b antibody at a dose of at least 15 mg / kg Q3W, administering a booster dose of the anti-FGFR2b antibody at 5-15 mg / kg 7-10 days after the first dose of the Q3W administration of the anti-FGFR2b antibody, and administering oxaliplatin at a dose of at least 65 mg / m 2 Q3W, intravenously at a dose of at least 20 mg / m 2In another embodiment, the method includes administering an anti-FGFR2b antibody at a dose of at least 20 mg / kg Q3W, administering a booster dose of the anti-FGFR2b antibody at 10-15 mg / kg 7-10 days after the first dose of the Q3W administration of the anti-FGFR2b antibody, and administering oxaliplatin at a dose of at least 65 mg / m 2 Q3W, intravenously at a dose of at least 20 mg / m 2 orally twice daily at a dose of 0.1 mg / kg or 0.2 mg / kg orally twice daily and an anti-PD-1 antibody Q3W.

[0086] In any of the methods of treating gastric cancer described herein, the anti-PD-1 antibody or anti-PD-L1 antibody may be administered intravenously in a Q3W regimen including any suitable dose. For example, an anti-PD-1 antibody such as nivolumab may be administered at a dose of about 240 mg to 480 mg (e.g., 250 mg, 300 mg, 400 mg, or 450 mg). In some embodiments, the method includes administering nivolumab Q3W at a dose of at least 300 mg, for example, 300 to 400 mg (e.g., 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, or 390 mg). For example, nivolumab may be administered Q3W at a dose of about 360 mg.

[0087] A study evaluating the safety, tolerability, and efficacy of bemarituzumab in combination with CAPOX or SOX chemotherapy, and optionally in combination with anti-PD-1 or anti-PD-L1 antibodies, in previously untreated advanced gastric or gastroesophageal junction cancer is described according to the method of some embodiments. The study may include the administration and schedule of bemarituzumab, CAPOX or SOX, and optionally nivolumab, as described in the examples.

[0088] In any of the methods of treating gastric cancer described herein, the cells of the subject's gastric cancer may express FGFR2b. For example, the cells of the subject's gastric cancer may overexpress FGFR2b protein, overexpress FGFR2b mRNA, or contain FGFR2b gene amplification. In some methods, the cells of the gastric cancer express FGFR2b protein as determined by immunohistochemistry (IHC). For example, at least 5%, 10%, 15%, or 20% of the gastric cancer cells overexpress FGFR2b as determined by IHC. For example, the cells of the subject's gastric cancer may have a FGFR2b staining intensity of 2+ or 3+. For example, at least 5% (e.g., 5%, 10%, 15%, or 20%) of the gastric cancer cells may have a FGFR2b staining intensity of 1+, 2+, or 3+. A subject's gastric cancer may be considered to overexpress FGFR2b if the cells of the subject's gastric cancer may have a FGFR2b staining intensity of 2+ or 3+, or if at least 5% of the gastric cancer cells may have a FGFR2b staining intensity of 1+, 2+ or 3+. In some methods, a subject is determined to overexpress FGFR2b if any cells of the gastric cancer have a FGFR2b staining intensity of 2+ or 3+ as determined by IHC. Subjects with gastric cancer that overexpress FGFR2b may be particularly likely to benefit from a treatment method comprising administering an anti-FGFR2b antibody (such as bemarituzumab) described herein. Optionally, the cells of the gastric cancer are also evaluated for PD-L1 expression, for example by IHC.

[0089] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLES

[0090] Example 1: Phase 1b study of bemarituzumab in combination with other anticancer therapies in previously untreated advanced gastric or gastroesophageal junction cancer that overexpresses FGFR2b This example describes a phase 1b, open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of bemarituzumab in combination with other anticancer therapies in subjects with advanced gastric or gastroesophageal junction adenocarcinoma that expresses FGFR2b and has not received prior treatment for unresectable or metastatic disease.

[0091] Prior to enrollment in this study, subjects' tumor samples must demonstrate overexpression of FGFR2b. Fibroblast growth factor receptor 2b (FGFR2b) overexpression will be assessed centrally by immunohistochemistry (IHC) on tumor samples (archived or fresh biopsy within 6 months of signing the prescreening informed consent form [ICF]).

[0092] The study will include a pre-screening period for FGFR2b testing, a 28-day screening period, a treatment period, a safety follow-up (SFU) visit, and a long-term follow-up (LTFU) period. Subjects will be treated until disease progression, unacceptable toxicity, subject request, or death, whichever occurs first.

[0093] Subjects may continue nivolumab treatment beyond Response Evaluation Criteria in Early Solid Tumors (RECIST) v1.1 progressive disease (PD) as assessed by the investigator only if they meet all of the following criteria: (1) investigator-assessed clinical benefit, (2) tolerate the investigational drug, and (3) stable Eastern Cooperative Oncology Group (ECOG) performance status.

[0094] Post-progression dosing does not delay urgent intervention to prevent serious complications of disease progression (i.e., central nervous system (CNS) metastases).

[0095] Subjects who discontinue all study drug for reasons other than withdrawal of consent will visit the SFU approximately 28 (+3) days after their last dose of study drug. In addition, subjects will undergo long-term survival follow-up (LTFU) approximately every 3 months (± 1 month) for up to 2 years after their first dose of bemarituzumab.

[0096] Investigators will perform radiological assessments according to RECIST v1.1, every 6 weeks (± 7 days) until Week 56, then every 12 weeks (± 14 days). If subjects discontinue study drug prior to radiological disease progression, tumor assessments will continue until radiological progression or initiation of additional anti-cancer therapy. Primary and secondary objectives and endpoints are summarized below in Table 1, and exploratory endpoints are summarized in Table 2.

[0097] [Table 1]

[0098] [Table 2]

[0099] [Table 3]

[0100] The study will explore doses of bemarituzumab in combination with other anti-cancer therapies. The following combinations are being evaluated: Cohort A: bemarituzumab and CAPOX Cohort B: Bemarituzumab and SOX Cohort C: bemarituzumab plus CAPOX and nivolumab Cohort D: bemarituzumab plus SOX and nivolumab.

[0101] Subjects will be enrolled in cohorts of 3-6 per dose level, with escalation guided primarily by safety responses to different doses. Cohorts B and D will not enroll United States (US) subjects and are outside the scope of the US Food and Drug Administration Investigational New Drug application. Cohorts A and B can begin simultaneously.

[0102] Dose levels of bemarituzumab are as follows: Dose level 1: bemarituzumab 15 mg / kg (every 3 weeks (Q3W) intravenously (IV)) followed by 7.5 mg / kg (day 8 of cycle 1) in a 21-day cycle; Dose level 2: bemarituzumab 22 mg / kg (IV, Q3W) followed by 11 mg / kg (day 8 of cycle 1) in a 21-day cycle.

[0103] Dose level 2 in cohort A or B will be initiated after the Dose Level Review Team (DLRT) deems dose level 1 in that same combination cohort safe and tolerable.

[0104] Once DLRT deems the dose levels in Cohort A or B safe and tolerable, enrollment for Cohort C or D will begin to evaluate the safety and tolerability of the combinations tested in Cohort A or B in combination with nivolumab.

[0105] In cohorts C and D, if bemarituzumab dose level 2 was evaluated as the starting dose, dose level 1 could be used as the de-escalation dose level and enrolled if the criteria for dose de-escalation were met.

[0106] The Bayesian Optimal Interval (BOIN) guidelines with a target toxicity rate of 0.25 will be used to determine escalation / de-escalation for each cohort. Alternative dose levels or dosing schedules of bemarituzumab may be explored based on new safety and PK data.

[0107] Number of subjects Nine subjects will be enrolled in each of cohorts A and B (three subjects at dose level 1, then six at dose level 2), and six subjects will be enrolled in each of cohorts C and D at dose levels selected from cohorts A and B. Up to ten additional subjects may be enrolled at a given dose level in a given cohort to further evaluate safety. Thus, the minimum number of subjects to be studied is 30. If dose tapers occur after the first three subjects are enrolled in cohorts C or D, nine subjects will be enrolled initially instead of six in each of these cohorts (three at the dose level selected from cohorts A and B, and six at the lower dose level), bringing the study to a maximum of 96 subjects. The study may be amended at a later date to include additional combinations of cohorts and / or subjects for further safety or efficacy evaluation.

[0108] Summary of subject eligibility criteria Subjects are of age (≧18 years) with histologically diagnosed unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (not suitable for curative therapy) with FGFR2b overexpression. Subjects must be candidates for combination therapy for a given cohort (e.g., CAPOX or SOX with or without nivolumab), have evaluable disease (measurable or non-measurable) according to RECIST v1.1, and must not have received prior treatment for unresectable or metastatic disease. HER2-positive subjects are excluded.

[0109] Once consented to the study, subjects will provide a medical history and undergo screening safety tests to ensure they meet all study eligibility requirements.

[0110] dosage Bemarituzumab is administered as an IV infusion over approximately 30 minutes (± 10 minutes) via a peripheral vein or central venous catheter (21-day cycles). At the first dose level, 15 mg / kg bemarituzumab is administered IV on day 1 (D1) of each cycle every 21 days, with a single dose of 7.5 mg / kg administered on day 8 of cycle 1. At the second dose level, 22 mg / kg bemarituzumab is administered IV on D1 of each cycle every 21 days, with a single dose of 11 mg / kg administered on day 8 of cycle 1.

[0111] CAPOX (21-day cycle) begins with oxaliplatin administration on day 1 of each cycle, after completion of bemarituzumab (cohort A) or nivolumab (cohort C) infusion. On day 1, 130 mg / m 2 of oxaliplatin is administered IV over 120 minutes. On days 1 through 14, 1000 mg / m 2 of capecitabine twice daily (i.e., 1000 mg / m 2 , 1000 mg / m in the evening 2 ) is administered orally.

[0112] SOX (21-day cycle) begins with oxaliplatin administration on day 1 of each cycle, after completion of bemarituzumab (Cohort B) or nivolumab (Cohort D) infusion. On day 1, 130 mg / m 2 of oxaliplatin will be administered IV over 120 minutes. On days 1 through 14, 40 mg / m 2 of S-1 twice daily (i.e., 40 mg / m 2 , 40 mg / m in the evening 2 ) is administered orally.

[0113] Nivolumab administration (21-day cycles) will begin after completion of the bemarituzumab infusion on day 1 of each cycle. On day 1, 360 mg of nivolumab will be administered IV over 30 minutes (± 10 minutes).

