Treatment of Solid Tumors

Abstract

Methods are described for treating solid tumors in a subject, such as squamous cell carcinoma (such as head and neck squamous cell carcinoma), ER-PR-HER2 / neu- ("triple negative") breast cancer, intrahepatic cholangiocarcinoma, lung adenocarcinoma, and gynecological malignancies. The methods may include administering to the subject an anti-FGFR2b antibody.

Description

[Technical field]

[0001] Embodiments herein relate to the use of antibodies against fibroblast growth factor 2 (FGFR2), including antibodies against the FGFR2 isoform FGFR2-IIIb (also referred to as FGFR2b), in the treatment of solid tumors, such as, for example, squamous cell carcinoma (such as head and neck squamous cell carcinoma), "triple negative" breast cancer, intrahepatic cholangiocarcinoma, lung adenocarcinoma, and gynecological malignancies.

[0002] INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY The present specification incorporates by reference in its entirety the nucleotide / amino acid sequence listing, which was submitted contemporaneously herewith and is identified as follows: One XML document of 13,839 bytes entitled "10131-WO01-SEC.xml", created on March 27, 2023.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 328,789, filed April 8, 2022; U.S. Provisional Patent Application No. 63 / 377,266, filed September 27, 2022; and U.S. Provisional Patent Application No. 63 / 492,047, filed March 24, 2023, the disclosures of which are incorporated herein by reference. [Background technology]

[0004] Fibroblast growth factor receptor 2b (FGFR2b) is overexpressed in some gastric / gastroesophageal junction (GC / GEJ) cancers and is a target for novel therapies 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, at 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 regions of the receptor. The linker between D1 and D2 contains a continuous stretch of acidic amino acids called the "acid box" (AB). The region containing D1 and AB is thought to be involved in the autoinhibition of the receptor, which is relieved by binding to a ligand.

[0005] FGFRs are characterized by multiple alternative splicing of their mRNAs, which leads to various isoforms (Ornitz et al., J. Biol. Chem. 271:15292, 1996; see also Swiss-Prot P21802 and isoforms P21802-1 to -20 for the sequence of FGFR2 and its isoforms). Notably, there are forms that contain all three Ig domains (α isoforms) or only the two Ig domains D2 and D3 domains but lack D1 (β isoforms). For FGFR1, FGFR2, and FGFR3, all forms contain half of D3, designated IIIa, but for the other half of D3, two exons are available alternatively, leading to IIIb and IIIc forms. For FGFR2, these are designated FGFR2-IIIb and FGFR2-IIIc (or simply FGFR2b and FGFR2c, respectively); the corresponding beta forms are designated FGFR2(beta)IIIb and FGFR2(beta)IIIc. The FGFR2-IIIb form of FGFR2 (also designated K-sam-II) is a high affinity receptor for both FGF1 and KGF family members (FGF7, FGF10, and FGF22), while 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 members of the KGF family (Ornitz et al., supra) and is therefore also designated KGFR.

[0006] FGFRs and their isoforms are differentially expressed in various tissues. FGFR2-IIIb (and IIIb-type 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). Certain FGF ligands of these receptors have the opposite expression pattern. Thus, KGF subfamily members, including FGF7 (KGF), FGF10, and FGF22, bind only to FGFR2-IIIb (Zhang et al., supra), are expressed in mesenchymal tissues, and therefore may be paracrine effectors of epithelial cells (Ornitz et al., supra). In contrast, FGF4 subfamily member FGF4-6 binds to FGFR2-IIIc and is expressed in both epithelial and mesenchymal lineages, and may therefore have either 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 knocking out FGFR2-IIIb in mice leads to severe embryonic defects and embryonic lethality (De Moerlooze et al., Development 127:483, 2000).

[0007] Besides gastric cancer, other epithelial malignancies have been reported to overexpress FGFR2 at the DNA or protein level, including head and neck squamous cell carcinoma (Brands et al., 2017), esophageal cancer (Kato et al., 2013), colorectal cancer (Li et al., 2019), intrahepatic cholangiocarcinoma (Churi et al., 2014), pancreatic cancer (Kang et al., 2019), breast cancer (Reinjtes et al., 2013), ovarian cancer (Tyulyandina et al., 2018), cervical cancer (Sun et al., 2019), endometrial cancer (Gatius et al., 2011; Dutt et al., 2008), and others (Wu et al., 2013). Treatment of such malignancies typically involves the use of multiple modalities, such as surgery, systemic anticancer therapy (SACT), and radiation therapy, either alone, in combination, or sequentially. There remains a need for effective monotherapy for certain types of solid tumors. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Zhang et al.,J.Biol.Chem.281:15694,2006 [Non-Patent Document 2] Mohammadi et al.,Cytokine Growth Factor Revs,16:107,2005 [Non-Patent Document 3] Ornitz et al.,J.Biol.Chem.271:15292,1996 [Non-Patent Document 4] Miki et al.,Proc.Natl.Acad.Sci.USA 89:246,1992 [Non-Patent Document 5] Duan et al.,J.Biol.Chem.267:16076,1992 [Non-Patent Document 6] Finch et al.,Dev.Dyn.203:223,1995 [Non-Patent Document 7] De Moerlooze et al.,Development 127:483,2000 [Non-Patent Document 8] Brands et al., 2017 [Non-Patent Document 9] Kato et al., 2013 [Non-Patent Document 10] Li et al., 2019 [Non-Patent Document 11] Churi et al., 2014 [Non-Patent Document 12] Kang et al., 2019 [Non-Patent Document 13] Reinjtes et al., 2013 [Non-Patent Document 14] Tyulyandina et al., 2018 [Non-Patent Document 15] Sun et al., 2019 [Non-Patent Document 16] Gatius et al., 2011 [Non-Patent Document 17] Dutt et al., 2008 [Non-Patent Document 18] Wu et al., 2013 Summary of the Invention [Means for solving the problem]

[0009] The present disclosure provides a method of treating a solid tumor in a subject, comprising administering to the subject an anti-FGFR2b antibody monotherapy comprising either: (a) an initial administration of an anti-FGFR2b antibody at a dose of greater than 20 mg / kg to less than 30 mg / kg, followed by subsequent administrations of the anti-FGFR2b antibody at doses of 12 to 20 mg / kg, each at two weeks after the initial administration and Q2W thereafter, the subsequent administrations being lower doses than the initial administration; or (b) an every-two-weekly (Q2W) regimen of an anti-FGFR2b antibody at a dose of greater than 10 mg / kg to less than 20 mg / kg, followed by a single subsequent administration of the anti-FGFR2b antibody at a dose of 5 to 10 mg / kg, one week after the initial administration of the anti-FGFR2b antibody.

[0010] In some embodiments of the above methods, or any of the methods of treating a solid tumor herein, the solid tumor is selected from the group consisting of squamous cell carcinoma (such as head and neck squamous cell carcinoma), ER-PR-HER2 / neu- ("triple negative") breast cancer, pancreatic ductal adenocarcinoma, intrahepatic cholangiocarcinoma, colorectal adenocarcinoma, and gynecological malignancies.

[0011] In some embodiments of the above methods, or any of the methods of treating a solid tumor herein, the solid tumor is selected from the group consisting of squamous cell carcinoma (such as head and neck squamous cell carcinoma), "triple negative" breast cancer, intrahepatic cholangiocarcinoma, lung adenocarcinoma, and gynecological malignancies.

[0012] In some embodiments of the above methods, or any of the methods of treating solid tumors herein, the anti-FGFR2b antibody monotherapy is administered as second or subsequent line therapy for the solid tumor, such as third or subsequent line therapy.

[0013] In some embodiments of the above methods, or any method of treating a solid tumor herein, the squamous cell carcinoma is head and neck carcinoma or squamous cell esophageal carcinoma. In some embodiments of the above methods, or any method of treating a solid tumor herein, the squamous cell carcinoma is head and neck squamous cell carcinoma.

[0014] In some embodiments of the above methods, or any of the methods of treating a solid tumor herein, the gynecological malignancy is selected from the group consisting of ovarian epithelial cancer (including fallopian tube and primary peritoneal cancer), endometrial cancer, and cervical cancer.

[0015] In some embodiments of the above methods, or any of the methods of treating a solid tumor herein, the squamous cell carcinoma is post-platinum-based chemotherapy and / or post-PD-1 inhibitor.

[0016] In some embodiments of the above methods, or any of the methods of treating a solid tumor herein, the triple-negative breast cancer is post-chemotherapy, post-PARPi (if BRCA mutated), post-PD-1 inhibitor therapy, and / or post-anti-trop-2 therapy.

[0017] In some embodiments of the above methods, or any method of treating a solid tumor herein, the pancreatic ductal adenocarcinoma is post-platinum-based chemotherapy, the intrahepatic cholangiocarcinoma is post-platinum-based chemotherapy and post-targeted therapy if targeted therapy is eligible, and / or the colorectal adenocarcinoma is post-bevacizumab therapy, post-oxaliplatin-based chemotherapy, post-irinotecan-based chemotherapy, and / or post-additional prior therapy based on RAS, BRAF, and dMMR / MSI-H status.

[0018] In some embodiments of the above methods, or any of the methods of treating solid tumors herein, the gynecological malignancy is post-platinum-based chemotherapy and / or is platinum chemorefractory.

[0019] In some embodiments of the above methods, or any of the methods of treating a solid tumor herein, the cells of the solid tumor overexpress FGFR2b mRNA or protein, or contain FGFR2 gene amplification.

[0020] In some embodiments of the above methods, or any of the methods of treating a solid tumor herein, the solid tumor overexpresses FGFR2b as determined by immunohistochemistry (IHC).

[0021] In some embodiments of the above methods, or any method of treating a solid tumor herein, cells of the solid tumor are FGFR2b positive as determined by IHC, optionally at least 5%, 10%, or 20% of the cells are FGFR2b positive.

[0022] In some embodiments of the above methods, or any method of treating a solid tumor herein, cells of the solid tumor exhibit 2+ and / or 3+ FGFR2b staining as determined by IHC, and optionally at least 5%, 10%, or 20% of the cells exhibit said FGFR2b staining.

[0023] In some embodiments of the above methods, or any of the methods of treating a solid tumor herein, the cells of the solid tumor are PD-L1 positive as determined by IHC staining.

[0024] In some embodiments of the above methods, (a) the initial administration of anti-FGFR2b antibody is at a dose of greater than 20 mg / kg to 25 mg / kg or less, followed by subsequent administrations of anti-FGFR2b antibody at doses of 12 to 17 mg / kg, respectively, 2 weeks after the initial administration and Q2W thereafter.

[0025] In some embodiments of the above methods, or any method of treating a solid tumor herein, (a) the initial administration of anti-FGFR2b antibody is at a dose of 22-25 mg / kg, followed by subsequent administrations of anti-FGFR2b antibody at doses of 12-17 mg / kg, each 2 weeks after the initial administration and Q2W thereafter.

[0026] In some embodiments of the above methods, or any method of treating a solid tumor herein, (a) the initial administration of anti-FGFR2b antibody is at a dose of about 22 mg / kg, followed by subsequent administrations of anti-FGFR2b antibody at a dose of about 15 mg / kg, each administered 2 weeks after the initial administration and Q2W thereafter.

[0027] In some embodiments of the above methods, or any method of treating a solid tumor herein, (b) the Q2W regimen of anti-FGFR2b antibody is at a dose of 12-17 mg / kg, and the subsequent single dose of anti-FGFR2b antibody one week after the first dose of anti-FGFR2b antibody is at a dose of 7-8 mg / kg.

[0028] In some embodiments of the above methods, or any method of treating a solid tumor herein, (b) the Q2W regimen of anti-FGFR2b antibody is at a dose of about 15 mg / kg, and the subsequent single administration of anti-FGFR2b antibody one week after the first administration of anti-FGFR2b antibody is at a dose of about 7.5 mg / kg.

[0029] In some embodiments of the above methods, or any of the methods of treating solid tumors herein, the anti-FGFR2b antibody is administered intravenously.

[0030] In some embodiments of the above methods, or any of the methods of treating solid tumors herein, the anti-FGFR2b antibody comprises a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 6, an HCDR2 of SEQ ID NO: 7, and an 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.

[0031] In some embodiments of the above methods, or any of the methods of treating solid tumors herein, the anti-FGFR2b antibody is afucosylated.

[0032] In some embodiments of the above methods, or any of the methods of treating solid tumors herein, the heavy chain variable region of the anti-FGFR2b antibody comprises an amino acid sequence that is 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 that is at least 95% identical to SEQ ID NO:5.

[0033] In some embodiments of the above methods, or any of the methods of treating solid tumors herein, 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.

[0034] In some embodiments of the above methods, or any of the methods of treating a solid tumor herein, the anti-FGFR2b antibody comprises a heavy chain of SEQ ID NO: 1, a light chain of SEQ ID NO: 2, and the anti-FGFR2b antibody lacks fucose at Asn297 (EU numbering).

[0035] In some embodiments of the above methods, or any of the methods of treating solid tumors herein, the anti-FGFR2b antibody is bemarituzumab.

[0036] In some embodiments of the above methods, or any method of treating a solid tumor herein, bemarituzumab is administered intravenously, and (a) the initial dose of bemarituzumab is at a dose of greater than 20 mg / kg up to and including 25 mg / kg, followed by subsequent doses of 12 to 17 mg / kg, respectively, 2 weeks after the initial dose and Q2W thereafter.

[0037] In some embodiments of the above methods, or any method of treating a solid tumor herein, bemarituzumab is administered intravenously, and (a) the first dose of bemarituzumab is at a dose of 22-25 mg / kg, followed by subsequent doses of 12-17 mg / kg, each administered 2 weeks after the first dose and Q2W thereafter.

[0038] In some embodiments of the above methods, or any method of treating a solid tumor herein, bemarituzumab is administered intravenously, and (a) an initial dose is at a dose of about 22 mg / kg, followed by subsequent doses of bemarituzumab, each at a dose of about 15 mg / kg, 2 weeks after the initial dose and Q2W thereafter.

[0039] In some embodiments of the above methods, or any method of treating a solid tumor herein, bemarituzumab is administered intravenously, and (b) the Q2W regimen of bemarituzumab is at a dose of 12-17 mg / kg, and the subsequent single dose of bemarituzumab 1 week after the first dose is at a dose of 7-8 mg / kg.

[0040] In some embodiments of the above methods, or any method of treating a solid tumor herein, bemarituzumab is administered intravenously, and (b) the Q2W regimen of bemarituzumab is at a dose of about 15 mg / kg, and the subsequent single dose of bemarituzumab one week after the first dose is at a dose of about 7.5 mg / kg. [Brief description of the drawings]

[0041] [Figure 1A] FIG. 1 is a diagram of a method for treating various solid tumor types. [Figure 1B] FIG. 1 is a diagram of a method for treating various solid tumor types. [Figure 2A] 2A and 2B are diagrams of amino acid sequences. Figure 2A illustrates the amino acid sequence of an anti-FGFR2b antibody of some embodiments. Figure 2B illustrates the amino acid sequence of FGFR2 of some embodiments. [Figure 2B] 2A and 2B are diagrams of amino acid sequences. Figure 2A illustrates the amino acid sequence of an anti-FGFR2b antibody of some embodiments. Figure 2B illustrates the amino acid sequence of FGFR2 of some embodiments. [Figure 3A] 1 is a graph showing ADCC response of solid tumor cells treated with bemarituzumab according to some embodiments. [Figure 3B]1 is a graph showing ADCC response of solid tumor cells treated with bemarituzumab according to some embodiments. [Figure 3C] 1 is a graph showing ADCC response of solid tumor cells treated with bemarituzumab according to some embodiments. [Figure 3D] 1 is a graph showing ADCC response of solid tumor cells treated with bemarituzumab according to some embodiments. [Figure 3E] 1 is a graph showing ADCC response of solid tumor cells treated with bemarituzumab according to some embodiments. [Figure 3F] 1 is a graph showing ADCC response of solid tumor cells treated with bemarituzumab according to some embodiments. [Figure 3G] 1 is a graph showing ADCC response of solid tumor cells treated with bemarituzumab according to some embodiments. [Figure 3H] 1 is a graph showing ADCC response of solid tumor cells treated with bemarituzumab according to some embodiments. [Figure 3I] 1 is a graph showing ADCC response of solid tumor cells treated with bemarituzumab according to some embodiments. [Figure 4-1] 1 is a summary of the activity schedule for the study described in Example 2. [Figure 4-2] 1 is a summary of the activity schedule for the study described in Example 2. [Figure 4-3] 1 is a summary of the activity schedule for the study described in Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] Described herein is a method for treating a solid tumor in a subject. The cells of the solid tumor may overexpress FGFR2 isoform FGFR2-IIIb (also known as FGFR2b). The method may include administering an anti-FGFR2b antibody, such as bemarituzumab, to the subject. The method may include administering the anti-FGFR2b antibody as a monotherapy (e.g., as a single therapeutic agent). It is contemplated herein that the anti-FGFR2b antibody monotherapy may be administered in two possible dose-setting regimens. For example, one anti-FGFR2b antibody monotherapy may include an initial administration of an anti-FGFR2b antibody at a dose of greater than about 20 mg / kg to about 30 mg / kg or less, such as 20-25 mg / kg, 21-30 mg / kg, or 22-25 mg / kg, or 25-30 mg / kg, followed by administration of an anti-FGFR2b antibody at a dose of about 12-20 mg / kg, such as about 12-17 mg / kg (e.g., 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, or 17 mg / kg), about 15-17 mg / kg, or about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg, two weeks after the initial administration, and Q2W thereafter. For example, the anti-FGFR2b antibody may be administered Q2W, where the subject is initially administered at a dose of greater than 20 mg / kg to 25 mg / kg, such as 22-25 mg / kg, followed by a dose of 12-17 mg / kg, such as 15-17 mg / kg, two weeks after the initial administration, and then Q2W, respectively. For example, the anti-FGFR2b antibody may be administered Q2W, where the subject is initially administered at a dose of 22-25 mg / kg, such as 22 mg / kg, 23 mg / kg, 24 mg / kg, or 25 mg / kg, followed by a dose of 15-17 mg / kg, such as 15 mg / kg, 16 mg / kg, or 17 mg / kg, two weeks after the initial administration, and then Q2W, respectively. For example, an anti-FGFR2b antibody may be administered to a subject Q2W with an initial dose of about 22 mg / kg, followed by subsequent doses of about 15 mg / kg, two weeks after the initial dose, and Q2W thereafter.

[0043] Further anti-FGFR2b antibody monotherapy may include a regimen of administering an anti-FGFR2b antibody at a dose of greater than about 10 mg / kg to about 20 mg / kg or less, such as 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg, and one week after the first administration of the anti-FGFR2b antibody, administering a single dose of an anti-FGFR2b antibody at a dose of about 5 to 10 mg / kg, such as 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg, every two weeks (Q2W). For example, a Q2W regimen of an anti-FGFR2b antibody is a dose of 12-17 mg / kg (e.g., 15-17 mg / kg), and a subsequent single dose of the anti-FGFR2b antibody one week after the first dose of the anti-FGFR2b antibody is a dose of 7-8 mg / kg. For example, a Q2W regimen of an anti-FGFR2b antibody is a dose of about 15 mg / kg, and a subsequent single dose of the anti-FGFR2b antibody one week after the first dose of the anti-FGFR2b antibody is a dose of about 7.5 mg / kg.

[0044] Alterations in the FGF / FGFR2 signaling pathway have been reported in the literature for multiple tumor types. Data from The Cancer Genome Atlas (TCGA) have reported that detection of FGFR2 overexpression by mRNA is common among epithelial cancers. Among the cancers with high expression (fragments per kilobase of transcript per million [FPKM] >10) are cholangiocarcinoma (93.3%), ovarian cancer (78.8%), pancreatic cancer (33.9%), triple-negative breast cancer (41.8%), head and neck cancer (57.5%), esophageal squamous cell carcinoma (45.7%), endometrial cancer (46.7%), cervical cancer (29.4%), and colorectal cancer (12.9%). Immunohistochemistry (IHC) suggests overexpression (as subjects with 2+ / 3+ FGFR2b membrane staining in tumor cells) in ovarian cancer (19%, 95%CI 14%-24%), endometrial cancer (23%, 95%CI 17%-29%), head and neck squamous cell carcinoma (22%, 95%CI 15%-29%), cervical cancer (10%, 95%CI 4%-16%), triple-negative breast cancer (8%, 95%CI 4%-13%), lung adenocarcinoma (6%, 95%CI 1%-11%), and intrahepatic cholangiocarcinoma (iCCA, 1%, 95%CI 0%-3%) (Table 10). Evaluation of bemarituzumab in subjects with tumors that overexpress FGFR2b may improve outcomes in these subjects by providing targeted inhibition of tumor growth signaling.

[0045] Anti-FGFR2b antibody As used herein, "antigen binding protein" has its customary and usual meaning as understood by those of skill in the art in light of the present disclosure. It refers to a protein that specifically binds to a designated antigen. The term encompasses intact antibodies and derivatives, variants, fragments, and mutants thereof. Antigen binding proteins also include bivalent and polyvalent / multivalent constructs and bispecific and polyspecific / 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 may be administered to a subject. By way of example, the antigen binding protein may comprise or consist of an antibody, such as bemarituzumab.

[0046] An antibody is an example of an antigen-binding protein. As used herein, "antibody" has its customary and ordinary meaning as understood by those of skill in the art in light of the present disclosure. It refers to any isotype of immunoglobulin with specific binding 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, human or humanized antibodies can be of any isotype, including IgG (including IgG1, IgG2, IgG3, and IgG4 subtypes), IgA (including IgA1 and IgA2 subtypes), IgM, and IgE. Human IgG antibodies generally contain 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" in that different portions of the antibody may be derived from two or more different antibodies from the same or different species. It will be understood that once an antibody is obtained from a source, it may be further engineered, for example to enhance stability and folding. Thus, it will be understood that a "human" antibody may be obtained from a source and may have undergone further engineering, for example, in the Fc region. An engineered antibody may still be referred to as a type of human antibody. Similarly, variants of human antibodies, such as those that have undergone affinity maturation, are also understood to be "human antibodies" unless otherwise specified. In some embodiments, the antigen binding protein comprises, consists essentially of, or consists of a human, humanized, or chimeric monoclonal antibody.

[0047] A "heavy chain" of an antigen binding protein (such as an antibody) comprises a variable region ("VH") and three constant regions: CH1, CH2, and CH3. A "light chain" of an antigen binding protein (such as an antibody) comprises a variable region ("VL") and a constant region ("CL"). Human light chains include kappa and lambda chains.

[0048] "Antigen-binding region" refers to a protein or a portion of a protein that specifically binds to a designated antigen. For example, a portion of an antigen-binding protein that contains amino acid residues that interact with an antigen to confer to the antigen-binding protein its specificity and affinity for the antigen is referred to as an "antigen-binding region". The antigen-binding region also typically includes one or more "complementary binding regions" ("CDRs") of an antibody. A "CDR" is an amino acid sequence that contributes to antigen-binding specificity and affinity. Antigen-binding regions of antibody heavy and light chains generally exhibit the same overall structure, including relatively conserved framework regions held together by three CDRs. The CDRs from the two chains of each heavy / light chain pair typically align with the framework regions to form a structure that specifically binds to a specific epitope on a target protein. From the N-terminus to the C-terminus, naturally occurring light and heavy chain variable regions both typically follow the following order of these elements: FR1, CDR1, FR2, CDR2, FR3, CDR3 and 4. A numbering system has been devised to assign numbers to the amino acids that occupy each position in each of 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 in 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.

[0049] In the methods described herein, an antigen binding protein against FGFR2b, such as an antibody, may be used. The antibody may specifically bind to FGFR2b. In some embodiment methods, the anti-FGFR2b antigen binding protein binds with higher affinity to FGFR2b than to FGFR2-IIIc. For example, the anti-FGFR2b antibody may not 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 may result in inhibition of phosphorylation of FGFR2 or MAP kinase downstream of FGFR2. In some embodiment methods, the anti-FGFR2b antigen binding protein (eg, an antibody), upon binding to FGFR2b, inhibits binding between FGFR2b and its FGF ligand, such as FGF1 and / or FGF2.