[0114] Rationale for bemarituzumab dosing The proposed dose levels 1 and 2 for this study are 15 mg / kg IV, Q3W with one bolus of 7.5 mg / kg on day 8 of cycle 1, and 22 mg / kg IV, Q3W with one bolus of 11 mg / kg on day 8 of cycle 1, respectively. This study uses dosing every 3 weeks (Q3W) instead of every 2 weeks (Q2W), consistent with the Q3W regimens of CAPOX and SOX. The target Q2W dose selection used to support the Q3W dose selection for this study is summarized below. The starting dose proposed in this study (dose level 1) is the target Q2W dose of bemarituzumab evaluated in FPA144-004 (15 mg / kg Q2W with one boost dose of 7.5 mg / kg on day 8 of cycle 1), which will continue to be evaluated in Phase 3 studies (20210096, 20210098), but with the dosing frequency of Q2W reduced to Q3W. Dose level 2 was selected as a proportional increase of the target Q2W dose, taking into account the increase in the Q3W dosing interval in the linear dose range. Dose level 2 was chosen to be the first to evaluate the end of dosing interval concentration at steady state (C trough,ss ) and the area under the serum concentration versus time curve during the dosing interval at steady state divided by the dosing interval of the target Q2W dose (C avg,ss ) and the highest concentration (C max ) higher than the target Q2W dose, safety is acceptable and efficacy is expected. In summary, the dose selected at dose level 2 is primed to balance safety and efficacy based on the safety and efficacy data observed in the FPA144-004 study.

[0115] In the FPA144-004 study of bemarituzumab 15 mg / kg Q2W with one additional dose of 7.5 mg / kg on day 8 of cycle 1 in patients with previously untreated advanced gastric or gastroesophageal junction cancer, in combination with mFOLFOX6, prespecified statistical significance was achieved for all three prespecified efficacy endpoints: ORR, PFS, and OS. A population PK analysis using PK data from FPA144-001, FPA144-002, and FPA144-004 studies predicted no covariates with a clinically meaningful effect on bemarituzumab exposure, but identified baseline weight, baseline albumin, sex, and combination therapy as statistically significant covariates for bemarituzumab PK. In combination with mFOLFOX6, dose adjustments based on these factors are not required in this population. Exposure-response analysis showed that 15 mg / kg Q2W plus one boost dose of 7.5 mg / kg on day 8 of cycle 1 provided an appropriate balance between safety and efficacy. Therefore, in the phase 3 study, we selected 15 mg / kg every 2 weeks plus one boost dose of 7.5 mg / kg on day 8 of cycle 1 as the target Q2W dose, and continued the study in combination with mFOLFOX6.

[0116] Capecitabine and Oxaliplatin (CAPOX) Dosing Rationale Capecitabine is 1000 mg / m 2 twice daily (i.e., 1000 mg / m in the morning 2 , 1000 mg / m in the evening 2 ) is given orally for 14 days followed by 1 week off. Capecitabine must be taken with food. Oxaliplatin is given at 130 mg / m on day 1 of each cycle. 2 It is administered IV. This regimen is the standard of care and has been tested in patients with advanced gastric and / or gastroesophageal junction cancer (Park et al., 2008; Kim et al., 2012; National Comprehensive Cancer Network, 2021).

[0117] Rationale for Oxaliplatin and S-1 (SOX) Dosage S-1 is 40 mg / m 2 twice daily (i.e., 40 mg / m in the morning 2 , 40 mg / m in the evening 2 ) or banded by body surface area (BSA) according to local standard of care for 14 days, followed by 1 week off. Oxaliplatin was administered orally at 130 mg / m on day 1 of each cycle. 2 This regimen is the standard of care in Japan and has been tested in patients with advanced gastric and / or gastroesophageal junction cancer (Boku et al., 2019; Kim et al., 2012).

[0118] Nivolumab dosing rationale Nivolumab is administered at 360 mg IV Q3W, which is the approved dose for nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy for subjects with metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma.

[0119] Statistical considerations Considerations regarding subject numbers If the true DLT rate is 30% with 3 subjects treated at a dose level in a given cohort, then the probability of observing at least one DLT is 66%, with 6 subjects the probability increases to 89%, and with 13 or more subjects the probability exceeds 99%.

[0120] Preliminary DLRT Review For each cohort, the DLRT will convene after groups of 3-6 subjects have completed the 21-day dose-finding DLT evaluation period and 21 days after the last subject has been enrolled in the dose cohort to review all available safety, tolerability, laboratory, and PK data.

[0121] Primary and final analyses The primary analysis is planned after the last subject completes the SFU period. The final analysis is planned after all subjects have completed the study.

[0122] Analysis method Descriptive statistics are provided for selected demographic, safety, PK, efficacy, and biomarker data. Descriptive statistics for continuous data include mean, median, standard deviation, and range, and categorical data are summarized using frequency counts and percentages. Response rates are presented with 95% exact CIs. Time-to-event endpoints are summarized using the Kaplan-Meier method.

[0123] End of exam An individual subject is considered to have completed the study once they have completed their last visit as shown in the schedule in Table 3. The study end date is defined as the date when the last subject at all sites was evaluated or received an intervention for evaluation in the study (i.e., the last visit of the last subject), including any additional parts of the study (e.g., LTFU, antibody testing) if applicable.

[0124] [Table 4]

[0125] [Table 5]

[0126] [Table 6]

[0127] [Table 7]

[0128] [Table 8]

[0129] [Table 9]

[0130] [Table 10]

[0131] [Table 11]

[0132] [Table 12]

[0133] [Table 13]

[0134] [Table 14]

[0135] Study population The Investigator will maintain a screening log of all potential study candidates that contains limited information about the potential candidate (e.g., screening date). This log can be completed and updated by interactive response technology (IRT). Eligibility criteria will be assessed at the time of screening. Appropriate written informed consent must be obtained prior to conducting any study-specific activities / procedures. No prior approval of protocol deviations (also known as protocol waivers or exemptions) to recruitment and enrollment criteria will be provided.

[0136] Selection Criteria Subjects are eligible to participate in the study only if they meet all of the following criteria: Subjects have provided informed consent prior to commencing any study-specific activities / procedures. ·Age 18 (or the legal age of majority in your country, whichever is higher) or older at the time of signing the ICF. -Pathologically confirmed gastric or gastroesophageal junction adenocarcinoma. Unresectable, locally advanced, or metastatic disease (not amenable to curative therapy). · The tumor overexpresses FGFR2b as determined by a centrally performed IHC test. - Eastern Cooperative Oncology Group performance score (ECOG-PS) of 0 to 1 Have adequate organ function defined as: Absolute neutrophil count ≥ 1.5 x 10 9 / L o Platelet count ≧100×10 9 / L Hemoglobin ≥ 9 g / dL AST and ALT < 3 x upper limit of normal [ULN] (or < 5 x ULN in case of hepatic impairment). Total bilirubin < 1.5 x ULN (or < 2 x ULN in case of hepatic impairment; excluding subjects with Gilbert's disease) Creatinine clearance (CrCl) ≥ 50 mL / min, calculated or measured using the Cockcroft-Gault formula ([140-age] x body weight [kg] / [72 x creatinine mg / dL]) (x 0.85 for women). A 24-hour urine collection is not required, but is possible. International normalized ratio (INR) or prothrombin time (PT) < 1.5 x ULN Subjects are candidates to receive CAPOX (Cohorts A, C) or SOX (Cohorts B, D) and / or nivolumab (Cohorts C, D). ·Ability to take oral medications. Measurable disease or non-measurable but evaluable disease per RECIST v1.1.

[0137] Exclusion criteria Subjects will be excluded from the study if any of the following criteria apply:

[0138] Disease-related Untreated or symptomatic CNS metastases and / or leptomeningeal disease Subjects with asymptomatic CNS metastases are eligible if they have been clinically stable and have not required intervention (including the use of corticosteroids) for at least 4 weeks. Subjects treated for brain metastases were eligible if they met the following criteria: o Definitive treatment completed at least 2 weeks prior to the first scheduled dose of study drug (stereotactic radiosurgery at least 7 days prior to the first scheduled dose of study drug). o At least 7 days prior to the first dose of investigational drug: Any CNS disease is clinically stable, the subject is not taking steroids for CNS disease (unless taking steroids for reasons unrelated to CNS disease), and the subject is taking a stable dose or is not taking an antiepileptic medication.

[0139] Other medical conditions Known HER2-positive status (defined by a positive IHC test with fluorescence in situ hybridization [FISH] of 3+ or IHC2+).

[0140] Cardiac dysfunction or any of the following clinically significant cardiac diseases, e.g., unstable angina within 6 months prior to the first dose of study drug, acute myocardial infarction within 6 months prior to the first dose of study drug, New York Heart Association (NYHA) class II-IV congestive heart failure, uncontrolled hypertension (defined as mean systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg but not optimally treated (measured according to the European Society of Hypertension / European Society of Cardiology [ESH / ESC] 2013 guidelines), uncontrolled arrhythmias requiring antiarrhythmic therapy other than beta-blockers or digoxin, active coronary artery disease, or corrected QT interval (QTc) ≥ 470.

[0141] Peripheral sensory neuropathy grade 2 or greater.

[0142] Active or uncontrolled infection requiring systemic treatment within 14 days prior to the first dose of the study drug.

[0143] Known human immunodeficiency virus (HIV) infection with a CD4+ T cell (CD4+) count less than 350 cells / mL, hepatitis C infection (subjects with hepatitis C who have achieved a sustained virologic response following antiviral therapy are permitted), or hepatitis B infection (subjects with hepatitis B surface antigen [SAg] or core antibodies who have achieved a sustained virologic response to antiviral therapy for hepatitis B are permitted).

[0144] History of interstitial lung disease.

[0145] Evidence or recent (within 6 months) history (of corneal defects, corneal ulcers, keratitis or keratoconus), history of corneal transplant, or other known corneal abnormalities that may place you at increased risk of developing a corneal ulcer. Recent (within 6 months) corneal surgery or ophthalmic laser treatment.

[0146] Evidence of ongoing acute (within 4 weeks) or progressive ophthalmologic abnormalities or symptoms.

[0147] Unwilling to avoid wearing contact lenses while taking the study drug.

[0148] Gastrointestinal (GI) tract disease that precludes taking oral medications, malabsorption syndromes, need for IV nutritional support, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).

[0149] History of other malignancies within the past 2 years, with the following exceptions: Curatively treated non-melanoma skin malignancies Cervical intraepithelial neoplasia - Stage I uterine cancer curatively treated - Curatively treated ductal carcinoma in situ or lobular carcinoma in situ, not currently receiving systemic therapy Localized prostate cancer that has been surgically treated with curative intent and is presumed to be cured

[0150] Cohorts C and D only: History of solid organ transplant Active autoimmune disease that required systemic treatment (excluding replacement therapy) within the past two years, or any other disease that required immunosuppressive therapy during the study.

[0151] Previous / Concurrent Therapies Previous treatment for metastatic or unresectable disease. Prior adjuvant or neoadjuvant therapy for localized disease is permitted if completed >6 months prior to the first dose of study drug. Palliative radiation therapy is permitted if completed >14 days before the first dose of study drug. All treatment-related toxicities must resolve to Grade ≤1 prior to the first dose of study drug, except for alopecia or toxicity deemed irreversible (defined as present and stable for >21 days) not otherwise specified in the exclusion criteria.

[0152] Prior treatment with any selective inhibitor of the FGF-FGFR pathway.

[0153] Major surgical procedure within 28 days prior to first dose of study drug.

[0154] Minor surgeries requiring local / epidural anesthesia must be completed >72 hours prior to the first dose of investigational drug. In all cases, subjects must be adequately recovered and stable prior to dosing.