[0050] Binding of antigen binding proteins (e.g., antibodies) to FGFR2b and inhibition of binding between FGFR2b and FGF can be determined by ELISA assays, e.g., as described in U.S. Pat. No. 8,101,723, or by chip-based assays, e.g., as described in Example 2 of WO 2015 / 017600. In some embodiments, the antibodies comprise ADCC activity, and in some embodiments, have enhanced ADCC activity, e.g., as described in WO 2015 / 017600. ADCC activity may be determined, e.g., as described in Example 3 of WO 2015 / 07600. In some embodiments, the antibodies may 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 is capable of increasing 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, e.g., as described in Example 2 of WO 2017 / 091577.

[0051] 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 terminated by 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 number 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 a portion of an antibody molecule that is not afucosylated. Within a population of antibodies, an antibody is considered afucosylated if less than 5% of the antibodies in the population contain 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 of the present specification 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.

[0052] In some embodiments, the afucosylated anti-FGFR2b antibody mediates antibody-dependent cell-mediated cytotoxicity (ADCC) more effectively in the presence of human effector cells than an antibody containing fucose at the same amino acid sequence. 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.

[0053] An exemplary 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 embodiment methods, 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 embodiment methods, the anti-FGFR2b antibody is bemarituzumab.

[0054] 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 addition, in some embodiments, it is 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 still binds 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 at least one order 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 embodiments, the anti-FGFR2b antibody comprises a heavy chain variable region that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 96%, 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%, 96%, 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%, 96%, 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%, 96%, 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%, 96%, 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 of SEQ ID NO:4 are substituted, inserted, and / or deleted. These substitutions, insertions, or deletions may occur in regions outside the CDRs (i.e., in the FRs). In some embodiments, a total of 1 to 10, 1 to 5, or 1 to 3 amino acids of SEQ ID NO:5 are substituted, inserted, and / or deleted. These substitutions, insertions, or deletions may occur in regions outside the CDRs (i.e., in the FRs). In some embodiments, a total of 1 to 10, 1 to 5, or 1 to 3 amino acids of SEQ ID NO:4 are substituted, inserted, and / or deleted. These 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 of SEQ ID NO:5 are replaced, inserted, and / or deleted, and up to 10 amino acids of SEQ ID NO:4 are replaced, inserted, and / or deleted. These replacements, 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 of SEQ ID NO:5 are replaced, inserted, and / or deleted, and up to 5 amino acids of SEQ ID NO:4 are replaced, inserted, and / or deleted. These replacements, 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 of SEQ ID NO:5 are replaced, inserted, and / or deleted, and up to 3 amino acids of SEQ ID NO:4 are replaced, inserted, and / or deleted. These replacements, insertions, or deletions may occur in regions outside the CDRs (i.e., in the FRs). In some embodiments, a total of 1 to 10, 1 to 5, or 1 to 3 amino acids of SEQ ID NO: 4 are substituted, inserted, and / or deleted. 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.

[0055] 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 (hereby incorporated by reference in its 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 hereby incorporated by reference. The heavy chain variable region sequence of antibody HuGAL-FR21 is underlined in Figure 13 of U.S. Pat. No. 8,101,723B2, which is hereby specifically incorporated by reference. The light and heavy chain variable regions of GAL-FR22 are provided, for example, as SEQ ID NOs: 7 and 8 in U.S. Pat. No. 8,101,723B2, while the Kabat CDRs and light and heavy chain variable regions are also provided in FIG. 16 of this patent, which are incorporated herein by reference. Hybridomas producing GAL-FR21, GAL-FR22 and GAL-FR23 have been deposited at the American Type Culture Collection, PO Box 1549, Manassas VA, USA, 20108, under ATCC numbers 9586, 9587 and 9408 on November 6, 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.

[0056] Bemarituzumab is an afucosylated humanized monoclonal antibody that targets fibroblast growth factor (FGF) receptor isoform 2b (FGFR2b) with a dual mechanism of FGF binding inhibition and antibody-dependent cellular cytotoxicity. Any of the anti-FGFR2b antibodies of the methods described herein may 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 the HCDR1-3 and LCDR1-3 of bemarituzumab. Bemarituzumab may be produced in a Chinese hamster ovary cell line that lacks the FUT8 gene, so that the antibody produced 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, enhancing immune cell-mediated tumor cell killing.

[0057] Bemarituzumab inhibits FGFR2b phosphorylation and cell proliferation stimulated by FGF ligands in cell cultures of gastric cancer, breast cancer, and non-small cell lung 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 contemplated 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 contemplated that bemarituzumab is specific to the FGFR2b receptor and therefore does not interfere with the signaling of other FGF / FGFRs, including 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 hyperphosphatemia associated with FGFR TKIs (Catenacci et al., 2020; Dienstmann et al., 2014; Sequist et al., 2014; Andre et al., 2013; Brown et al., 2005).

[0058] Bemarituzumab monotherapy has been investigated in a Phase 1 dose-finding study (FPA144-001), and in combination with mFOLFOX6 chemotherapy in FGFR2b-positive gastric cancer in the FIGHT study. Bemarituzumab efficacy has been correlated with the degree of FGFR2b overexpression by immunohistochemistry (IHC) in gastric cancer, and a manageable safety profile has been demonstrated in combination with mFOLFOX6. Genomic and IHC data suggest that other carcinomas may also have significant FGFR2b overexpression rates. Bemarituzumab blocks FGFR2b phosphorylation, downregulates the receptor, and inhibits downstream signaling. The effect on downstream signaling was measured by examining the phosphorylation of FGFR substrate-2 (FRS2), a protein that is directly phosphorylated by FGFR2 protein. Each of these mechanisms has been investigated in vitro and in vivo and, without being limited by theory, appears to contribute to the antitumor activity of bemarituzumab. In human tumor xenograft models overexpressing FGFR2b, bemarituzumab shows dose-dependent antitumor activity with regressions and complete responses at well-tolerated doses.

[0059] 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. The 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 faster clearance in 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 for doses above this level when administered at weekly intervals. PK studies supporting the toxicokinetic studies showed a dose-dependent increase in exposure (AUC), supporting the reliability of this study in determining toxicity. Significant and reproducible developmental toxicity was observed in embryo-fetal development in prenatal and postnatal developmental studies at all dose levels (5-100 mg / kg / dose).Thus, in some embodiments, it is contemplated that subjects treated with bemarituzumab are not pregnant.

[0060] Bemarituzumab has demonstrated an acceptable safety profile. Identified risks when used in combination with mFOLFOX6 include corneal toxicity, infusion reactions, gastrointestinal toxicity (stomatitis and mucosal inflammation), nail toxicity, and elevated AST and ALT. Corneal events are extremely common with bemarituzumab, with the most common adverse event being dry eye. Nearly all events were non-serious, but grade 3 events such as ulcerative keratitis and punctate keratitis, which can lead to vision loss, have also been observed. The majority of corneal events typically resolve with treatment interruption or discontinuation and standard intervention for corneal events. Thus, in some embodiments, it is contemplated that subjects treated with bemarituzumab will be further treated with an ocular lubricant. Ocular lubricants may be administered prophylactically to reduce the risk of corneal events.

[0061] In some methods described herein, bemarituzumab may be provided in a drug product 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.

[0062] An anti-FGFR2b antibody, such as bemarituzumab, may be administered intravenously in the methods described herein.

[0063] Methods for treating solid tumors with FGFR2b overexpression Solid tumors Described herein are methods of treating a solid tumor in a subject, such as squamous cell carcinoma, ER-PR-HER2 / neu- ("triple negative") breast cancer, intrahepatic cholangiocarcinoma, lung adenocarcinoma, and gynecological malignancies. The squamous cell carcinoma can be, for example, head and neck cancer. The gynecological malignancies can be, for example, ovarian epithelial carcinoma (including fallopian tube and primary peritoneal cancer), endometrial cancer, or cervical cancer. In some embodiments, the solid tumor is selected from squamous cell carcinoma, triple negative breast cancer, pancreatic ductal adenocarcinoma, intrahepatic cholangiocarcinoma, colorectal adenocarcinoma, and gynecological malignancies.

[0064] In some embodiments, anti-FGFR2b antibody monotherapy is administered as a second-line or later therapy for solid tumors, such as third-line or later. The term "second-line therapy" as used herein refers to treatment of a disease or condition after an initial treatment ("first-line" treatment or therapy) has failed, stopped working, or has side effects that the patient cannot tolerate. Therapies or treatments administered after second-line therapy can be referred to as "beyond" second-line therapy, or numerically (e.g., "third" or "fourth" line therapy). In some embodiments, anti-FGFR2b antibody monotherapy is administered as a second-line or later therapy after first-line therapy, including, for example, chemotherapy, radiation, and / or immunotherapy. For example, the solid tumor can be after platinum-based chemotherapy, after PD-1 inhibitor therapy, after poly(ADP-ribose) polymerase inhibitor (PARPi) therapy (for BRCA mutations), after anti-trop-2 therapy, or after targeted therapy. In some embodiments, the solid tumor can be squamous cell carcinoma after platinum-based chemotherapy and / or after PD-1 inhibitors. In some embodiments, the solid tumor can be triple-negative breast cancer after chemotherapy, after PARPi (if BRCA mutated), after PD-1 inhibitor therapy, and / or after anti-trop-2 therapy. In some embodiments, the solid tumor can be pancreatic ductal adenocarcinoma after platinum-based chemotherapy. In some embodiments, the solid tumor can be intrahepatic cholangiocarcinoma after platinum-based chemotherapy and after targeted therapy if the targeted therapy is eligible. In some embodiments, the solid tumor can be colorectal adenocarcinoma after bevacizumab therapy, after oxaliplatin-based chemotherapy, after irinotecan-based chemotherapy, and / or after additional prior therapy based on RAS, BRAF, and dMMR / MSI-H status. In some embodiments, the solid tumor can be a gynecological malignancy after platinum-based chemotherapy and / or platinum chemoresistant.

[0065] A method comprising administering an anti-FGFR2b antibody The methods described herein may include administering an anti-FGFR2b antibody monotherapy. For example, the anti-FGFR2b antibody monotherapy may include a biweekly (Q2W) regimen of an initial administration of an anti-FGFR2b antibody at a dose of greater than 20 mg / kg to less than or equal to 30 mg / kg, followed by subsequent administrations of the anti-FGFR2b antibody at doses of 12 to 20 mg / kg, two weeks after the initial administration, and Q2W thereafter, each subsequent administration being at a lower dose than the initial administration. In another example, the anti-FGFR2b antibody monotherapy may include a biweekly (Q2W) regimen of an anti-FGFR2b antibody at a dose of greater than 10 mg / kg to less than or equal to 20 mg / kg, followed by a single subsequent administration of the anti-FGFR2b antibody at a dose of 5 to 10 mg / kg, one week after the initial administration of the anti-FGFR2b antibody. The subsequent administrations or doses of the anti-FGFR2b antibody may be referred to as "intervention" doses.

[0066] In some of the methods, the anti-FGFR2b antibody is administered to the subject Q2W at a dose of greater than 20 mg / kg to less than or equal to 30 mg / kg, such as greater than 20 mg / kg to less than or equal to 25 mg / kg. In some of the methods, the anti-FGFR2b antibody is administered to the subject Q2W at a dose of about 22-25 mg / kg (e.g., 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, or a range defined by any two of the foregoing values). In some of the methods, the anti-FGFR2b antibody is administered to the subject Q2W at a dose of 22 mg / kg. According to some of the methods described herein, an additional dose or "intervening" dose of the anti-FGFR2b antibody may be 12-20 mg / kg, such as 12-17 mg / kg, and may be administered two weeks after the first administration of the anti-FGFR2b antibody and Q2W thereafter. According to some methods described herein, an initial administration of anti-FGFR2b antibody may be followed by subsequent administrations of anti-FGFR2b antibody Q2W, each at a dose of about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, or a range defined by any two of the foregoing values. By way of example, the additional dose or "intervening" dose may be about 15 mg / kg.

[0067] In some of the methods, the anti-FGFR2b antibody is administered to the subject Q2W at a dose of greater than 10 mg / kg to 20 mg / kg or less. In some of the methods, the anti-FGFR2b antibody is administered to the subject Q2W at a dose of about 12 to 17 mg / kg (e.g., 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, or a range defined by any two of the foregoing values). In some of the methods, the anti-FGFR2b antibody is administered to the subject Q2W at a dose of 15 mg / kg. In some embodiments, one week after the initial administration of anti-FGFR2b antibody, the method may include administering a single dose of anti-FGFR2b antibody at a dose of 5-10 mg / kg (e.g., 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, or a range defined by any two of the foregoing values). By way of example, the additional dose or "intervention" dose may be about 7-8 mg / kg, such as about 7.5 mg / kg.