[0155] Use of oral coumarin derivative anticoagulants.

[0156] Cohorts C and D only: Recent use (past 24 weeks) of the antifungal agent flucytosine.

[0157] Cohorts C and D only: Systemic agents >10 mg / day or immunosuppressive doses of prednisone or equivalent must be discontinued at least 2 weeks prior to the first dose of investigational drug. Short-term administration of high-dose corticosteroids and / or continuous low-dose prednisone (<10 mg / day) is permitted. Additionally, inhaled, intranasal, intraocular, and / or joint injections of corticosteroids are permitted. Subjects who experience severe, life-threatening, or recurrent (Grade ≥2) immune-mediated adverse events, or infusion-related reactions (including subjects who have led to permanent discontinuation during treatment with an immuno-oncology agent).

[0158] Previous / concurrent clinical trial experience Currently receiving treatment in another investigational device or investigational drug trial within 28 days of enrollment in this clinical trial. Other investigational treatments while participating in this study are excluded.

[0159] Other Exclusions Female subjects of childbearing potential who are not willing to use the protocol-specified contraceptive method during treatment and for an additional 9 months after the last protocol-mandated dose of drug.

[0160] Female subjects who are breastfeeding or plan to breastfeed during the study and up to 5 days after the last protocol-required dose of drug.

[0161] Female subjects who are planning to become pregnant during the study and up to 9 months after the last protocol-required dose of drug.

[0162] Female subjects of childbearing potential with a positive pregnancy test determined by a high-sensitivity urine or serum pregnancy test at screening and within 72 hours prior to the first dose of study drug.

[0163] Male subjects with a female partner of fertile potential who practice abstinence (abstaining from heterosexual intercourse) or are unwilling to use contraception for an additional 6 months after the last dose of protocol-mandated drug.

[0164] Male subjects who are willing to abstain from donating sperm during treatment and for an additional 6 months after the last dose of protocol-mandated medication.

[0165] Known allergy, hypersensitivity, or contraindication to any component of the bemarituzumab formulation, including polysorbates, or to platinum-containing medicines, capecitabine (including subjects with complete dihydropyrimidine dehydrogenase [DPD] deficiency; Cohorts A, C), S-1 (including subjects with complete DPD deficiency; Cohorts B, D), or nivolumab (Cohorts C, D).

[0166] A subject who, to the best of the subject's and the investigator's knowledge, is unlikely to be able to complete all protocol-required study visits or procedures and / or will not be able to comply with all required study procedures (e.g., clinical outcome assessments).

[0167] History or evidence of any other clinically significant disorder, condition, or disease (other than those outlined above) that, if presented, the investigator or an Amgen physician determines would pose a risk to the subject's safety or interfere with the evaluations, procedures, or completion of the study.

[0168] Bemarituzumab, CAPOX or SOX, and nivolumab Information regarding bemarituzumab, CAPOX, SOX, and nivolumab in the study, including dosing and dosing instructions, is shown in Tables 4 and 5 below.

[0169] [Table 15]

[0170] [Table 16]

[0171] Dose level determination The study explores doses of bemarituzumab in combination with other anticancer therapies. The study DLT period is 21 days after the first dose. In a given cohort, a DLRT meeting will be held once 3–6 subjects have been enrolled at a particular dose level and followed for safety for 21 days. The DLRT evaluates all available safety, laboratory, and PK data, as well as rules generated from the BOIN design (Liu and Yuan, 2015; Yuan et al., 2016), to derive dose recommendations. The DLRT may recommend escalation to the next planned dose level, continuation at the current dose level, de-escalation to a lower dose level, or termination of the cohort. BOIN escalation / de-escalation guidelines for each cohort will be derived with a target toxicity rate of 0.25. Dose escalation decisions consider all available safety data from all cohorts and include available data beyond the 21-day DLT window. After receiving the DLRT recommendation, the team will make the final decision and notify the principal investigator in writing of the dose modification decision.

[0172] The DLRT will use guidelines for each cohort based on the BOIN design, as described below: Subjects in a given cohort will be treated at Dose Level 1. To assign doses to subjects in the next cohort, the guidelines in Table 6 will be used, with the following exceptions: By "preclude" it is meant that the current and higher doses are excluded from the cohort to prevent treating future subjects at these doses due to excessive toxicity. If a dose is eliminated, it will be tapered to the next lower dose level. If the lowest dose is eliminated, the cohort will be stopped for safety. If no effect (ie, titration, tapering, or elimination) is elicited, new subjects are treated at the current dose. If the current dose is the lowest dose and rules indicate dose tapering, new subjects will be treated at the lowest dose if the number of DLTs does not reach the exclusion boundary, at which point the study will be stopped for safety. If the current dose is the maximum dose and rules indicate dose escalation, treat new patients at the maximum dose.

[0173] Step 2 is repeated until a minimum of 6 and a maximum of 16 subjects have reached the target dose level and a decision is made to maintain the current dose per Table 6.

[0174] [Table 17]

[0175] Dose-limiting toxicity Dose-limiting toxicity during dose-finding is defined as any of the following adverse events determined by the investigator to be causally related to the study drug: Grade 4 neutropenia of any duration Febrile neutropenia Grade 4 thrombocytopenia Grade 2 or greater bleeding or Grade 3 thrombocytopenia lasting more than 7 days Grade 4 anemia Grade 5 toxicity (e.g., death not due to disease progression) Grade 3 ophthalmic adverse events that do not resolve within 7 days Grade 4 ophthalmic adverse events Grade 4 Laboratory Values Grade 4 vomiting or diarrhea Grade 3 vomiting or grade 3 diarrhea lasting more than 3 days despite optimal medical support Grade 3 nausea lasting 3 days or more despite optimal medical support Grade 3 fatigue lasting more than a week Subjects who meet the criteria for Hy's Law cases (i.e., severe drug-induced liver injury [DILI]) will be considered DLT. Hy's Law cases are defined as AST or ALT levels ≥ 3xULN, serum TBIL levels > 2xULN, or an International Normalized Ratio (INR) > 1.5, without evidence of cholestasis, and with no other clear alternative explanation for the observed liver-related laboratory abnormalities (see Section 11.7 for further discussion of Hy's Law cases and management of liver function). Other grade 3 or higher adverse events with the following exceptions: DLT Exclusion: Asymptomatic grade 3 electrolyte abnormalities that last less than 72 hours, are clinically uncomplicated, and resolve spontaneously or respond to medical intervention. DLT Exemptions: Other selected laboratory abnormalities that are not clinically relevant or likely to be harmful to the subject (e.g., Grade 3 lymphopenia, Grade 3 hypoalbuminemia) and / or that can be corrected by substitution or modification. DLT exclusion: Transient (improved to Grade 1 or less within 6 hours of onset) Grade 3 infusion-related adverse events. DLT exclusion: Grade 3 endocrine disorders adequately controlled with hormone replacement therapy.

[0176] Subjects enrolled in the dose-finding study may be replaced if they are not evaluable for DLTs (e.g., if they do not receive the planned study treatment [at least 100% of the planned dose for IV formulation and at least 80% of the planned dose for oral formulation]) or if they discontinue study treatment before completion of the DLT evaluation period for reasons other than experiencing a DLT. Replaced subjects may continue in the study at the discretion of the investigator and after consultation with the medical monitor.

[0177] If an adverse event is clearly attributable to any component of the combination regimen (based on its known safety profile) and does not exceed expected severity, this particular adverse event may be considered not subject to a DLT.

[0178] Rules for adjusting, delaying, withholding, or resuming bemarituzumab doses, or permanently discontinuing Bemarituzumab may be discontinued for adverse events related to bemarituzumab according to the guidelines outlined in Table 7.1. Reasons for delays in bemarituzumab administration will be recorded on each subject's CRF.

[0179] After Cycle 1, the bemarituzumab dose should only be recalculated if body weight has changed by >10% from body weight on Cycle 1 Day 1 (C1D1). If the dose is recalculated due to a weight change of >10% from C1D1, the body weight used for the recalculated dose should serve as the new baseline for evaluation of subsequent dose recalculation.

[0180] If dose reductions or interruptions outside of these guidelines are considered by the investigator, consultation with the sponsor or designee is required. Cycles may be delayed to manage toxicity. Cycle delays longer than 21 days should be discussed with the medical monitor prior to resumption.

[0181] Corneal Events: Subjects who experience a corneal event within 100 days of the last dose of bemarituzumab, whether or not related to bemarituzumab, should be evaluated by an ophthalmologist. Subjects who report eye pain or irritation, or changes in vision should be evaluated by an ophthalmologist. Additional guidance is provided in Tables 7.1, 7.2, and 7.3.

[0182] [Table 18]

[0183] [Table 19]

[0184] [Table 20]

[0185] Rules for adjusting, delaying, withholding or restarting CAPOX dose, and permanent discontinuation Oxaliplatin Dose modifications of oxaliplatin will be permitted according to institutional standards or local package insert.

[0186] Neurotoxicity Oxaliplatin should be avoided in patients with grade 2 peripheral sensory neuropathy (moderate dysesthesias [without discomfort] or dysesthesias [with discomfort]) or limitation of instrumental activities of daily living. If toxicity improves to grade 1 or less, resume oxaliplatin to 75% of the initial dose. If oxaliplatin is avoided for 6 weeks (2 consecutive doses) due to neurotoxicity, discontinue oxaliplatin.

[0187] Renal dysfunction In patients with normal renal function or mild to moderate renal impairment (CrCl>50 mL / min), the full dose of oxaliplatin can be administered. In patients with severe renal impairment, the dose of oxaliplatin should be reduced to 75% of the initial dose.

[0188] Hematological toxicity: In grade 2 or grade 3 thrombocytopenia, oxaliplatin should be reduced to 75% of the initial dose. In grade 4 thrombocytopenia, oxaliplatin should be reduced to 50% of the initial dose. In grade 3 or grade 4 neutropenia or febrile neutropenia, the oxaliplatin dose should be reduced to 75% of the initial dose.

[0189] Allergic reactions If a subject experiences a grade 1 or 2 allergic reaction to oxaliplatin, premedication should be administered in accordance with institutional practice prior to subsequent administration of study drug. If a grade 1 or 2 allergic reaction persists into the next cycle, appropriate premedication escalation should be administered in accordance with institutional practice prior to administration of oxaliplatin. Subjects who experience a grade 3 or 4 allergic reaction should discontinue treatment with oxaliplatin.

[0190] Capecitabine Dose modifications of capecitabine are permitted according to institutional standards or local package insert.

[0191] General dose modification guidelines for capecitabine are shown in Table 8. Toxicity from capecitabine administration may be managed by symptomatic treatment, dose interruption, and adjustment of the capecitabine dose. Once the dose has been reduced, it should not be increased later. The only exception to this practice is in the case of nausea / vomiting. If grade 2 or higher nausea and / or vomiting occurs despite adequate antiemetic therapy, the chemotherapy dose should be reduced by 25% for the next dose. Appropriate antiemetic therapy should include at least two agents (e.g., 5HT-3 receptor antagonist, NK1 receptor antagonist). If tolerated, return to 100% dose may be permitted at the investigator's discretion. Chemotherapy cycles may be delayed to manage toxicity. Cycle delays longer than 21 days should be discussed with the medical monitor before resuming treatment.

[0192] Doses of capecitabine omitted due to toxicity will not be substituted or restored; instead, subjects should resume their planned treatment cycles. There is a risk of drug interactions between phenytoin and capecitabine. Inhibition of CYP2C9 by capecitabine may increase phenytoin concentrations, potentially increasing toxic concentrations of phenytoin, so the dose of phenytoin may need to be reduced when used in combination with capecitabine.

[0193] The enzyme deficiency, dihydropyrimidine dehydrogenase deficiency, may initially manifest as a severe, life-threatening reaction to fluoropyrimidines. Evaluation for DPD deficiency should be considered if the following occur after capecitabine administration: severe diarrhea, mucositis, neutropenia, or neurotoxicity.

[0194] [Table 21]

[0195] SOX dosage adjustment, delay, withholding or resumption rules, permanent discontinuation S-1 Dose modifications of S-1 will be permitted according to institutional standards or local package insert.

[0196] General dose modification guidelines for S-1 are shown in Table 9. Toxicity from S-1 administration may be managed by symptomatic treatment, dose interruption, and S-1 dose adjustment. Once the dose has been reduced, it should not be increased later. The only exception to this practice is in the case of nausea / vomiting. If grade 2 or higher nausea and / or vomiting occurs despite antiemetic therapy, the chemotherapy dose should be reduced at the next dose. If tolerated, reverting to the standard dose may be permitted at the investigator's discretion. If the treatment requires a shorter drug holiday, this should be done after confirming that there are no drug-induced abnormalities in laboratory findings (hematological, liver function, and renal function tests) and no gastrointestinal symptoms, i.e., that the drug is safe. A minimum of 7 days of drug holiday should be observed. Cycle delays longer than 21 days should be discussed with the medical monitor before resuming treatment. Doses of S-1 omitted due to toxicity will not be replaced or restored; instead, subjects should resume their planned treatment cycles.

[0197] There is a risk of drug interactions between phenytoin and S-1. Inhibition of CYP2C9 by S-1 may increase phenytoin concentrations, potentially increasing toxic concentrations of phenytoin, so the dose of phenytoin may need to be reduced when used concomitantly with S-1.

[0198] The enzyme deficiency, dihydropyrimidine dehydrogenase (DPD) deficiency, may initially manifest as a severe, life-threatening reaction to fluoropyrimidines. Evaluation for DPD deficiency should be considered if the following events occur after S-1 administration: severe diarrhea, mucositis, neutropenia, or neurotoxicity.

[0199] If oxaliplatin administration is discontinued for any reason prior to disease progression, S-1 may be continued until disease progression or unacceptable toxicity. If S-1 is permanently discontinued, oxaliplatin must be discontinued. Table 9 shows the recommended dose modifications for S-1. Further details can be found in local prescribing information. Institutional dose reduction guidelines may also apply.

[0200] [Table 22]

[0201] Rules for adjusting, delaying, withholding or resuming nivolumab dose, and permanent discontinuation Dose reduction of nivolumab is not recommended. In general, nivolumab should be discontinued for immune-mediated adverse reactions of grade 3 or higher, and should be permanently discontinued for life-threatening (grade 4 or higher) immune-mediated adverse events, recurrent severe (grade 3) immune-mediated reactions requiring systemic immunosuppressive therapy, or failure to reduce corticosteroid dose to 10 mg or less prednisone or equivalent daily within 12 weeks after starting steroids. Further information is provided in Table 10. If nivolumab is discontinued due to toxicity, chemotherapy and bemarituzumab may be continued. If all components of chemotherapy are discontinued, nivolumab may be continued. If any component of nivolumab is delayed or discontinued during the first 3 cycles, bemarituzumab should be continued as scheduled. If any component of nivolumab is delayed for up to 7 days after the first 3 cycles, bemarituzumab should also be delayed to coincide with the administration of nivolumab. If any component of nivolumab is discontinued for more than 7 days or after the first 3 cycles, bemarituzumab should be continued as scheduled.

[0202] Reasons for discontinuation of nivolumab will be recorded in each subject's eCRF.

[0203] [Table 23]

[0204] [Table 24]

[0205] Treatment Compliance If subjects are dosed at the site, they will receive bemarituzumab, oxaliplatin, and nivolumab (if applicable) directly from the Investigator or designee under medical supervision. The date and time of each dose administered at the clinic will be recorded on the source document and recorded in the eCRF.

[0206] Capecitabine and S-1 will be administered by the subject at home. Compliance will be assessed by direct questioning, review of the diary, and counting of returned investigational medication. The following procedures will be used to ensure proper medication accountability: Emphasis on medication accountability during start-up meetings. Medication accountability will be monitored throughout the study. Each subject will be instructed to return all investigational medication packaging and unused materials to the study site at each visit. The study site will keep a record of all investigational medication administered to and returned by the subject throughout the study. Study site personnel will return unused investigational medication to all subjects. Each subject will be instructed to keep a study diary to document that he / she is taking the investigational medication correctly.

[0207] Subjects must receive at least 80% but not more than 100% of the scheduled dose to be considered compliant with the administration of capecitabine and S-1. Similarly, subjects may be considered noncompliant if they are determined by the investigator to have intentionally or repeatedly taken less than or more than the prescribed dose (i.e., less than 80% or more than 100%). The possibility of discontinuing a subject due to noncompliance with the study drug will be discussed between the investigator and the medical monitor before making a final decision to discontinue the subject.

[0208] Previous and Concomitant Treatments Previous treatment All previous medications must be recorded on the designated eCRF form. Previous therapies taken / used within 3 months prior to enrollment will be collected.

[0209] For previous treatments for gastric or gastroesophageal junction cancer, the following will be collected: therapy name, setting, dose, units, frequency, start date, stop date, best response, and reason for stoppage. For anticancer therapies consisting of multiple individual components, information for each component will be collected. For all other previous treatments, the following will be collected: therapy name, indication, dose, units, frequency, route, start date, and stop date.

[0210] Combination treatment During the study, the investigator may prescribe any concomitant medications or treatments deemed necessary to provide adequate supportive care.

[0211] Prophylactic use of ocular lubricants and eyelid hygiene is recommended to reduce the risk of corneal toxicity. Ocular lubricants (e.g., preservative-free artificial tears) should be self-administered three times daily throughout the treatment period and for 30 days after the last dose. They may be polyvinyl alcohol-based or liquid polyol-based. If preservative-free are not available, preservative-containing preparations are acceptable. Methylcellulose-based lubricants should not be used. Viscous lubricants that may cause smearing should be avoided.

[0212] Concomitant therapies will be collected from informed consent until the end of SFU, except for ophthalmologic and anticancer therapies, which will be collected by LTFU. For concomitant therapies including vaccines, the name of therapy, indication, dose, unit, frequency, route, start date, and stop date will be collected.

[0213] For subsequent treatments for gastric or gastroesophageal junction cancer, the name of the agent, start date, and stop date will be collected.

[0214] Study drug discontinuation and subject withdrawal / withholding Subjects have the right to withdraw from investigational product and / or other protocol-required treatments, protocol procedures, or the entire study at any time and for any reason without prejudice to future medical care by the physician or institution.

[0215] The investigator and / or sponsor may decide to exclude a subject from the investigational product, investigational device, and / or other protocol required treatments, protocol procedures, or the entire trial at any time before the completion of the trial for the following reasons:

[0216] Discontinuation of study drug A subject (or legal representative) may refuse to continue with the investigational product and / or other protocol required treatments and / or procedures at any time during the study but may continue to participate in the study. In this case, the investigator must discuss with the subject the appropriate process for discontinuing the investigational product or other protocol required treatments, discuss with the subject the various options for follow-up (e.g., in person, by phone / email, via family / friends, communication / contact with other treating physicians, review of medical records, etc.), and the possibility of continuing the activity schedule in Table 3, including collection of data including endpoints, adverse events, and record this decision in the subject's medical record. A subject who discontinues the investigational product and / or other protocol required treatments and / or procedures should not be automatically removed from the study. Whenever safe and feasible, it is essential that the subject remains in the study to ensure safety monitoring and / or collection of outcome data.

[0217] Evaluation of reasons or procedures for early removal of an investigational product as required by the protocol may include any of the following: - Deciding on the sponsor Untraceable ·death Adverse Events Subject requirements - Ineligibility decision Deviations from Protocol Non-compliance ·Disease progression oRadiological progression (RECISTv1.1) o Clinical progression (investigator assessment) The need for alternative therapies ·pregnancy.

[0218] Withdrawal / withholding of subjects from clinical trials Withdrawal of consent to a clinical trial means that the subject does not wish to undergo further treatment or procedures required by the protocol and that the subject is unwilling or unable to continue further participation in the trial. Subject data up to the withdrawal of consent will be included in the analysis of the study and, if permitted, publicly available data after withdrawal of consent may be included. The investigator must discuss with the subject the appropriate procedures for withholding from the trial and record the subject's decision to withhold in the subject's medical record. Subjects who withhold or are excluded from treatment or testing will not be replaced. If a subject withholds from a trial, the subject may request the destruction of any samples collected but not tested.

[0219] Reasons for excluding a subject from the study include: - Deciding on the sponsor Withdrawal of consent to participate in a clinical trial ·death - Untraceable.

[0220] Untraceable Subjects are considered lost to follow-up if they do not return for a scheduled visit and cannot be contacted by the study site.

[0221] If a subject does not return to the clinic for a required study visit, the following actions must be taken: Sites must contact subjects to reschedule any missed visits as soon as possible, advise subjects of the importance of maintaining their assigned visit schedule, and confirm whether the subject wishes and / or is able to continue in the study. If a subject is determined to be lost to follow-up, the investigator or designee must make every effort to re-establish contact with the subject (three phone calls, if possible, and, if necessary, a certified letter or local equivalent to the subject's last known mailing address). These contact attempts will be documented in the subject's medical record. If a subject continues to be unreachable, he or she will be considered to have been withheld from the study due to the primary reason being loss to follow-up. For subjects lost to follow-up, investigators should search publicly available records, where permitted, to ascertain vital status. This will ensure that the data set generated as a result of the trial is as comprehensive as possible.

[0222] Efficacy assessment and procedures Radiography image evaluation Disease extent will be assessed by contrast-enhanced computed tomography (CT) / magnetic resonance imaging (MRI) according to RECIST v1.1. Low-dose CT should be utilized whenever possible to reduce radiation exposure to subjects.

[0223] Screening scan: A screening scan should be performed within 28 days prior to Cycle 1 Day 1 (scans may be performed within 31 days). If there are multiple screening scans, the one closest to enrollment will be used as the baseline.

[0224] Radiological evaluation should include CT / MRI of the chest, abdomen, and pelvis, as well as evaluation of all other known sites of disease according to institutional criteria.

[0225] All subjects with brain metastases must undergo a brain MRI. All brain scans for subjects with brain metastases must be MRI unless MRI is contraindicated, followed by CT with contrast is acceptable. Brain imaging (MRI or CT) should be performed if signs or symptoms suggestive of CNS metastases are present.