[0068] For any of the methods described herein, the anti-FGFR2b antibody can be bemarituzumab.A method of treating a solid tumor in a subject according to some embodiments is illustrated in FIG.

[0069] According to the methods of some embodiments, a study is described to evaluate the safety and efficacy of bemarituzumab monotherapy in subjects across multiple solid tumors with FGFR2b overexpression and recurrent / refractory unresectable and / or metastatic disease. The study may include dosing and scheduling of bemarituzumab as described in Example 2.

[0070] For any of the methods of treating a solid tumor described herein, the cells of the solid tumor of the subject may express FGFR2b. For example, the cells of the solid tumor of the subject may overexpress FGFR2b protein, overexpress FGFR2b mRNA, or contain FGFR2b gene amplification. In some methods, the cells of the solid tumor express FGFR2b protein as determined by immunohistochemistry (IHC). For example, at least 5% (e.g., 5%, 10%, or 20%) of the cells of the solid tumor of the subject may be FGFR2b positive as determined by IHC. For example, the cells of the solid tumor of the subject may have a FGFR2b staining intensity of 2+ and / or 3+. For example, at least 5% (e.g., at least 5%, 10%, or 20%) of the cells of the solid tumor may have a FGFR2b staining intensity of 1+, 2+, or 3+. A subject's solid tumor may be considered to overexpress FGFR2b if the cells of the solid tumor of the subject may have a FGFR2b staining intensity of 2+ or 3+, or if at least 5% (e.g., at least 5%, 10%, or 20%) of the cells of the solid tumor may have a FGFR2b staining intensity of 1+, 2+, or 3+. For example, at least 5% of the cells of the solid tumor of the subject may have a FGFR2b staining intensity of 2+ and / or 3+. For example, at least 10% of the cells of the solid tumor of the subject may have a FGFR2b staining intensity of 2+ and / or 3+. It is contemplated that subjects with solid tumors that overexpress FGFR2b are particularly likely to benefit from a treatment method comprising administering an anti-FGFR2b antibody (such as bemarituzumab) as described herein. Optionally, the cells of the solid tumor are also assessed for PD-L1 expression, for example, by IHC.

[0071] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLES

[0072] Example 1: Administration of Bemarituzumab to Breast and Lung Cancer Cell Lines The ADCC activity of bemarituzumab was measured in vitro in squamous cell lung cancer and breast cancer cell lines that were determined to express FGFR2b surface expression by flow cytometry. Squamous cell lung cancer cell lines (KNS-62, LC1F, HARA, EPLC-272H, SW900, NCIH2170, LUDLU1, and SW1573) and triple-negative breast cancer (TNBC) cell lines (HCC1569, HCC1806, HCC38, HCC1187, BT20, and HCC1937) were evaluated for FGFR2b mRNA expression [ENST00000457416.6[FPKQ]] and for FGFR2b protein surface expression by flow cytometry. As positive controls, gastric cancer cell lines SNU16-Luc, SNU16, and KATOIII were also evaluated. In this flow cytometry experiment, cells were incubated with bemarituzumab or a control antibody of the same isotype, and then binding was detected using an anti-human IgG1 antibody conjugated to allophycocyanin (APC). Mean fluorescence intensity (MFI) was quantified by flow cytometry. As shown in Table 1 below, squamous cell lung cancer cell lines KNS-62, EPLC-272H, LC1F, HARA, SW900, and LUDLU1 showed an MFI of at least 10, as did triple-negative breast cancer (TNBC) cell lines HCC1569, HCC1806, HCC38, BT20, and HCC1937.

[0073] The effect of bemarituzumab on antibody-dependent cellular cytotoxicity (ADCC) was evaluated for each of these cell lines. Cancer cell lines were co-cultured with Jurkat-Luc effector cells in 96-well plates with a fixed number of effector cells (75,000 cells per well) and an effector to target cell ratio of 2.5:1 or 5:1. Cells were treated with 20 mg / mL bemarituzumab and then incubated at 37°C for 20 hours. ADCC was assessed using Promega's ADCC reporter bioassay (G7018) with a luminescence readout. Figures 3A-I summarize the ADCC curves. ADCC activity was observed in squamous lung cancer cell lines and breast cancer cell lines that exhibited surface expression of FGFR2b above 10 MFI. It could therefore be concluded that bemarituzumab has the ability to induce ADCC in FGFR2b-positive triple-negative breast cancer cells and squamous lung cancer cells.

[0074] [Table 1]

[0075] Example 2: Phase 1b / 2 basket study of bemarituzumab monotherapy in solid tumors with FGFR2b overexpression Here we describe a Phase 1b / 2, open-label, multicenter, exploratory signal detection basket study evaluating the efficacy and safety of bemarituzumab monotherapy in subjects across multiple solid tumors with FGFR2b overexpression and relapsed / refractory unresectable and / or metastatic disease.

[0076] The study includes a pre-screening period with central testing demonstrating FGFR2b overexpression, a 28-day screening period, a treatment period, a safety follow-up (SFU) period, and a long-term follow-up (LTFU) period. Subjects who discontinue bemarituzumab will have an SFU visit 28 days (+3 days) after their last dose of study treatment. In addition, subjects will have LTFU for survival up to 2 years from their first dose of bemarituzumab approximately every 3 months (± 1 month) after the SFU visit. Subjects will be treated until disease progression, unacceptable toxicity, subject request, or death (whichever occurs first).

[0077] Radiographic assessment will be performed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 every 8 weeks (± 7 days) from Day 1 of Cycle 1 through Week 56, then every 12 weeks (± 14 days) until radiographic progression or initiation of subsequent anticancer therapy. Primary and secondary objectives and endpoints are summarized in Table 2 below.

[0078] [Table 2]

[0079] [Table 3]

[0080] The study will include two parts: monotherapy dose-finding in all tumor types (Part 1, Phase 1b) (i.e., a total of 9-18 subjects regardless of tumor type), followed by monotherapy dose expansion (Part 2, Phase 2) for each of the following eight tumor cohorts at selected dose levels from Part 1. For both parts of the study, tumor samples from subjects will be required to demonstrate FGFR2b overexpression prior to entry into the study. Tumor specimens collected since completion of most recent cancer therapy are recommended.

[0081] The study will enroll subjects in eight tumor cohorts based on cancer type: 1. Head and neck squamous cell carcinoma 2. Triple-negative breast cancer (ER-, PR-, HER2 / neu-) 3. Intrahepatic cholangiocarcinoma 4. Lung adenocarcinoma 5. Ovarian epithelial carcinoma, including fallopian tube and primary peritoneal carcinoma 6. Endometrial adenocarcinoma 7. Cervical cancer 8.Other solid tumors

[0082] Requirements for number of prior lines of therapy vary by study cohort, as outlined in the inclusion criteria below.

[0083] The study may be amended to add or remove cohorts based on enrollment rates, prevalence of FGFR2b overexpression at prescreening, preliminary efficacy and safety data, and evolving data on other potential solid tumor indications with FGFR2b overexpression. Study cohorts may be modified to specific histological subtypes based on emerging data on FGFR2b overexpression and response rates. Recruitment / enrollment in any of the above cohorts may be challenging due to the potentially low frequency of FGFR2b overexpression in certain disease settings. Thus, the sponsor reserves the right to stop recruitment / enrollment in any cohort due to delayed or no accrual. Cohort 10 (other solid tumors) will be closed when all other cohorts are closed to enrollment, regardless of the number of patients enrolled at that time.

[0084] Part 1 will begin with dose level 1 (22 mg / kg intravenously [IV] on day 1 of cycle 1, followed by 15 mg / kg IV every 2 weeks [Q2W] starting on day 15). The study DLT evaluation period will be 28 days. A Dose Level Review Team (DLRT) meeting will be held once 3-6 subjects have completed the DLT evaluation period. Depending on observed safety data, the following may occur: (1) enrollment at dose level 1; or (2) dose de-escalation to dose level 1A; or (3) initiation of part 2 of the study. Escalation / de-escalation guidelines will be derived using a modified Toxicity Probability Internal (mTPI)-2 design using a target toxicity probability of 0.25 with an acceptable toxicity probability interval of (0.20, 0.30). Part 1 will continue until a maximum sample size of 18 is reached or the number of subjects treated at a given dose level reaches 9 and the mTPI-2 algorithm dictates to remain at that dose level. In addition, 3-6 Japanese subjects will be enrolled, either as part of the initial dose evaluation in Part 1 or as a supplement when the phase 2 recommended dose (RP2D) is determined. Japanese subjects may be enrolled in Part 2 once the DLRT is deemed RP2D safe for Japanese subjects globally.

[0085] Number of targets The study will enroll 9-18 subjects in part 1, independent of tumor cohort, and potentially up to 6 additional Japanese subjects, for a total of 288-303 subjects. Part 2 will enroll up to 36 subjects in each of the 10 planned tumor cohorts (part 1 subjects assigned to the same dose level used in part 2 will contribute to this total of 36 subjects, so some tumor cohorts may enroll fewer than 36 subjects in part 2).

[0086] Summary of eligibility criteria Subjects must be 18 years of age or older (or legal age of adulthood in their country, whichever is higher) and have histologically or cytologically confirmed cancer of the type outlined in the study design. Subjects must have unresectable, locally advanced, or metastatic disease. Subjects must have FGFR2b overexpression as determined by centrally performed immunohistochemistry (IHC) testing. All subjects must have measurable disease according to RECIST v.1.1.

[0087] treatment The planned dose of bemarituzumab in this study (dose level 1) is 22 mg / kg IV on day 1 of cycle 1, followed by 15 mg / kg IV Q2W thereafter starting on day 15. One treatment cycle will be 14 days. Dose level 1A will include bemarituzumab 15 mg / kg IV Q2W starting on day 1 of cycle 1 + one additional 7.5 mg / kg dose on day 8 of cycle 1 only to explore whether a dose taper from dose level 1 is necessary.

[0088] Statistical considerations Sample size considerations In part 1, if there are 9 subjects treated at a dose level and the true DLT rate is 25%, there is a 92% probability that at least 1 DLT will be observed. In part 2, the Clopper-Pearson exact 95% lower confidence limits for observed objective response rates (ORRs) of 11.1%, 16.7%, 22.2%, 27.8%, and 33.3% in 36 subjects are 3.1%, 6.4%, 10.1%, 14.2%, and 18.6%, respectively; subjects in part 1 randomized to the same dose levels used in part 2 contribute to this total of 36 subjects.

[0089] Interim analysis In Part 1, a DLRT will be convened during and after its completion (28 days after the last subject enrolled in Part 1) to review all available safety, tolerability, laboratory, and PK data.

[0090] In Part 2, a data review team (DRT) will review the safety data after a specified number of subjects in the full analysis set have had an opportunity to be followed for 8 weeks, regardless of tumor type. To make these determinations, the DRT will use its clinical judgment in reviewing all relevant safety data and will use stopping guidelines based on a Bayesian posterior probability of >85% of a posterior probability of a grade 4 or higher treatment-related adverse event rate of >20% using a beta(1,1) prior distribution.

[0091] In addition to safety data review, the DRT will oversee non-binding interim analyses for futility planned to occur after the first 12 and 24 subjects dosed in a given tumor cohort have had an opportunity to complete 16 weeks of disease assessment (2 scans). Enrollment will not be paused to perform a futility analysis. Stopping for futility is based on a predicted probability of <20% of ORR >15% after all 36 subjects have been enrolled and have had an opportunity to complete 16 weeks of disease assessment. A non-informative beta (1,1) prior distribution will be used. A cohort may be stopped for futility if 0 of 12 subjects or 1 of 24 or less subjects have an OR. Additional interim analyses will be performed by tumor cohort for select efficacy and safety endpoints once all subjects enrolled in that tumor cohort have had an opportunity to complete 16 weeks of disease assessment prior to the primary analysis of the entire study.