[0226] Subsequent scans: All subsequent scans should be performed in the same manner (e.g., with the same contrast, MRI field strength) as screening, preferably on the same scanner. If the imaging modality must be changed (e.g., unscheduled evaluation), consultation with the medical monitor is recommended.

[0227] During treatment and follow-up, radiological imaging of the chest, abdomen, pelvis, and all other known sites of disease will be performed regardless of treatment cycle, as specified in the activity schedule (see Table 3). Imaging may also be performed more frequently if clinically indicated, at the discretion of the managing physician. Radiological imaging and tumor evaluations will be performed until initiation of new anticancer therapy, progression of disease, death, withdrawal of consent, or end of study, whichever occurs first. Determination of disease response for clinical management and response evaluation will be performed at the clinical site according to RECIST v1.1.

[0228] Safety assessment The planned time points for all safety evaluations are listed in Table 3.

[0229] Vital signs The following measurements must be performed: systolic / diastolic blood pressure, heart rate, respiratory rate, and temperature. The subject must be in a sitting position, quiet and calm, for at least 5 minutes before the blood pressure assessment is performed. The position selected for the subject should be the same, used throughout the study and recorded on the Vital Signs eCRF. The temperature location selected for the subject should be the same, used throughout the study and recorded on the Vital Signs eCRF.

[0230] Electrocardiogram (ECG) Subjects must be quiet and calm in the supine position for at least 5 minutes before the ECG assessment is performed. If unable to do so, subjects should be in the lateral position whenever possible. The ECG must include the following measurements: heart rate, QRS, QT, QTc, PR intervals. The Principal Investigator or designated site physician will review all ECGs. Once signed, the original ECG tracing will be retained with the subject's source documents.

[0231] Laboratory test evaluation The Investigator is responsible for reviewing laboratory results and recording any clinically significant changes that occur during the study in the Event eCRF. The Investigator must determine whether abnormal values ​​in individual subjects represent a clinically significant change from the subject's baseline value. In general, abnormal laboratory findings that are not clinically significant (based on the Investigator's judgment) will not be recorded as adverse events. However, laboratory changes that require treatment or adjustment of current therapy will be considered adverse events. Clinical sequelae (not laboratory abnormalities) will be recorded as adverse events, if applicable.

[0232] All clinical laboratory evaluations required by the protocol must be performed according to the activity schedule (Table 3).

[0233] Life Status Vital status must be obtained for all subjects, within the bounds of local law. This includes subjects who may have discontinued study visits, whether or not they have withdrawn consent, and should include querying of public databases, as appropriate. In the case of death, the date of death and reported cause of death should be obtained.

[0234] Ophthalmological examination Ophthalmologic examinations will be performed according to the activity schedule in Table 3. Ophthalmologic adverse events of any grade occurring up to 100 days after the last dose of bemarituzumab should be reported.

[0235] Ophthalmologic examination should include distance-corrected visual activity of each eye recording visual acuity as logMAR equivalent, slit-lamp examination of the anterior segment, ocular surface staining (e.g., fluorescein), dilated retinal examination, or three-field retinal photography. In addition, macular optical coherence tomography (OCT) is especially necessary for subjects diagnosed with retinal pigment epithelium (RPE) detachment.

[0236] Ophthalmic examinations should be performed regardless of dose delays according to the activity schedule. Ophthalmic examinations may be repeated at any time if clinically indicated. If a subject has persistent ophthalmic findings, evaluation should continue after the SFU visit until resolution of findings, withdrawal of consent, death, or loss to follow-up. Ophthalmic adverse events should be monitored by an ophthalmologist until resolution.

[0237] For ophthalmic adverse events, the following measures will be taken: Standard of care management Guidelines for investigators on dose modifications and interruptions are provided in Table 7.3. Subjects should be evaluated if there is a clinically significant change compared to the previous examination or if there are any ocular signs or symptoms of Grade 2 or higher.

[0238] Adverse events The adverse event grading scale used in this study will be the Common Terminology Criteria for Adverse Events (CTCAE) version v5.0.

[0239] Investigators are responsible for reporting all investigator-observed or subject-reported adverse events occurring from the first dose of study drug / study treatment / protocol required treatment through the end of the SFU visit using the Events eCRF. Adverse events are planned to be recorded within 28(+3) days of the last day of study drug administration.

[0240] Serious Adverse Events Investigators are responsible for reporting all investigator-observed or subject-reported serious adverse events or all subject-reported serious adverse events occurring up to 28(+3) days after the last day of study drug administration using the Event eCRF. During the prescreening period, only serious adverse events related to prescreening procedures will be collected. Serious adverse events suspected to be related to the study drug should be recorded until the end of the study.

[0241] All serious adverse events will be collected, recorded, and reported to the sponsor or designee within 24 hours of the investigator becoming aware of the event. The investigator will provide updated data on serious adverse events to the sponsor within 24 hours of receiving them.

[0242] Due to differences between the regulatory criteria and the CTCAE grading scale for serious adverse events, if an adverse event meets the Grade 4 CTCAE toxicity grading criteria (e.g., laboratory abnormalities reported as Grade 4 without indicating a life-threatening condition), it is also at the investigator's discretion to report these abnormalities as serious adverse events. For adverse events that meet this circumstance, comprehensive documentation of the severity of the event must be recorded in the subject's medical record.

[0243] If the investigator learns of a serious adverse event suspected to be related to the investigational drug or any fatal adverse event (whether or not causally related) after the end of the protocol-defined reporting period, the investigator will report such serious adverse events within 24 hours after becoming aware of the event.

[0244] Serious adverse events reported outside the protocol-defined reporting periods will be recorded as study cases in the safety database based on their relationship to the investigational product and will be handled accordingly.

[0245] If further safety-related data are needed to satisfy regulatory reporting requirements for reportable events, additional information may need to be collected from subject records after the subject has completed the study.

[0246] Investigators should actively follow up each subject at subsequent visits / contacts after the first AE / SERV report. All AEs and SAEs will be followed until resolved, stabilized, otherwise described, or the subject is lost to follow-up.

[0247] Prompt notification of serious adverse events by investigators to sponsors is essential to ensure that legal obligations and ethical responsibilities for the safety of subjects and investigational products during clinical trials are met.

[0248] Sponsors have a legal responsibility to inform both local and other regulatory authorities about the safety of investigational medicinal products during clinical trials. Sponsors will comply with country-specific regulatory requirements regarding safety reporting to regulatory authorities, IRBs / IEC, and investigators.

[0249] Individual safety reports should be prepared for any suspected unexpected serious adverse events in accordance with local regulatory requirements and sponsor policy and sent to the investigator as appropriate.

[0250] Investigators who receive a separate safety report from the sponsor containing serious adverse events or other specific safety information (e.g., a summary or list of serious adverse events) should submit it with the Investigator Brochure and notify the IRB / IEC, as appropriate, in accordance with local requirements.

[0251] To comply with global serious adverse event reporting regulations, in trials where the trial allocation is blinded, the trial allocation of subjects who experience serious adverse events, unexpected adverse events, and related adverse events may be unblinded by Amgen prior to submission to regulatory authorities. Aggregate analyses may also be unblinded by the safety assessment team, as appropriate. Investigators will send relevant serious adverse event reports to regulatory authorities in accordance with local requirements.

[0252] Adverse events of particular interest Selected adverse events known as bemarituzumab adverse events of special interest are ocular adverse events of any grade or severity occurring up to 100 days after the last dose of bemarituzumab and should be collected as adverse events. Ocular adverse events (including corneal adverse events) should be graded using the Ocular Toxicity Grading Scale. Subjects should be assessed for possible bemarituzumab adverse events of special interest prior to each dose.

[0253] Pregnancy and breastfeeding Details of all pregnancies and / or lactation in female subjects and female partners of male subjects will be collected and reported. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, and ectopic pregnancy) will be considered serious adverse events.

[0254] A highly sensitive (serum) pregnancy test should be performed in females of childbearing potential at screening and within 72 hours of starting study drug treatment. Women who have undergone tubal ligation / occlusion should have a pregnancy test per protocol requirements.

[0255] A high-sensitivity (urine or serum) pregnancy test should be performed every cycle until 28(+3) days after discontinuing treatment as required by the protocol. Additional on-treatment pregnancy tests may be performed at the investigator's discretion or in accordance with local laws and regulations.

[0256] Pharmacokinetic evaluation Approximately 4 mL whole blood samples will be collected for measurement of bemarituzumab serum concentrations as specified in the activity schedule (Table 3). Record the actual sample collection date and time (24 hour clock) for each sample.

[0257] Pharmacogenetic evaluation If the subject consents to the optional pharmacogenetic part of the study, DNA analyses can be performed. These optional pharmacogenetic analyses focus on inherited gene variations to evaluate their possible correlation with the disease and / or response to the treatment used in the study. The objectives of the optional studies include the use of genetic markers to aid in cancer research and / or to identify subjects likely to show a positive or negative response to the investigational drug. No additional sample collection is done in this part of the study. For subjects who consent to this / these analyses, DNA can be extracted.

[0258] Antibody Testing Procedure Blood samples for antibody testing will be collected according to the time points specified in the activity schedule (Table 3) for measurement of anti-bemarituzumab antibodies. Samples testing positive for binding antibodies can be further characterized.

[0259] Subjects with a positive antibody test at the last scheduled antibody time point and clinical sequelae thought to be potentially related to an anti-bemarituzumab antibody response will also be asked to return for additional follow-up testing. This testing will be performed approximately every 3 months from the last scheduled antibody time point and will continue until: (1) antibodies are no longer detectable; or (2) the subject has been followed for at least 1 year (± 4 weeks) after receiving bemarituzumab. All follow-up findings (both positive and negative) will be communicated to the study site. More frequent or longer testing may be requested if there are safety-related concerns.

[0260] Biomarkers A biomarker is an objectively measured and evaluated indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention.

[0261] Biomarker assessment to determine eligibility Prescreening for FGFR2b overexpression testing by IHC requires the provision of formalin-fixed, paraffin-embedded archival tumor biopsy / resection or fresh biopsy. Fine needle aspirates, bone biopsies, and cytology samples are inadequate sample types. Sample collection of primary tumors and metastatic sites is acceptable. Fibroblast growth factor receptor 2b (FGFR2b) positive overexpression status is required for enrollment, and subjects must consent to tumor tissue analysis. If fresh tissue samples need to be collected, these should be collected according to local standard of care procedures that are not expected to present additional significant risks to the subject's health, safety, and welfare.

[0262] Subjects will be selected for enrollment based on FGFR2b overexpression, as determined by a research in vitro diagnostic (IVD) IHC assay at a central laboratory. The research IVD used to select subjects is the VENTANA FGFR2b (FPR2-D) Assay, an IHC test to detect FGFR2b protein in tumor tissue. Subjects' tissues must be evaluated according to the VENTANA FGFR2b (FPR2-D) Assay scoring algorithm to determine FGFR2b status. Timing of sample collection is described in the Activity Schedule (Table 3).