[0092] Analysis method Primary efficacy and safety analyses are based on all enrolled subjects who received at least one dose of study drug. Continuous variables are described as mean, median, quartiles, minimum, and maximum. Categorical data are summarized as frequency counts and percentages. Response rates are summarized with exact 95% confidence intervals. Time-to-event endpoints are summarized as Kaplan-Meier (KM) quartiles and KM rates at the time of selection. Final analysis will be performed when all subjects across all tumor cohorts have completed the study. Time-to-event endpoints will be updated with further follow-up at the time of final analysis. No statistical hypotheses testing will be performed in this study.

[0093] Rationale for bemarituzumab dosing For phase 1 of this study, bemarituzumab was selected at 22 mg / kg on day 1 of cycle 1 followed by 15 mg / kg Q2W starting on day 15 based on the following data:

[0094] In the Phase 1 FPA144-001 monotherapy dose escalation study, bemarituzumab demonstrated linear clearance from 1 mg / kg to 15 mg / kg in subjects with solid tumors, including gastric cancer. In the linear dose range, the highest observed serum concentrations (C max ) and AUC increased in a dose-proportional manner. Estimated half-lives by noncompartmental analysis ranged from 6.01 to 11.7 days for doses of 1 mg / kg to 15 mg / kg, supporting Q2W or less frequent dosing.

[0095] Observed concentrations at the end of the dosing interval for bemarituzumab (C trough The target value of ≥60 μg / mL of FGFR2b-Fc was derived from non-clinical studies, including binding affinity to human FGFR2b-Fc and human FcγRIIIa (V158), in vitro receptor occupancy, and in vivo efficacy studies.

[0096] Target 60μg / mL C trough Supporting the hypothesis that a minimum C value of 60 μg / mL should be used, all subjects who demonstrated a partial response (PR) in the FIH FPA144-001 study of FGFR2b overexpression achieved a target C value of 60 μg / mL or higher, regardless of dose level. trough,ss Among all subjects treated with the 15 mg / kg Q2W dose regimen in Study FPA144-001, 23 of 51 subjects achieved the target C trough At the same dose, 14 of 16 subjects achieved a target C concentration of 60 μg / mL or higher by week 8 (steady state). trough This was achieved.

[0097] Goal C troughBecause shortening the time to achieve concentrations may help maximize the potential benefit from bemarituzumab, one additional dose of 7.5 mg / kg was added on day 8 of cycle 1 to achieve this goal.

[0098] Observed PK data from the Phase 1 portion of Study FPA144-004 showed that all subjects with PK data treated with 15 mg / kg Q2W plus one additional dose of 7.5 mg / kg on Day 8 of Cycle 1 achieved target C trough Achieve concentration C max The results indicated that the C-terminal β-blocker concentration (C-C) was within the range observed in study FPA144-001. Thus, the addition of a single dose of 7.5 mg / kg on day 8 of cycle 1 increased the C-terminal β-blocker concentration (C-C) by 1.5 mg / kg. max Without increasing the target C trough The time to reach this was minimized.

[0099] The FPA144-004 study, combining bemarituzumab 15 mg / kg Q2W dosing with an additional dose of 7.5 mg / kg on day 8 of cycle 1 in combination with mFOLFOX6, achieved prespecified statistical significance across all three of its prespecified efficacy endpoints, including objective ORR, PFS, and OS, in subjects with FGFR2b-positive, non-HER2-positive, frontline advanced gastric and gastroesophageal junction cancer. In addition, a population PK analysis using PK data from studies FPA144-001, FPA144-002, and FPA144-004 indicated that no covariates were likely to have a clinically meaningful effect on bemarituzumab exposure and treatment in the gastric and gastroesophageal junction cancer population, although baseline weight, baseline albumin, sex, and concomitant therapy were identified as statistically significant covariates for the PK of bemarituzumab. No dose adjustments based on any of these factors would be necessary. In addition, a preliminary exposure-response analysis supported that bemarituzumab 15 mg / kg Q2W with one additional dose of 7.5 mg / kg on day 8 of cycle 1 provided an appropriate balance of safety and efficacy, based on manageable safety and favorable efficacy data.

[0100] Rationale for Loading Dose In this study, subjects will achieve initial target serum exposures of bemarituzumab by adding a loading dose of 22 mg / kg on Cycle 1 Day 1 (preceded by 15 mg / kg Q2W from Day 15 onwards). As noted above, in a previous clinical trial of bemarituzumab (FPA-144-004), a 15 mg / kg dose on Cycle 1 Day 1 was followed by an additional dose of 7.5 mg / kg on Cycle 1 Day 8 to help achieve these initial target exposures (target trough ranges). Population PK modeling and simulations indicate that the 22 mg / kg dose on Cycle 1 Day 1 has a similar C-value as the 15 mg / kg dose on Cycle 1 Day 1 followed by an additional dose of 7.5 mg / kg on Cycle 1 Day 8. trough is indicated to be achieved by day 15. Thus, the 22 mg / kg loading dose on day 1 not only helps achieve the initial target exposure, but also improves subject convenience by eliminating the need for an additional 7.5 mg / kg dose on day 8.

[0101] For Phase 2 of the study, a recommended dose of bemarituzumab will be identified based on the overall safety, tolerability, and PK assessments from Phase 1 of the study.

[0102] End of Study An individual subject is considered to have completed the study if he or she has completed the last visit indicated in the activity schedule detailed in FIG.

[0103] The study end date will be defined as the date when the last subject at all sites has been assessed or has received the intervention for evaluation in the study (i.e., last visit for the last subject), including any additional parts of the study (e.g., long-term follow-up, antibody testing), if applicable.

[0104] Study population Investigators will maintain prescreening and screening records for all potential study candidates that contain limited information about the potential candidate (e.g., screening date). Eligibility criteria will be assessed at screening. Appropriate written informed consent must be obtained prior to any study-specific activities / procedures. Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, will not be provided.

[0105] Inclusion criteria Subjects are eligible for inclusion in the study only if all of the following criteria apply: Subjects provide informed consent / assent prior to the initiation of any study-specific activities / procedures. Be 18 years of age (or the legal age of adulthood in your country, whichever is higher) or older at the time of signing the Informed Consent Form (ICF). Histologically or cytologically confirmed cancer of one of the following types that is refractory to or has subsequently relapsed after at least one prior standard of care regimen in the advanced / metastatic setting, as specified below. If no standard of care therapy exists for a subject, or if the subject cannot tolerate or refuses standard of care anti-cancer therapy, the subject may be permitted to participate in the study after consultation between the investigator and an Amgen medical monitor. Subjects who have not received all approved or standard of care therapies for their cancer must be informed of the options available to them in lieu of receiving bemarituzumab before agreeing to participate in the study. Head and neck squamous cell carcinoma: one or more lines of treatment Triple-negative breast cancer: 2 or more lines of treatment Intrahepatic cholangiocarcinoma: one or more lines of treatment Lung adenocarcinoma: at least platinum-based chemotherapy, checkpoint inhibitors, and targeted therapy (i.e., if molecular testing identifies targetable mutations in EGFR, ALK, etc.) Platinum-resistant epithelial ovarian cancer, including fallopian tube and primary peritoneal cancer, defined as progression on or within 6 months of a platinum-containing regimen: 1 or more lines of treatment Endometrial adenocarcinoma: one or more lines of treatment Cervical cancer: One or more lines of treatment Other solid tumors: ≥1 line of therapy Unresectable, locally advanced, or metastatic tumor (for which curative therapy is not indicated) Tumors that overexpress FGFR2b as determined by centrally performed immunohistochemistry (IHC) testing Measurable disease according to RECIST v1.1 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate hematological and organ function, defined as: Absolute neutrophil count ≥ 1.5 × 10 9 / L Platelet count ≥ 100 × 10 9 / L Hemoglobin ≥ 9 g / dL AST and ALT < 3 x upper limit of normal [ULN] (or < 5 x ULN if liver disease is present). Total bilirubin < 1.5 x ULN (or < 2 x ULN if liver disease or Gilbert's disease is present). Calculated or measured creatinine clearance (CrCl) ≥ 30 mL / min 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 acceptable. International normalized ratio (INR) or prothrombin time (PT) < 1.5 x ULN, except for subjects on anticoagulant therapy who must remain on a stable dose of anticoagulant therapy for 6 weeks prior to enrollment.

[0106] Exclusion criteria Subjects will be excluded from the study if any of the following criteria apply:

[0107] Disease-related Untreated or symptomatic central nervous system (CNS) metastases or leptomeningeal disease. Subjects with asymptomatic CNS metastases are eligible if they have been clinically stable for at least 4 weeks and have not required any intervention (including the use of corticosteroids). Subjects with previously treated brain metastases are eligible if they meet the following criteria: Completed definitive therapy at least 2 weeks prior to the first planned dose of study treatment (for stereotactic radiosurgery at least 7 days prior to the first planned dose of study treatment) At least 7 days prior to the first planned dose of study treatment: Any CNS disease must be clinically stable, the subject must be off steroids for the CNS disease (unless steroids are indicated for reasons unrelated to the CNS disease), and the subject must be off or on a stable dose of an antiepileptic drug.

[0108] For the other solid tumor cohort, primary tumors of the CNS, squamous non-small cell lung cancer, gastric adenocarcinoma, and gastroesophageal junction adenocarcinoma are excluded.

[0109] Other medical conditions History of other malignancies within the past 2 years, with the following exceptions: Curatively treated non-melanoma skin malignancies ·Non-invasive cervical cancer - Stage I uterine cancer curatively treated -Definitively treated ductal or lobular carcinoma in situ who are not currently receiving any systemic therapy Localized prostate cancer that has been surgically treated with curative intent and presumed to be curative

[0110] Impaired cardiac function or clinically significant cardiac disease included unstable angina within 6 months prior to the first dose of study treatment, acute myocardial infarction <6 months prior to the first dose of study treatment, New York Heart Association (NYHA) class II to IV congestive heart failure, uncontrolled hypertension (defined as mean systolic blood pressure >160 mmHg or diastolic >100 mmHg despite optimal therapy), uncontrolled cardiac arrhythmias requiring antiarrhythmic therapy other than beta-blockers or digoxin, active coronary artery disease, or corrected QT interval (QTc) ≥ 470.

[0111] Active infection or any uncontrolled infection requiring systemic treatment within 14 days prior to the first dose of study treatment.

[0112] Known human immunodeficiency virus (HIV) infection with a CD4+ T cell (CD4+) count <350 cells / μL, hepatitis C infection (subjects with hepatitis C who have achieved a sustained virologic response following antiviral therapy are acceptable), or hepatitis B infection (subjects with hepatitis B surface antigen [SAg] or core antibodies specific for hepatitis B who have achieved a sustained virologic response are acceptable).

[0113] History of systemic disease or ophthalmologic disorder requiring chronic use of ophthalmic steroids.

[0114] Any ongoing ophthalmologic abnormalities or acute symptoms (within 4 weeks) or evidence of active progression.

[0115] Unwillingness to avoid contact lens wear during study treatment and for at least 100 days after treatment ends.

[0116] History of, or evidence of, recent (within 6 months) corneal surgery or ophthalmic laser treatment or recent (within 6 months) corneal defect, corneal ulcer, keratitis, or keratoconus, or other known corneal abnormality that may place the patient at increased risk of developing a corneal ulcer.

[0117] Previous medical history / concomitant therapy Prior treatment with any clinically tested selective inhibitor of the FGF-FGFR pathway (however, this does not include approved standard treatments for oncology indications).

[0118] Any anticancer or immunotherapy within 4 weeks prior to enrollment; Palliative radiation therapy is permitted, provided it is completed no earlier than 14 days before the first dose of study treatment. All treatment-related toxicities must have resolved to Grade 1 or less prior to the first dose of study treatment, except for alopecia or toxicities deemed irreversible (defined as stable for >21 days) not otherwise described in the exclusion criteria.

[0119] Major surgical procedure within 28 days prior to the first dose of study treatment. Minor surgeries requiring local / epidural anesthesia must be completed no earlier than 72 hours prior to the first dose of study treatment. In all cases, subjects must be adequately recovered and stable prior to treatment administration.

[0120] Previous / concurrent clinical trial participation Are currently receiving treatment in another investigational device or investigational drug study, or have completed treatment in one or more other investigational device or investigational drug studies within 28 days. Other investigational procedures while participating in this study are excluded.

[0121] Other Exclusions Female subjects of childbearing potential who are not willing to use protocol-specified contraception (see Appendix 5 (Section 11.5)) during treatment and for an additional 90 days after the last dose of bemarituzumab.

[0122] Female subjects who are breastfeeding or plan to breastfeed while on study and up to 90 days after the last dose of bemarituzumab.

[0123] Women who plan to become pregnant while on study and up to 90 days after the last dose of bemarituzumab.

[0124] Women of childbearing potential with a positive pregnancy test at screening determined by a high-sensitivity serum pregnancy test.

[0125] The subject has known hypersensitivity to any of the formulations administered during titration.

[0126] To the best of the subject's and the investigator's knowledge, the subject will not be able to afford to complete all study visits or procedures required by the protocol and / or comply with all required study procedures.

[0127] History or evidence of any other clinically significant disorder, condition, or disease (other than those outlined above) that, in the opinion of the Investigator or, if opinion is sought, an Amgen physician, may pose a risk to the subject's safety or interfere with the evaluations, procedures, or completion of the study.

[0128] Subjects classified as vulnerable groups (prisoners, inmates in institutions, adult subjects in legal care [judicial custody or guardianship] or other persons who may be considered vulnerable), unless otherwise noted (e.g. illiterate or visually impaired persons).

[0129] Target registration The following items are required before subjects will participate in any study-specific activities / procedures: a copy of the institution's written Institutional Review Board / Independent Ethics Committee (IRB / IEC) protocol approval, an informed consent form, and all other subject information and / or recruitment materials, if applicable.

[0130] The subject or the subject's legally authorized representative must personally sign and date the IRB / IEC and approved informed consent prior to the initiation of any study-specific procedures.

[0131] Each subject who enters the screening period of the study (defined as when the subject signs the informed consent) will receive a unique subject identification number prior to the performance of any study-related activities / procedures. The subject identification number will be assigned using Interactive Response Technology (IRT). This number will be used to identify the subject throughout the clinical trial and must be used on all study records involving the subject.

[0132] Subject identification numbers must remain constant throughout a clinical trial; they must not be changed after initial assignment, including when subjects are rescreened.

[0133] A subject will be considered enrolled when the Investigator determines that the subject meets all eligibility criteria. The Investigator will document this determination and date in the subject's medical record and in / on the Enrollment Case Report Form (CRF).

[0134] Screening failures A screen fail is defined as a subject who consents to participate in the pivotal clinical trial but does not subsequently enroll in the study (subjects who do not overexpress FGFR2b during prescreening will not be counted as screen failers). A minimum set of screen fail information will be collected, including demographic information, screen fail details, eligibility criteria, medical history, prior treatment history, and any serious adverse events. Those who do not meet the entry criteria for the study (screen failers) may be rescreened.

[0135] Bemarituzumab Information regarding bemarituzumab in this study, including dosing and administration instructions, is provided in Table 3 below.

[0136] [Table 4]

[0137] Dose level determination Part 1 may explore two dose levels: dose level 1 (22 mg / kg IV on day 1 of cycle 1 followed by 15 mg / kg Q2W thereafter starting on day 15) and dose level 1A (15 mg / kg IV Q2W + one additional dose of 7.5 mg / kg on day 8 of cycle 1). Part 1 of the study will begin with dose level 1 (22 mg / kg IV on day 1 of cycle 1 followed by 15 mg / kg Q2W thereafter starting on day 15). The study DLT evaluation period will be 28 days. A Dose Level Review Team (DLRT) meeting will be held once 3-6 subjects have completed the DLT period.

[0138] In Part 1, DLRT will use guidelines based on the mTPI-2 design. The mTPI-2 escalation / de-escalation guidelines for each dose cohort will be derived with a target toxicity probability of 0.25 and an acceptable toxicity probability interval of (0.20,0.30). If the probability of exceeding the target DLT (i.e., exclusion boundary) at a dose level is estimated at 95% or greater, the dose level will be considered unsafe and no additional subjects will be enrolled at that dose level. Specific guidelines are listed below: Treat subjects in the first treatment arm at dose level 1 Use the guidelines in Table 4 to assign a dose to subjects in the next treatment arm. "Exclusion" means excluding the current dose and any higher doses from the study because of excessive toxicity, thereby preventing treatment of any future subjects at those doses. When a dose is dropped, a taper to dose level 1A will occur. When the lowest dose is dropped, the study will be stopped for safety reasons. · When at a lower dose and dose escalation is indicated by regulation, treat new subjects with the higher dose. · If this does not lead to any treatment (i.e., tapering or elimination), new subjects will be treated at their current dose. When the current dose is the lowest dose and dose tapering is indicated by regulation, new subjects will be treated at that lowest dose unless the number of DLTs reaches the exclusion boundary, at which point the study will be stopped for safety reasons. When the current dose is the highest dose and regulations dictate dose escalation, treat new patients at that highest dose.

[0139] The above steps are repeated until a maximum sample size of 18 is reached or the number of subjects treated at the current dose reaches 9, and the decision according to Table 4 is to maintain the current dose.

[0140] [Table 5]

[0141] Dose-limiting toxicity Dose-limiting toxicity was defined as any of the following adverse events during the DLT evaluation period (28 days) that the investigator deemed to be at least possibly related to bemarituzumab: Grade 4 neutropenia of any duration ·Febrile neutropenia Grade 4 thrombocytopenia Grade 3 thrombocytopenia associated with >Grade 2 bleeding or lasting >7 days Grade 4 anemia Grade 5 toxicity (e.g., death not due to disease progression) Any grade 3 ophthalmic adverse event that does not resolve within 3 days Any grade 4 ophthalmic adverse event Any Grade 4 laboratory value Any 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 Any subject who meets the criteria for High's Law cases (i.e., severe drug-induced liver injury [DILI]) will be considered a DLT. High's Law cases are defined as AST or ALT values ​​of ≥ 3xULN, and serum total bilirubin (TBIL) levels > 2xULN or INR > 1.5, with no signs of cholestasis and no other obvious alternative explanation for the observed liver-related laboratory abnormalities (see Section 11.7 for further discussion of High's Law cases and liver function management). Any other grade 3 or higher adverse event, except: - DLT exclusion criteria: asymptomatic grade 3 amylase and / or lipase activity lasting less than 72 hours and without radiographic evidence of pancreatitis - DLT exclusion criteria: asymptomatic grade 3 electrolyte abnormalities lasting less than 72 hours, not clinically relevant, and resolving spontaneously or responding to medical intervention - DLT exclusion criteria: other selected laboratory abnormalities that are not clinically relevant or do not appear to be deleterious to the subject (e.g., grade 3 lymphopenia, grade 3 hypoalbuminemia) and / or that can be corrected with supplementation or modification. - DLT exclusion criteria: Transient (resolution to grade 1 or less within 6 hours) grade 3 infusion-related adverse events

[0142] Subjects enrolled in dose-finding may be replaced if they are not evaluable for DLTs (e.g., they did not receive the planned study treatment [100% planned dose of bemarituzumab] or study treatment was terminated before completion of the DLT evaluation period for reasons other than the occurrence of a DLT). Replaced subjects may continue in the study at the discretion of the investigator and after consultation with the medical monitor. Individual dose titration will be discontinued due to the occurrence of any DLT or if the criteria are not met.

[0143] Bemarituzumab dosage adjustments, delays, withdrawals or resumption rules, and permanent discontinuation Bemarituzumab doses may be withheld for bemarituzumab-related adverse events according to the guidelines outlined in Table 5.1, Table 5.2, and Table 5.3. The reason for any bemarituzumab dose delay should be documented on each subject's CRF.

[0144] After Cycle 1, the bemarituzumab dose must be recalculated only if there is a greater than 10% change in body weight from Cycle 1 Day 1. If the dose is recalculated due to a greater than 10% change in body weight from Cycle 1 Day 1, the body weight used for the recalculated dose must serve as the new baseline for subsequent evaluations of dose recalculation.

[0145] If dose reductions or interruptions that do not fall within these guidelines are being considered by the investigator, they will require discussion with the sponsor or designee.

[0146] Cycles may be postponed for management of toxicity. Postponement of any cycle for more than 21 days, regardless of the reason, must be discussed with the medical monitor prior to resumption.

[0147] Corneal events Any subject who experiences a corneal event within 100 days of receiving their last dose of bemarituzumab should be evaluated by an ophthalmologist, regardless of whether it is considered related to bemarituzumab. Any subject who complains of ocular pain or irritation or vision changes should be evaluated by an ophthalmologist. Tables 5.1, 5.2, and 5.3 provide further guidance.

[0148] [Table 6]

[0149] [Table 7]

[0150] [Table 8]

[0151] [Table 9]

[0152] Prior Treatment All past medication history must be recorded in the designated eCRF form. Past medication history taken / used within 3 months prior to enrollment will be collected.

[0153] For prior anticancer therapy for the cancer under study, collect name of therapy, setting, dose, unit, frequency, start date, end date, best response, and reason for discontinuation, dating back to initial diagnosis. For anticancer therapy that contains multiple separate components, information on each component must be collected. For all other prior treatment history, collect name of therapy, indication, dose, unit, frequency, route, start date, and end date.

[0154] Combination treatment Throughout the study, the Investigator may prescribe any concomitant medications or treatments deemed necessary to provide adequate supportive care, with the exception of certain treatments.

[0155] 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) must be self-administered at least three times daily throughout the entire treatment period and for 28 days (+3 days) after administration of the last dose. Ocular lubricants may be polyvinyl alcohol or liquid polyol-based. If preservative-free is not available, preserved formulations are acceptable. Methylcellulose-based lubricants should not be used. Viscous lubricants that may cause blurred vision should be avoided.

[0156] For concomitant therapies, information should be collected from informed consent until the end of SFU, with the exception of ophthalmologic and anticancer therapies, which are collected until LTFU. For concomitant therapies, including vaccines, the name of therapy, indication, dose, unit, frequency, route, start date, and end date will be collected. For subsequent anticancer therapies administered for the cancer under study, the name of the drug, start date, and end date will be collected.

[0157] Discontinuation of study treatment and subject withdrawal / dropout Subjects have the right to withdraw from the investigational product and / or other protocol required treatment, from the protocol procedures, or from the study as a whole at any time and for any reason without prejudice to their future medical management by the physician or at the institution.

[0158] The investigator and / or sponsor may decide to withdraw one or more subjects from the investigational drug, investigational device, and / or other protocol-required treatment, protocol procedures, or from the study as a whole at any time prior to completion of the study.

[0159] Discontinuation of study treatment A subject (or legally authorized representative) may decline to continue receiving 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. If this occurs, the investigator should discuss with the subject the appropriate process for discontinuing investigational product or other protocol required treatments and must discuss with the subject the possibility of continuing the activity schedule, including alternative options for follow-up (e.g., in person, by phone / email, through family / friends, through correspondence / communication with other treating physicians, from review of medical records) and data collection, including endpoints and adverse events (see Figure 4), and must document the decision in the subject's medical record. Subjects who discontinue 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 subjects remain in the study to ensure safety monitoring and / or outcome data collection.

[0160] Reasons for early removal from one or more protocol-required investigational product or procedural decisions may include any of the following: Decision by sponsor Unable to track cases ·death Adverse Events Target Request - Ineligibility was determined Protocol deviations Non-compliance Disease progression - Radiographic progression (RECIST v1.1) - Clinical progression (investigator assessment) · Demand for alternative therapies ·pregnancy

[0161] Subject Withdrawal / Dropout from Study Withdrawal of consent to a study signifies that the subject no longer wishes to undergo the treatment or procedure required by the protocol and that the subject is unwilling or unable to continue further participation in the study. The subject's data up until the withdrawal of consent will be included in the study's analysis, and publicly available data after withdrawal of consent may be included, if permitted. The investigator will discuss with the subject the appropriate procedure for withdrawal from the study and the subject's decision to withdraw must be documented in the subject's medical record.

[0162] If a subject drops out of the study, he or she may request the destruction of any samples that have been collected but not tested.

[0163] Reasons for removing a subject from the study included the following: decision by the sponsor, withdrawal of consent from the study, death, and loss to follow-up.

[0164] Lost to follow-up cases If a subject repeatedly fails to show up for scheduled visits and cannot be contacted by the study site, the subject will be considered lost to follow-up.