[0263] Subjects not demonstrating FGFR2b overexpression by IHC are not eligible for enrollment. Samples resulting in FGFR2b overexpression show moderate to strong membranous staining. It is the responsibility of each investigator to obtain tumor samples suitable for analysis of FGFR2b positivity for enrollment. Standard of care biopsy samples may be used if the specimen was taken within 6 months prior to screening or a fresh biopsy. If available, blocks are preferred, but unstained slides are encouraged in lieu of blocks. Submitted tumor samples must be in sufficient quantity to allow for IHC analysis; see the Clinical Laboratory Manual for details. Processing, labeling, and shipping instructions for tumor slide or tumor block samples are detailed in the Laboratory Manual distributed with the specimen collection kit.

[0264] Once tumor samples are received, analysis will be performed as efficiently as possible and results of FGFR2b overexpression status will be reported to the Principal Investigator or designee.

[0265] Biomarker evaluation during the study When possible, PD-L1 testing will be performed on remaining chronic archived pre-treatment tissue for the indications listed in the activity schedule in Table 3.

[0266] Biomarker Discovery Samples are taken for exploratory biomarker analysis aimed at understanding the mechanism of action of the drug, assessing the amount of tumor growth, or predicting disease progression and response to the investigational drug or protocol required therapy. These samples may also be used to develop methods that allow for a better understanding of the disease. Studies may be designed to identify subjects most likely to respond positively or negatively to bemarituzumab or protocol required therapy to study and further understand gastric cancer.

[0267] Blood and tissues will be collected for biomarker development at the time points specified in the schedule of activities (Table 3) if permitted according to local regulations and agreed by the ethical committee (EC) / institutional review board (IRB). Blood samples will be collected for assessment of circulating tumor / cell-free DNA mutational profiles and potential associations with clinical endpoints. Circulating tumor / cell-free DNA assessment will be used for somatic mutation profiling. Tumor samples will be used to examine protein expression, including FGFR2b, PD-L1, and other potential biomarkers that may include RNA or DNA gene expression or somatic (tumor) mutation analysis.

[0268] Statistical considerations Statistical hypotheses No statistical hypotheses are tested.

[0269] Sample size determination If the true DLT rate is 30% with 3 subjects treated at a dose level in a given cohort, then the probability of observing at least one DLT is 66%, with 6 subjects the probability increases to 89%, and with 13 or more subjects the probability exceeds 99%.

[0270] Analysis population The following populations are defined in Table 11:

[0271] [Table 25]

[0272] Covariates If appropriate, relationships between covariates and endpoints may be investigated and documented in the statistical analysis plan.

[0273] Subgroups If appropriate, subgroups may be investigated and specified in the statistical analysis plan.

[0274] statistical analysis A statistical analysis plan will be developed and finalized prior to database lock. Below is a summary of the timing and methods of the planned statistical analyses.

[0275] Planning Analysis Interim analysis and early discontinuation guidelines During the DLRM period, all available cumulative data (safety, tolerability, laboratory, PK, and efficacy) will be reviewed by cohort before making any dose escalation or de-escalation recommendations. Adverse events and DLTs observed in all subjects will be continually evaluated, fully integrated into all DLRMs, and considered in all enrollment and dose decisions. DLRMs will occur during dose discovery and 21 days after the last subject is enrolled in a dose cohort.

[0276] Guidelines for dose escalation or deescalation to the next dose level will be determined using the BOIN design (see Table 6).

[0277] The primary analysis will be planned after all subjects have completed the SFU period. The final analysis will be planned after all subjects have completed the study.

[0278] Analysis method Data will be summarized by cohort and dose level. Descriptive statistics for continuous data include mean, median, standard deviation, and range; categorical data will be summarized using frequency counts and percentages. Unless otherwise specified, data will be summarized using the safety analysis set.

[0279] Confidence intervals (CIs) for proportions are estimated using the exact method proposed by Clopper and Pearson (Clopper and Pearson, 1934). The Kaplan-Meier (KM) method is used to estimate medians and percentiles of time to event endpoints, and the Brookmeyer and Crowley method (Brookmeyer and Crowley, 1982) is used to calculate CIs. The Kaplan-Meier method is used to estimate landmarks of time to event endpoints (e.g., 1-year OS), and the Greenwood formula (Kalbfleisch and Prentice, 1980) is used to estimate standard errors for CI calculations.

[0280] [Table 26]

[0281] [Table 27]

[0282] Adverse events Subject incidence of all treatment-emergent adverse events will be tabulated by system organ class and preferred term. Tables of grade ≥ 3 adverse events, fatal adverse events, serious adverse events, adverse events leading to discontinuation / withholding of study drug, and adverse events of note will also be provided.

[0283] Clinical test results Analyses of safety laboratory endpoints will include summary statistics and shifts in safety laboratory grades between baseline and worst study values.

[0284] Vital signs Vital sign analysis will include summary statistics and shifts in vital sign values ​​between baseline and worst inter-study values.

[0285] physical measurements Analysis of the physical measurements includes summary statistics.

[0286] electro-cardiogram ECG measurements from this clinical trial will be performed according to standard care for routine safety monitoring, not for the purpose of evaluating potential QTc effects. Because these evaluations are not necessarily performed under rigorous conditions that would be expected to lead to meaningful evaluation of QTc data, summary and statistical analyses of ECG measurements are not planned, and these data are not expected to be useful for meta-analysis with data from other trials.

[0287] antibody formation The incidence and proportion of subjects developing anti-bemarituzumab antibodies at any time will be tabulated by treatment group.

[0288] Exposure to investigational drug Number of days of study drug administration, total amount of study drug administered, and dose intensity will be summarized using descriptive statistics.

[0289] Exposure to non-investigational drugs Number of days of non-investigational medication, total amount of non-investigational medication administered, and dose intensity will be summarized using descriptive statistics.

[0290] Exposure to concomitant medications The numbers and percentages of subjects receiving the treatment of interest will be summarized by preferred term for each treatment group, as coded by the World Health Organization drug dictionary.

[0291] Other analyses AUC, C max , C trough The pharmacokinetic parameters of bemarituzumab will be determined, including but not limited to: PK data collected from this study will be combined with PK data collected from other bemarituzumab studies for population PK analyses. Additional analyses will be performed to evaluate the relationship between bemarituzumab exposure and selected safety or efficacy, or relevant biomarker endpoints, if data are available. Details and results of these exploratory analyses will be described in separate reports.

[0292] Example 2: Treatment of gastric cancer patients with bemarituzumab and CAPOX Cohorts of patients with pathologically confirmed locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that overexpress FGFR2b will be treated with bemarituzumab at one of the following doses: (1) 15 mg / kg intravenously on Day 1 (D1) of Cycle 1 and Q3W thereafter, and 7.5 mg / kg as a single dose on Day 8 of Cycle 1; or (2) 22 mg / kg intravenously on D1 of Cycle 1 and Q3W thereafter, plus 11 mg / kg as a single dose on day 8 of Cycle 1.

[0293] In addition, these patients will receive CAPOX treatment after completion of the bemarituzumab infusion, specifically, 130 mg / m on day 1 of each cycle. 2 Oxaliplatin will be administered intravenously at a dose of 1000 mg / m over 120 minutes starting on days 1-14 of each cycle. Capecitabine will be administered at a dose of 1000 mg / m 2 is administered orally twice daily at a dose of 1000 mg / m 2 , 1000 mg / m in the evening 2 ).

[0294] The combination of bemarituzumab and CAPOX is effective in treating gastric or gastroesophageal junction adenocarcinoma in these patients, as measured by objective response (defined as complete response (CR) + partial response (PR)) determined according to Response Evaluation Criteria in Solid Tumors [RECIST v1.1].

[0295] Example 3: Treatment of gastric cancer patients with bemarituzumab and SOX Cohorts of patients with pathologically confirmed locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that overexpress FGFR2b will be treated with bemarituzumab at one of the following doses: (1) 15 mg / kg intravenously on Day 1 (D1) of Cycle 1 and Q3W thereafter, and 7.5 mg / kg as a single dose on Day 8 of Cycle 1; or (2) 22 mg / kg intravenously on D1 of Cycle 1 and Q3W thereafter, plus 11 mg / kg as a single dose on day 8 of Cycle 1.

[0296] In addition, these patients will receive treatment with SOX after completion of the bemarituzumab infusion, specifically, 130 mg / m on day 1 of each cycle. 2 Intravenous administration of oxaliplatin will be initiated at a dose of 40 mg / m over 120 minutes. S-1 will be administered intravenously at 40 mg / m on days 1-14 of each cycle. 2 is administered orally twice daily at a dose of 40 mg / m 2 , 40 mg / m in the evening 2 ).

[0297] The combination of bemarituzumab and SOX is effective in treating gastric or gastroesophageal junction adenocarcinoma in these patients, as measured by objective response (defined as complete response (CR) + partial response (PR)), determined according to the guidelines for Response Evaluation Criteria in Solid Tumors [RECIST v1.1].

[0298] Example 4: Treatment of gastric cancer patients with bemarituzumab and CAPOX Cohorts of patients with pathologically confirmed locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that overexpress FGFR2b will be treated with bemarituzumab at one of the following doses: (1) 15 mg / kg intravenously on Day 1 (D1) of Cycle 1 and Q3W thereafter, and 7.5 mg / kg as a single dose on Day 8 of Cycle 1; or (2) 22 mg / kg intravenously on D1 of Cycle 1 and Q3W thereafter, plus 11 mg / kg as a single dose on day 8 of Cycle 1.

[0299] In addition, these patients will receive CAPOX treatment after completion of the bemarituzumab infusion, specifically, 130 mg / m on day 1 of each cycle. 2 Oxaliplatin will be administered intravenously at a dose of 1000 mg / m over 120 minutes starting on days 1-14 of each cycle. Capecitabine will be administered at a dose of 1000 mg / m 2 is administered orally twice daily at a dose of 1000 mg / m 2 , 1000 mg / m in the evening 2 ).

[0300] The combination of bemarituzumab and CAPOX is effective in treating gastric or gastroesophageal junction adenocarcinoma in these patients, as measured by progression-free survival and / or overall survival.

[0301] Example 5: Treatment of gastric cancer patients with bemarituzumab and SOX Cohorts of patients with pathologically confirmed locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that overexpress FGFR2b will be treated with bemarituzumab at one of the following doses: (1) 15 mg / kg intravenously on Day 1 (D1) of Cycle 1 and Q3W thereafter, and 7.5 mg / kg as a single dose on Day 8 of Cycle 1; or (2) 22 mg / kg intravenously on D1 of Cycle 1 and Q3W thereafter, plus 11 mg / kg as a single dose on day 8 of Cycle 1.

[0302] In addition, these patients will receive treatment with SOX after completion of the bemarituzumab infusion, specifically, 130 mg / m on day 1 of each cycle. 2 Intravenous administration of oxaliplatin will be initiated at a dose of 40 mg / m over 120 minutes. S-1 will be administered intravenously at 40 mg / m on days 1-14 of each cycle. 2 is administered orally twice daily at a dose of 40 mg / m 2 , 40 mg / m in the evening 2 ).