[0165] If a subject fails to show up to the clinic for a required study visit, the following actions must be taken: Sites must contact subjects to attempt to reschedule any missed visits as soon as possible and advise subjects of the importance of maintaining and reviewing their assigned visit schedule to determine whether the subject wishes and / or is able to continue in the study. If a subject is considered lost to follow-up, the investigator or designee must make every effort to recontact the subject (by making three phone calls, if possible, and, if necessary, sending a certified letter to the subject's last known mailing address, or the local equivalent). These contact attempts must be documented in the subject's medical record. If the subject continues to be unable to be contacted, he or she will be considered to have dropped out of the study primarily due to loss to follow-up. For subjects lost to follow-up, investigators should verify vital status by searching publicly available records, where permitted, to ensure that the data set or data sets generated as study outcomes are as comprehensive as possible.

[0166] Efficacy assessment Radiation image evaluation Disease extent will be assessed by contrast-enhanced computed tomography (CT) / magnetic resonance imaging (MRI) according to RECIST v1.1. All radiological imaging will be performed according to institutional standards. Low-dose CT should be utilized whenever possible to reduce subject radiation exposure.

[0167] Screening scan: A screening scan must be performed within 28 days prior to Cycle 1 Day 1 (scan may be performed within 31 days) and includes a clinical examination and appropriate imaging technique (preferably a CT scan with appropriate slice thickness according to RECIST v1.1; MRI is also acceptable). If there are multiple screening scans, the one closest to the date of enrollment will be used as the baseline.

[0168] Radiological evaluation must include CT / MRI (with contrast) of the chest, abdomen, and pelvis, as well as review of all other known sites of disease. Tumor response assessment will be performed by the investigator according to RECIST v1.1 guidelines (section 11.9).

[0169] All subjects with brain metastases should have an MRI of the brain. All brain scans for subjects with brain metastases should be an MRI, unless MRI is contraindicated, followed by a CT with contrast is acceptable. Brain imaging (MRI or CT) should be performed if signs or symptoms suggestive of CNS metastases are present.

[0170] Subsequent scans: All subsequent scans should be performed with the same methodology (e.g., same contrast agent, MRI field strength) and ideally with the same scanner as during screening. If imaging modality must be changed (e.g., unplanned assessment), consultation with the medical monitor is recommended.

[0171] During treatment and follow-up, radiological imaging of the chest, abdomen, pelvis, and all other known disease sites will be performed independent of treatment cycles as specified in the activity schedule (see Figure 4). Imaging may also be performed more frequently if clinically indicated at the discretion of the managing physician. Radiological imaging and tumor evaluation will be performed until initiation of new anticancer therapy, disease progression, death, withdrawal of consent, or study termination, whichever occurs first.

[0172] Determination of disease response to clinical management and response assessment will be performed at the clinical site per RECIST v1.1. Confirmation of response with repeat scans is required 4 weeks after the initial documented response. Scans for intrahepatic cholangiocarcinoma, cervical cancer, and head and neck cancer may be submitted to a central imaging core laboratory for archiving and, if appropriate, for response determination including RECIST v1.1 and / or exploratory analysis (e.g., volumetric and viability tumor measurements).

[0173] Serum tumor markers Serum tumor markers specific for each tumor type should be collected according to an activity schedule (see Figure 4). Tumor markers found to be elevated at baseline should normalize for confirmation of radiological CR. In ovarian cancer subjects, CA-125 should be collected within 2 weeks of screening. CA-125 response is defined as at least a 50% reduction in CA-125 from the pretreatment sample. CA-125 response in ovarian cancer subjects should be confirmed and maintained for at least 28 days.

[0174] Safety assessment Planned time points for all safety evaluations are shown in Figure 4.

[0175] Vital signs The following measurements should be performed: systolic / diastolic blood pressure, heart rate, respiratory rate, and temperature. Subjects should be seated in a quiet, calm position for at least 5 minutes before blood pressure determination is performed. The position selected for a subject should be the same as that used throughout the study and should be documented on the Vital Signs CRF. The temperature site selected for a subject should be the same as that used throughout the study and should be documented on the Vital Signs CRF. All measurements will be recorded on the Vital Signs CRF.

[0176] Electrocardiogram (ECG) Subjects must be in a quiet, calm position in the supine position for at least 5 minutes before ECG reading is taken. If the subject is unable to be in the supine position, the subject will be recumbent to the maximum extent possible. The ECG must include the following measurements: heart rate, QRS, QT, QTc, and PR intervals. The PI or designated facility physician will review all ECGs. Once signed off, the original ECG tracing will be retained with the subject's source documents.

[0177] Clinical test results The Investigator is responsible for reviewing the laboratory results and recording of any clinically relevant changes that occurred during the study in the Event CRF. The Investigator must determine whether an individual study subject's abnormal value represents a clinically important change from the subject's baseline value. In general, laboratory abnormalities that are not clinically significant (based on the Investigator's judgment) will not be recorded as adverse events. However, laboratory changes that require adjustment of treatment or current therapy will be considered adverse events. When applicable, clinical sequelae (not laboratory abnormalities) will be recorded as adverse events.

[0178] All laboratory determinations required by the protocol must be performed according to the schedule of activities (Figure 4).

[0179] Vital Status Vital status must be obtained for all subjects within the limits of local law. This includes subjects who may have discontinued study visits with or without withdrawal of consent, and includes query of public databases, if necessary. In the event of death, the date and cause of death must be obtained.

[0180] Ophthalmological examination Ophthalmic examinations will be performed according to the activity schedule (Figure 4). Any grade ophthalmic adverse events occurring up to 100 days after the last dose of bemarituzumab must be reported by the investigator.

[0181] Ophthalmic examinations should include distance-corrected visual acuity for each eye separately, with visual acuity recorded as logMAR equivalents, anterior segment slit-lamp examination, tonometry, and ocular surface staining (e.g., fluorescein). In addition, dilated retinal examination or three-field retinal photography should be performed at screening and at each other ophthalmic examination. Additionally, optical coherence tomography (OCT) of the macula is required, especially for subjects with diagnosed or suspected retinal pigment epithelium (RPE) detachment. All assessments will be performed according to local practice.

[0182] Distance corrected visual acuity will be determined using a Snellen or Landolt chart and visual acuity must be recorded as logMAR equivalents. The same method must be used at screening and throughout the study. Other charts may be used but must be agreed upon in advance with the medical monitor.

[0183] Ophthalmic examinations should be performed according to the activity schedule regardless of dose delays (Figure 4). Ophthalmic examinations may be repeated at any time depending on clinical indication. If the subject has any persistent ophthalmic findings after the SFU visit, they should continue to be assessed until resolution of findings, withdrawal of consent, death, or loss to follow-up. Ophthalmic adverse events should be monitored by an ophthalmologist until resolution.

[0184] For ophthalmic adverse events, the following measurements will be performed: Standard of care management Provides dose modification and discontinuation guidelines for investigators (Table 5.1)

[0185] If there are any clinically significant changes compared to the previous examination, or if the subject has any grade 2 or higher ocular signs or symptoms, the subject should be evaluated by an ophthalmologist.

[0186] Adverse events The adverse event grading scale used in this study was the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

[0187] The investigator is responsible for ensuring that all investigator-observed or subject-reported adverse events occurring after administration of the first dose of investigational drug through the end of the SFU are reported using the event CRF.

[0188] Serious Adverse Events The investigator is responsible for ensuring that all investigator-observed or subject-reported serious adverse events occurring up to 28 days (+3 days) after the last day of the investigational product dosing interval following signing of informed consent are reported using the Event CRF.

[0189] 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 submit any updated serious adverse event data to the sponsor within 24 hours of it being available.

[0190] Because the CTCAE grading scale criteria differ from the regulatory criteria for serious adverse events, if an adverse event corresponds to CTCAE Toxicity Grading Scale criteria for Grade 4 (e.g., laboratory abnormalities reported as Grade 4 in the absence of life-threatening manifestations), it is at the investigator's discretion to also report those abnormalities as serious adverse events. For any adverse event for which this situation applies, comprehensive documentation of the severity of the event must be documented in the subject's medical record.

[0191] If the Investigator observes a serious adverse event suspected to be related to the IP or any fatal adverse event (regardless of causality) after completion of the protocol-required reporting period, then those serious adverse events will be reported on the Event CRF within 24 hours after the Investigator becomes aware of the event.

[0192] There is no requirement to actively monitor investigator-treated study subjects after a study on that subject is completed. However, if the investigator becomes aware of serious adverse events suspected to be related to the investigational drug after the protocol-required reporting period is completed, then those serious adverse events will be reported on the Event CRF within 24 hours after the investigator becomes aware of the event.

[0193] As one of the study endpoints is overall survival, the investigator is responsible for ensuring that all fatal serious adverse events (regardless of causality) are collected and reported within 24 hours of being noticed.

[0194] Serious adverse events reported outside the protocol-required reporting periods will be captured in the safety database as clinical trial cases and will be treated accordingly based on their relationship to the investigational product.

[0195] If further safety-related data become necessary to fulfill any regulatory reporting requirements for reportable events, it may then be necessary to collect additional information from subjects' records after they have left the study.

[0196] Follow-up of adverse events and serious adverse events After the initial AE / SERIOUS AE report, the Investigator must prospectively follow up each subject at subsequent visits / contacts. All AEs and SEVERE AEs will be followed until resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-up.

[0197] All new information about previously reported serious adverse events must be reported within 24 hours after the new information is noted. If specifically requested, the investigator may need to provide additional follow-up information, such as discharge summaries, medical records, or excerpts from the medical records. Information provided about serious adverse events must be consistent with the record in the event CRF.

[0198] Regulatory reporting requirements for serious adverse events If a subject permanently discontinues protocol-required treatment due to a serious adverse event, this information must be submitted to Amgen.

[0199] Prompt notification of serious adverse events by investigators to sponsors is critical to fulfilling legal obligations and ethical responsibilities regarding the safety of subjects in clinical trials and the safety of the investigational treatment.

[0200] Sponsors have a legal responsibility to inform both local and other regulatory authorities regarding the safety of the investigational treatment under clinical investigation. Sponsors will comply with local regulatory requirements regarding safety reporting to regulatory authorities, IRBs / IEC, and investigators.

[0201] Individual safety reports should be prepared in accordance with local regulatory requirements and sponsor policy regarding suspected unexpected serious adverse reactions and should be forwarded to the investigator as appropriate.

[0202] Investigators who receive individual safety reports containing serious adverse events or other specific safety information from the sponsor (e.g., a summary or list of serious adverse events) will file them with the Investigator Brochure and will notify the IRB / IEC as appropriate in accordance with local requirements.

[0203] For studies where treatment allocation is blinded, to comply with global serious adverse event reporting regulations, the treatment assignment of subjects who develop serious, unexpected, relevant adverse events may be unblinded prior to submission to regulatory authorities. If appropriate, aggregation analyses may also be unblinded by the safety assessment team. Investigators will receive notification of relevant serious adverse event reports sent to regulatory authorities according to local requirements.

[0204] Adverse events of particular interest Selected adverse events known as bemarituzumab 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 must be collected as adverse events. Ocular adverse events (including corneal adverse events) must be graded using the Ocular Toxicity Grading Scale. Subjects must be assessed for possible bemarituzumab events of special interest prior to each dose.

[0205] Pregnancy and breastfeeding Details of any pregnancy and / or lactation in female subjects will be collected from the start of study treatment until 90 days after the last dose of bemarituzumab.

[0206] Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, and ectopic pregnancy) are considered serious adverse events.

[0207] For females of childbearing potential, a high-sensitivity (serum) pregnancy test must be completed at screening and within 72 hours of starting study drug.

[0208] Women who have had bilateral tubal ligation / occlusion must undergo pregnancy testing in accordance with protocol requirements (if the female subject or the partner of the male subject becomes pregnant, this must be reported on the pregnancy notification paperwork).

[0209] Additional pregnancy tests should be performed on Day 1 of every other cycle during treatment and after protocol-required discontinuation of treatment, at Days 28 (+3 days) (SFU), 56 (± 3 days), and 75 (+3 days) after the last bemarituzumab dose.

[0210] Additional on-treatment pregnancy testing may be performed at the investigator's discretion or as required according to local laws and regulations.