[0303] The combination of bemarituzumab and SOX is effective in treating gastric or gastroesophageal junction adenocarcinoma in these patients, as measured by progression-free survival and / or overall survival.

[0304] Example 6: Treatment of gastric cancer patients with bemarituzumab, CAPOX and nivolumab Cohorts of patients with pathologically confirmed locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that overexpress FGFR2b will be treated with bemarituzumab at one of the following doses: (1) 15 mg / kg intravenously on Day 1 (D1) of Cycle 1 and Q3W thereafter, and 7.5 mg / kg as a single dose on Day 8 of Cycle 1; or (2) 22 mg / kg intravenously on D1 of Cycle 1 and Q3W thereafter, plus 11 mg / kg as a single dose on day 8 of Cycle 1.

[0305] These patients will also receive treatment with nivolumab after completion of the bemarituzumab infusion, administered intravenously at a dose of 360 mg over 30 minutes (± 10 minutes) on day 1 of each cycle.

[0306] In addition, these patients will receive CAPOX treatment after completion of the nivolumab infusion, specifically, 130 mg / m on day 1 of each cycle. 2 Oxaliplatin will be administered intravenously at a dose of 1000 mg / m over 120 minutes starting on days 1-14 of each cycle. Capecitabine will be administered at a dose of 1000 mg / m 2is administered orally twice daily at a dose of 1000 mg / m 2 , 1000 mg / m in the evening 2 ).

[0307] The combination of bemarituzumab, CAPOX and nivolumab is effective in treating gastric or gastroesophageal junction adenocarcinoma in these patients, as measured by objective response (defined as complete response (CR) + partial response (PR)) determined according to Response Evaluation Criteria in Solid Tumors [RECIST v1.1].

[0308] Example 7: Treatment of gastric cancer patients with bemarituzumab, SOX and nivolumab Cohorts of patients with pathologically confirmed locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that overexpress FGFR2b will be treated with bemarituzumab at one of the following doses: (1) 15 mg / kg intravenously on Day 1 (D1) of Cycle 1 and Q3W thereafter, and 7.5 mg / kg as a single dose on Day 8 of Cycle 1; or (2) 22 mg / kg intravenously on D1 of Cycle 1 and Q3W thereafter, plus 11 mg / kg as a single dose on day 8 of Cycle 1.

[0309] These patients will also receive treatment with nivolumab after completion of the bemarituzumab infusion, administered intravenously at a dose of 360 mg over 30 minutes (± 10 minutes) on day 1 of each cycle.

[0310] In addition, these patients will receive treatment with SOX after completion of the nivolumab infusion, specifically, 130 mg / m on day 1 of each cycle. 2 Intravenous administration of oxaliplatin will be initiated at a dose of 40 mg / m over 120 minutes. S-1 will be administered intravenously at 40 mg / m on days 1-14 of each cycle. 2 is administered orally twice daily at a dose of 40 mg / m 2 , 40 mg / m in the evening 2 ).

[0311] The combination of bemarituzumab, SOX and nivolumab is effective in treating gastric or gastroesophageal junction adenocarcinoma in these patients, as measured by objective response (defined as complete response (CR) + partial response (PR)) determined according to the guidelines for Response Evaluation Criteria in Solid Tumors [RECIST v1.1].

[0312] Example 8: Treatment of gastric cancer patients with bemarituzumab, CAPOX and nivolumab Cohorts of patients with pathologically confirmed locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that overexpress FGFR2b will be treated with bemarituzumab at one of the following doses: (1) 15 mg / kg intravenously on Day 1 (D1) of Cycle 1 and Q3W thereafter, and 7.5 mg / kg as a single dose on Day 8 of Cycle 1; or (2) 22 mg / kg intravenously on D1 of Cycle 1 and Q3W thereafter, plus 11 mg / kg as a single dose on day 8 of Cycle 1.

[0313] These patients will also receive treatment with nivolumab after completion of the bemarituzumab infusion, administered intravenously at a dose of 360 mg over 30 minutes (± 10 minutes) on day 1 of each cycle.

[0314] In addition, these patients will receive CAPOX treatment after completion of the nivolumab infusion, specifically, 130 mg / m on day 1 of each cycle. 2 Oxaliplatin will be administered intravenously at a dose of 1000 mg / m over 120 minutes starting on days 1-14 of each cycle. Capecitabine will be administered at a dose of 1000 mg / m 2 is administered orally twice daily at a dose of 1000 mg / m 2 , 1000 mg / m in the evening 2 ).

[0315] The combination of bemarituzumab, CAPOX and nivolumab is effective in treating gastric or gastroesophageal junction adenocarcinoma in these patients, as measured by progression-free survival and / or overall survival.

[0316] Example 9: Treatment of gastric cancer patients with bemarituzumab, SOX and nivolumab Cohorts of patients with pathologically confirmed locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that overexpress FGFR2b will be treated with bemarituzumab at one of the following doses: (1) 15 mg / kg intravenously on Day 1 (D1) of Cycle 1 and Q3W thereafter, and 7.5 mg / kg as a single dose on Day 8 of Cycle 1; or (2) 22 mg / kg intravenously on D1 of Cycle 1 and Q3W thereafter, plus 11 mg / kg as a single dose on day 8 of Cycle 1.

[0317] These patients will also receive treatment with nivolumab after completion of the bemarituzumab infusion, administered intravenously at a dose of 360 mg over 30 minutes (± 10 minutes) on day 1 of each cycle.

[0318] In addition, these patients will receive treatment with SOX after completion of the nivolumab infusion, specifically, 130 mg / m on day 1 of each cycle. 2 Intravenous administration of oxaliplatin will be initiated at a dose of 40 mg / m over 120 minutes. S-1 will be administered intravenously at 40 mg / m on days 1-14 of each cycle. 2 is administered orally twice daily at a dose of 40 mg / m 2 , 40 mg / m in the evening 2 ).

[0319] The combination of bemarituzumab, SOX and nivolumab is effective in treating gastric or gastroesophageal junction adenocarcinoma in these patients, as measured by progression-free survival and / or overall survival.

[0320] Example 10: Results of a Phase 1b Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Bemarituzumab in Combination with Other Anticancer Therapies in Subjects with Untreated Advanced Gastric or Gastroesophageal Junction Cancer Three cohorts of patients with pathologically confirmed locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with FGFR2b overexpression were administered the anti-FGFR2b antibody bemarituzumab (Bema) intravenously in combination with CAPOX with or without nivolumab (Nivo) according to the protocol described in Example 1. Specifically, two dose levels of bemarituzumab were tested in Cohort A (i.e., Cohort A, dose level 1 (DL1), and Cohort A DL2) as described in Example 1, along with Cohort C, according to the following dosing schedule: Cohort A DL1: Bema 15 mg / kg IV Q3W + 7.5 mg / kg single dose on day 8 of cycle 1 ("C1D8") + CAPOX (N=6; 6 / 6 patients had pharmacokinetic (PK) data available) Cohort A DL2: Bema 22mg / kg IV Q3W + 11mg / kg single dose C1D8 + CAPOX (N=4; PK data available for 4 / 4 patients) Cohort C: Bema 22 mg / kg IV Q3W + 11 mg / kg single dose C1D8 + CAPOX + Nivo (N=6; PK data available for 6 / 6 patients).

[0321] Serum concentrations of bemarituzumab were measured at pre-determined time points as shown in Table 3. A summary of preliminary PK parameters of bemarituzumab in treatment cycles 1 and 2 is shown in Table 12.

[0322] [Table 28]

[0323] No PK-related drug-drug interactions (DDIs) were observed between bemarituzumab and nivolumab in the CAPOX background. Furthermore, based on the known safety profile of bemarituzumab, there were no new safety findings in patients in Cohort A (DL1 and DL2) and Cohort C.

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Catenacci DVT,Rasco D,Lee J,et al.Phase I Escalation and Expansion Study of Bemarituzumab(FPA144)in Patients with Advanced Solid Tumors and FGFR2b Selected Gastroesophageal Adenocarcinoma.J Clin Oncol.2020;82(21):2418-2426. Clopper,CJ and Pearson ES.The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika.1934:404-416. Dienstmann R,Bahleda R, Barbara A,et al. First in human study of JNJ-42756493, a potent pan fibroblast growth factor receptor(FGFR)inhibitor in patients with advanced solid tumors.AACR 105th Annual Meeting 2014,San Diego,CA. Eisenhauer EA,Therasse P,Bogaerts J, et al.New response evaluation criteria in solid tumours:revised RECIST guideline(version 1.1).Eur J Cancer. 2009;45(2):228-247. 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Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma.Hum Pathol.2012;43(10):1559-1566. Kalbfleisch,J.D.and Prentice,R.L.(1980) The statistical analysis of failure time data.John Wiley and Sons,New York. Kang YK, Kang WK, Shin DB, et al. Capecitabine / Cisplatin Versus 5 Fluorouracil / Cisplatin as First-Line Therapy in Patients with Advanced Gastric Cancer: A Randomised Phase III Noninferiority Trial. Annals of Oncology. 2009;20:666-673. Katoh Y and Katoh M.Hedgehog signaling pathway and gastrointestinal stem cell signaling network(review).Int J Mol Med.2006;18(6):1019-1023. Kim GM,Jeung H-C,Rha SY,et al. A randomized phase III trial of S-1-oxaliplatin versus cepecitabine-oxaliplatin in advanced gastric cancer.Eur J Cancer.2012;48(4):518-526. Keam B,Im SA,Han SW,et al.Modified FOLFOX-6 chemotherapy in advanced gastric cancer:Results of phase II study and comprehensive analysis of polymorphisms as a predictive and prognostic marker.BMC Cancer.2008;8:148. Kim HS, Kim JH, Jang HJ,Han B,Zang DY. Pathological and Prognostic Impacts of FGFR2 Overexpression in Gastric Cancer:A Meta-Analysis. J Cancer.2019;10(1):20-27.Published 2019 Jan 1. Matsumoto K,Arao T, Hamaguchi T,et al. FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer.2012; 106(4):727-732. Moehler M, Shitara K, Garrido M,et al. LBA6_PR Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer / gastroesophageal junction cancer (GC / GEJC) / esophageal adenocarcinoma (EAC):First results of the CheckMate 649 study. Ann Oncol. 2020;31:S1191 10.1016 / j.annonc.2020.08.2296. National Cancer Institute(2015).SEER Stat Fact Sheets: Stomach Cancer.Retrieved February 25,2016,from http: / / seer.cancer.gov / statfacts / html / stomach.html. National Comprehensive Cancer Network, NCCN Guidelines for Gastric Cancer 2021.https: / / www.nccn.org / guidelines / guidelines-detail?category=1&id=1434. Okines AFC, Norman AR,McCloud P,Kang YK, Cunningham D. Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer.Ann Oncol.2009; 20(9):1529 1534. Park YH, Lee J-L,Ryoo B-Y,et al.Capecitabine in combination with oxaliplatin(XELOX)as a first-line therapy for advanced gastric cancer.Cancer Chemother Pharmacol.2008;61(4):623-629. Sequist LV, Cassier P,Varga A,et al. Phase I Study of BGJ398,a Selective Pan-FGFR Inhibitor in Genetically Preselected Advanced Solid Tumors.AACR 2014 Annual Meeting,San Diego,CA. Shah MA,Kang YK,Thuss-Patience PC,et al. Biomarker analysis of the GATSBY study of trastuzumab emtansine versus a taxane in previously treated HER2 positive advanced gastric / gastroesophageal junction cancer.Gastric Cancer. 2019;22(4):803-816. Shinkawa T,Nakamura K,Yamane N,et al.The Absence of Fucose but Not the Presence of Galactose or Bisecting N-Acetylglucosamine of Human IgG1 Complex-type Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular Cytotoxicity.J Biol Chem.2003;278(5):3466-3473. Shitara K, Doi T,Dvorkin M, et al.Trifluridine / tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer(TAGS):a randomised, double-blind,placebo-controlled,phase 3 trial.Lancet Oncol.2018;19(11):1437-1448. The GASTRIC Group. Benefit of Adjuvant Chemotherapy for Resectable Gastric Cancer.JAMA.2010;303(1729-1737):1729. Tokunaga R,Imamura Y,Nakamura K,et al.Fibroblast growth factor receptor 2 expression,but not its genetic amplification,is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma.Oncotarget.2016;7(15):19748-19761. Waddell T,Verheij M,Allum W,et al. Gastric Cancer:ESMO-ESSO-ESTRO Clinical Practice Guidelines for Diagnosis, Treatment, and Follow-up.Radiotherapy and Oncology.2014;110:189-194. Wagner AD,Grothe W,Haerting J,Kleber G,Grothey A,Fleig WE.Chemotherapy in advanced gastric cancer:a systematic review and meta-analysis based on aggregate data.J Clin Oncol.2006;24(18):2903-2909. Wagner AD,Syn NL,Moehler M,et al.Chemotherapy for advanced gastric cancer.Cochraine Database Syst Rev.2017;8(8):CD004064. Yamada Y, Higuchi K, Nishikawa K, et al.Phase III Study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer.Ann Oncol.2014;26(1):141-148.

[0325] All references cited in this specification, including publications, patent applications, and patents, are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0326] Use of the terms "a," "an," "the," and "at least one" and similar referents in describing the invention (especially in relation to the claims below) should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") should be construed to mean one item (A or B) selected from the listed items or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms "comprise," "have," "include," and "contain" should be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein, unless otherwise indicated herein. All of the methods described herein may be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any examples or exemplary language (e.g., "etc.") provided herein is merely intended to further clarify the invention, and does not impose limitations on the scope of the invention unless otherwise asserted. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0327] Preferred embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors expect that those skilled in the art will adopt such variations as necessary, and the inventors intend for the invention to be practiced in other forms than those specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or clearly contradicted by context.

Claims

1. 1. A method of treating gastric cancer in a subject, comprising: administering to the subject an anti-FGFR2b antibody; and To the above subject (a) oxaliplatin and capecitabine; or (b) Oxaliplatin and S-1 administering a chemotherapy regimen comprising The method includes:

2. 2. The method of claim 1, wherein the anti-FGFR2b antibody is administered at a dose of at least 15 mg / kg Q3W.

3. 2. The method of claim 1, wherein the anti-FGFR2b antibody is administered Q3W at a dose of 15-22 mg / kg, or greater than 15 mg / kg up to and including 22 mg / kg.

4. 4. The method of claim 2 or 3, further comprising administering a booster dose of 5-15 mg / kg of the anti-FGFR2b antibody 7-10 days after the initial dose of the Q3W administration of the anti-FGFR2b antibody.

5. The method of claim 4, wherein the booster dose of the anti-FGFR2b antibody is 6-9 mg / kg or 7-8 mg / kg.

6. 2. The method of claim 1, wherein the anti-FGFR2b antibody is administered at a dose of at least 20 mg / kg Q3W.

7. 7. The method of claim 6, wherein the anti-FGFR2b antibody is administered Q3W at a dose of 20-30 mg / kg, or 22-25 mg / kg, or greater than 22 mg / kg up to and including 30 mg / kg, or greater than 22 mg / kg up to and including 25 mg / kg.

8. 8. The method of claim 6 or 7, further comprising administering a booster dose of 10-15 mg / kg of the anti-FGFR2b antibody 7-10 days after the initial dose of the Q3W administration of the anti-FGFR2b antibody.

9. 9. The method of claim 8, wherein the booster dose of the anti-FGFR2b antibody is 9-13 mg / kg, or 10-12 mg / kg.

10. The method of any one of claims 1 to 9, wherein the anti-FGFR2b antibody is administered intravenously.

11. The oxaliplatin is administered at least 65 mg / m ２ and administering the capecitabine intravenously at a dose of at least 500 mg / m ２ The method of any one of claims 1 to 10, comprising orally administering the compound of formula (I) or (II) twice daily at a dose of

12. The oxaliplatin is 100 to 150 mg / m ２ is administered intravenously Q3W at a dose of 750-1500 mg / m ２ The method of claim 11, wherein the dose is orally administered twice daily.

13. The oxaliplatin is administered at least 65 mg / m ２ and administering the S-1 intravenously at a dose of at least 20 mg / m ２ The method of any one of claims 1 to 10, comprising orally administering the compound of formula (I) or (II) twice daily at a dose of

14. The oxaliplatin is 100 to 150 mg / m ２ is administered intravenously Q3W at a dose of 30-60 mg / m ２ The method of claim 13, wherein the dose is orally administered twice daily.

15. 13. The method of claim 1, wherein the anti-FGFR2b antibody is administered intravenously at a dose of 15-22 mg / kg Q3W, with a booster dose of 7-12 mg / kg administered 7-10 days after the first dose of the anti-FGFR2b antibody Q3W, wherein: The administration of the chemotherapy regimen comprises: (a) The oxaliplatin is administered at a concentration of 100 to 150 mg / m ２ and the capecitabine is administered intravenously at a dose of 750-1500 mg / m ２ orally twice daily at a dose of (b) The oxaliplatin is administered in a dose of 10 to 150 mg / m ２ and the S-1 was administered intravenously at a dose of 30-60 mg / m ２ Administer orally twice daily at a dose of A method comprising:

16. 13. The method of claim 1, wherein the anti-FGFR2b antibody is administered intravenously at a dose of 15-22 mg / kg Q3W, with a booster dose of 7-12 mg / kg administered 7-10 days after the first dose of the anti-FGFR2b antibody Q3W, wherein: The administration of the chemotherapy regimen comprises: (a) the oxaliplatin is 130 mg / m ２ and the capecitabine was administered intravenously at a dose of 1000 mg / m ２ orally twice daily at a dose of (b) the oxaliplatin at 130 mg / m ２ and the S-1 was administered intravenously at a dose of 40 mg / m ２ Administer orally twice daily at a dose of A method comprising:

17. 13. The method of claim 1, wherein the anti-FGFR2b antibody is administered intravenously at a dose of 22-30 mg / kg Q3W, with a booster dose of 10-12 mg / kg administered 7-10 days after the first dose of the anti-FGFR2b antibody Q3W, wherein: The administration of the chemotherapy regimen comprises: (a) the oxaliplatin is 130 mg / m ２ and the capecitabine was administered intravenously at a dose of 1000 mg / m ２ orally twice daily at a dose of (b) the oxaliplatin at 130 mg / m ２ and the S-1 was administered intravenously at a dose of 40 mg / m ２ Administer orally twice daily at a dose of A method comprising:

18. The method of any one of claims 1 to 17, further comprising administering to the subject an anti-PD-1 antibody or an anti-PD-L1 antibody.

19. 20. The method of claim 18, wherein the anti-PD-1 antibody or anti-PD-L1 antibody is administered Q3W.

20. 20. The method of claim 18 or 19, wherein the anti-PD-1 antibody comprises nivolumab, pembrolizumab, or cemiplimab, or the anti-PD-L1 antibody comprises atezolizumab, avelumab, or durvalumab.

21. 18. The method of any one of claims 1-17, further comprising administering nivolumab to the subject at a dose of at least 300 mg Q3W.

22. 22. The method of claim 21, wherein the nivolumab is administered at a dose of 300 mg to 400 mg Q3W.

23. 22. The method of claim 21, wherein the nivolumab is administered at a dose of 360 mg Q3W.

24. The anti-FGFR2b antibody is a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:6, a HCDR2 of SEQ ID NO:7, and a HCDR3 of SEQ ID NO:8; and A light chain variable region comprising a light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 9, an LCDR2 of SEQ ID NO: 10, and an LCDR3 of SEQ ID NO:

11. The method according to any one of claims 1 to 23, comprising:

25. 25. The method of claim 24, wherein the anti-FGFR2b antibody is afucosylated.

26. 26. The method of claim 24 or 25, wherein the heavy chain variable region of the anti-FGFR2b antibody comprises an amino acid sequence at least 95% identical to SEQ ID NO:4, and the light chain variable region of the anti-FGFR2b antibody comprises an amino acid sequence at least 95% identical to SEQ ID NO:

5.

27. The method of any one of claims 24 to 26, wherein the heavy chain variable region of the anti-FGFR2b antibody comprises the amino acid sequence of SEQ ID NO: 4, and the light chain variable region of the anti-FGFR2b antibody comprises the amino acid sequence of SEQ ID NO:

5.

28. The method of any one of claims 24 to 27, wherein the anti-FGFR2b antibody comprises a heavy chain of SEQ ID NO: 1 and a light chain of SEQ ID NO:

2.

29. The method of any one of claims 1 to 28, wherein the anti-FGFR2b antibody is bemarituzumab.

30. The method of any one of claims 1 to 29, wherein the gastric cancer cells overexpress FGFR2b.

31. The method of any one of claims 1 to 30, wherein the cells of the gastric cancer overexpress FGFR2b mRNA or protein or contain an amplification of the FGFR2 gene.

32. 32. The method of claim 30 or 31, wherein the gastric cancer cells overexpress FGFR2b as measured by immunohistochemistry (IHC).

33. 33. The method of any one of claims 30-32, wherein at least 5%, 10%, 15%, or 20% of cells of the gastric cancer express FGFR2b as measured by IHC.

34. 33. The method of any one of claims 30 to 32, wherein the cells of the gastric cancer have an FGFR2b staining intensity of at least 2+, or 3+ as measured by IHC, e.g., at least 5%, 10%, 15%, or 20% of the cells of the gastric cancer have the FGFR2b staining intensity.

35. 33. The method of any one of claims 30-32, wherein any of the gastric cancer cells have an FGFR2b staining intensity of at least 2+, or 3+ as measured by IHC.

36. The method of any one of claims 30 to 32, wherein at least 10% of cells of the gastric cancer have an FGFR2b staining intensity of at least 2+, or 3+, as measured by IHC.

37. The method of any one of claims 1 to 36, wherein the chemotherapy regimen comprises: (a) oxaliplatin and capecitabine.

38. 38. The method of any one of claims 1 to 37, wherein the gastric cancer comprises gastric cancer or gastroesophageal junction cancer.

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