[0211] Pharmacokinetic evaluation Collect whole blood samples for measurement of serum bemarituzumab concentrations as specified in the Activity Schedule (Figure 4). Instructions for collection and handling of biological specimens will be provided by the sponsor. Record the actual date and time (24-hour clock) of each sample.

[0212] Pharmacogenetics assessment If the subject consents to the optional pharmacogenetic portion of the study, DNA analyses may be performed. These optional pharmacogenetic analyses focus on inherited genetic variations to evaluate their possible correlation with disease and / or responsiveness to the treatment used in the study. This optional assessment is separate from the genomic analysis of somatic mutations in tumor and circulating tumor DNA (ctDNA) samples included as part of the main study. The goals of this optional study include aiding in cancer research through the use of genetic markers and / or identifying subjects who may have a positive or negative response to the investigational drug. No additional samples will be collected for this part of the study. For subjects who consent to this / these analyses, DNA may be extracted.

[0213] Antibody Testing Procedure For measurement of anti-bemarituzumab antibodies, one or more blood samples for antibody testing will be collected according to the time points specified in the activity schedule (Figure 4). Samples testing positive for binding to antibodies may be further characterized.

[0214] Subjects who test positive for antibodies at the last scheduled antibody time point and have clinical sequelae deemed potentially related to the anti-bemarituzumab antibody response will also be required to return for additional follow-up testing, which 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) subjects have been followed for at least 1 year (± 4 weeks) after bemarituzumab administration. More frequent or longer-term testing may be required if safety-related concerns arise.

[0215] Biomarkers Biomarkers are objectively measured to assess cell biological processes, pathogenic processes, or pharmacological responses to therapeutic intervention.

[0216] Eligibility determination by biomarker assessment Archival tumor biopsy / resection (bone biopsy and cytology samples excluded) formalin-fixed and paraffin-embedded (within 5 years or fresh biopsy if archival sample is not available) for prescreening by IHC for FGFR2b overexpression status must be provided and subjects must consent to tumor tissue analysis. If FGFR2b overexpression is confirmed, PD-L1 will also be tested in the remaining prescreening tissue in head and neck squamous cell carcinoma, triple-negative breast cancer, lung adenocarcinoma, cervical cancer, and endometrial cancer, if available.

[0217] Subjects will be selected for enrollment based on FGFR2b overexpression status as determined by clinical trial assay (CTA) IHC assay in a central Clinical Laboratory Improvement Amendments (CLIA)-licensed laboratory (Roche Tissue Diagnostics, Tucson, Arizona, US) that meets United States (US) regulatory requirements. Timing of sample collection will be described in the Activity Schedule (Figure 4). Specimen collection of primary tumors and metastatic sites will be permitted. If fresh tissue samples need to be collected, they should be obtained according to local standard of care procedures that are not expected to pose any significant additional risk to the subject's health, safety, and welfare.

[0218] The CTA used for subject selection is the VENTANA FGFR2b (FPR2 D) Assay, an IHC test that determines FGFR2b overexpression status (positive, negative) in neoplastic tissue. Samples considered to have a positive FGFR2b overexpression status exhibit moderate (2+) to strong (3+) membrane staining in tumor cells.

[0219] Subjects deemed negative for FGFR2b overexpression status using IHC (absence of moderate or strong membrane staining in tumor cells) are not eligible for enrollment. Acquisition of adequate tumor specimens for analysis of FGFR2b status for enrollment is the responsibility of each investigator. Blocks are preferred when available, although unstained slides are recommended in lieu of blocks. Tumor specimens submitted must be in sufficient quantity to allow for IHC analysis; see the Laboratory Manual for details. Instructions for processing, labeling, and shipping of tumor slide or tumor block specimens are detailed in the Laboratory Manual distributed with the specimen collection kit.

[0220] Upon receipt of the tumor specimen, analysis will be performed as efficiently as possible and the results of FGFR2b overexpression status will be communicated back to the investigator or designee. If available, programmed death-ligand-1 testing will be performed on the remaining prescreening tissue for the indications listed in Figure 4. This PD-L1 testing is a prescreening assessment performed to understand PD-L1 expression and overlap with FGFR2b, but the results of the test do not determine eligibility.

[0221] Biomarker Discovery Samples are collected to generate or address biomarker hypotheses related to bemarituzumab activity (e.g., to evaluate potential biomarkers that may correlate with treatment response). These samples may also be used to develop methods that allow a better understanding of the disease to be gained.

[0222] Where local regulations allow and Ethics Committee (EC) / Institutional Review Board (IRB) agreement is obtained, blood and tissues will be collected at the time points specified in the timeline of activities (Figure 4) for biomarker discovery. Blood samples will be collected and adjudicated for circulating tumor / cell-free DNA mutation profiles for possible association with clinical endpoints. Circulating tumor DNA plasma analysis will include mandatory paired analysis of subject blood samples to identify and selectively remove germline variants to help refine and determine tumor-specific mutations. Somatic mutation profiles will be generated using circulating tumor / cell-free DNA (ctDNA) adjudication. Germline mutation results will not be reported.

[0223] If tumor samples or optional biopsy samples are available, they may be used to examine protein expression, RNA and DNA gene expression, or somatic (tumor) mutation analysis may be performed after additional consent is provided. If tumor tissue is available, analysis of tumor-specific mutations or epigenetic changes may be performed (e.g., somatic mutations). Exploratory genomic analysis of tumor tissue, or biopsy, may include paired sequencing analysis of a subject's blood cell pellet sample to identify and selectively remove germline variants to help refine and determine tumor-specific mutations. Germline mutation results will not be reported. None of these samples will be used for screening of genetic traits. Plasma samples will be collected as outlined in Figure 4, and biomarker analysis, such as proteomic analysis, may be performed.

[0224] Biomarker development / future research Biomarker development refers to the use of samples collected for biomarker discovery in future studies after the completion of this study.

[0225] Of particular interest in oncology are molecular changes underlying the carcinogenic process that may identify cancer subtype, disease stage, determine tumor volume, or predict disease progression, metastasis, and response to one or more investigational drugs or treatments required by a protocol.

[0226] If consent is provided by the subject, any remaining samples collected at the times specified in the Schedule of Activities (Figure 4), including samples collected for biomarker determination, may be used for future studies. No additional samples will be collected for biomarker development / future studies.

[0227] To learn more about and gain a better understanding of cancer, one or more studies may be designed to identify subjects most likely to respond, either positively or negatively, to one or more investigational drugs.

[0228] Statistical considerations Statistical hypotheses No statistical hypothesis testing is performed.

[0229] Determining sample size In part 1, if there are 9 subjects treated at a dose level and the true DLT rate is 25%, there is a 92% probability that at least 1 DLT will be observed. In part 2, the Clopper-Pearson exact 95% lower confidence limits for the ORRs of 11.1%, 16.7%, 22.2%, 27.8%, and 33.3% observed in 36 subjects are 3.1%, 6.4%, 10.1%, 14.2%, and 18.6%, respectively; subjects in part 1 randomized to the same dose levels used in part 2 contribute to this total of 36 subjects (see Table 6).

[0230] [Table 10]

[0231] Analysis population The following populations are defined:

[0232] [Table 11]

[0233] Covariates Relationships between covariates and endpoints may be explored and specified in the Statistical Analysis Plan (SAP) as appropriate.

[0234] Subgroups Subgroups may be explored and specified in the Statistical Analysis Plan (SAP) as appropriate.

[0235] statistical analysis A statistical analysis plan will be prepared and compiled prior to database lock. Below is an outline of the timing and methods for the statistical analysis plan. To preserve the integrity of the study, the final analysis will be performed and reported after the completion of the study.

[0236] Analysis Plan Part 1 In Part 1, a DLRT will be held during and after completion of Part 1 (28 days after the last subject enrolled in Part 1) to review all available safety, tolerability, laboratory, and PK data. For dose-finding decisions, the DLRT will use guidelines based on the mTPI-2 design as described in Section 6.2.1.

[0237] Part 2 Regardless of tumor type, the DRT will review safety data after the designated number of subjects in the full analysis set have had an opportunity to be followed for 8 weeks. The designated number of subjects that will trigger the DRT review is specified in column 1 of Table 7. To make these determinations, the DRT will use its clinical judgment when reviewing all relevant safety data and will use the stopping guidelines in Table 7 based on a greater than 85% Bayesian posterior probability of a greater than 20% posterior probability of a grade 4 or higher treatment-related adverse event rate using a dβ(1,1) prior distribution.

[0238] [Table 12]

[0239] futility The DRT will oversee non-binding interim analyses for futility planned to occur after the first 12 and 24 subjects in the safety population for a given tumor type cohort have had an opportunity to complete 16 weeks of disease assessment (2 scans). Enrollment will not be paused to perform futility analyses. Stopping for futility is based on a less than 20% predictive probability of an ORR greater than 15% after all 36 subjects have been enrolled and have had an opportunity to complete 16 weeks of disease assessment. A non-informative beta (1,1) prior distribution will be used. A cohort may be stopped for futility if 0 of 12 subjects or 1 of 24 subjects have an OR (CR or PR). Table 8 provides stopping guideline sample sizes ranging from 11 to 35, allowing the DRT to assess multiple cohorts of different sample sizes in the same review. The operational characteristics of the stopping guidelines are described in Table 9.

[0240] [Table 13]

[0241] [Table 14]

[0242] Prior to the primary analysis of the entire study, additional interim analyses will be conducted by tumor cohort for select efficacy and safety endpoints once all subjects enrolled in that tumor cohort have had an opportunity to complete 16-week disease assessment.

[0243] Primary and final analyses The primary analysis will occur when all subjects across all tumor types have completed the safety follow-up visit. All efficacy and safety endpoints will be analyzed in this primary analysis. The final analysis will occur when all subjects across all tumor types have completed the study. Time-to-event endpoints will be updated with further follow-up at the time of the final analysis.

[0244] Analysis method Parts 1 and 2 will be analyzed separately. For Part 1, safety analyses will be presented by tumor type combined; efficacy analyses will be presented by tumor type only if there is sufficient sample size. For Part 2, efficacy analyses will be presented by tumor type; safety analyses will be presented by tumor type and overall. Primary efficacy and safety analyses will be based on all enrolled subjects who received at least one dose of study drug. Continuous variables will be described as mean, median, quartiles, minimum, and maximum. Categorical data will be summarized as frequency counts and percentages.

[0245] Confidence intervals (CIs) for proportions were estimated using the exact method proposed by Clopper and Pearson (Clopper and Pearson, 1934). The Kaplan-Meier (KM) method was used to estimate medians and percentiles for time-to-event endpoints, and CIs were calculated using the Brookmeyer and Crowley method (Brookmeyer and Crowley, 1982). The Kaplan-Meier method was used to estimate landmarks for time-to-event endpoints (e.g., 1-year OS), and the Greenwood formula (Kalbfleisch and Prentice, 1980) was used to estimate standard errors used to calculate CIs.

[0246] [Table 15]

[0247] [Table 16]

[0248] Adverse events Subject incidence rates of all treatment-emergent adverse events (e.g., ocular events) will be tabulated by system organ class and preferred term. Tables of grade ≥ 3 events, grade ≥ 4 events, fatal adverse events, serious adverse events, adverse events leading to discontinuation / withdrawal from study drug, and treatment-emergent adverse events of special note will also be provided.

[0249] Clinical test results Analyses of safety laboratory endpoints will include summary statistics over time. The shift in the worst safety laboratory grade from baseline to on-study will be tabulated.

[0250] Vital signs Analysis of vital signs will include summary statistics over time. Shifts in vital sign values ​​between baseline and worst values ​​during the study will be tabulated.

[0251] body measurements Anthropometric analyses will include summary statistics at baseline and possibly at selected post-baseline time points.

[0252] electro-cardiogram ECG measurements in this clinical trial will be performed according to standard of care for routine safety monitoring rather than for the purpose of determining potential QTc effects. Because these evaluations are not necessarily performed under the rigorous conditions expected to lead to meaningful evaluation of QTc data; summary and statistical analysis of ECG measurements is not planned, and these data are not expected to be useful for meta-analysis with data from other studies.

[0253] antibody formation The incidence and percentage of subjects developing anti-bemarituzumab antibodies at any time point will be tabulated.

[0254] Exposure to investigational drug Number of days taking study drug, total dose of study drug, and dose intensity will be summarized using descriptive statistics.

[0255] Exposure to concomitant medications Numbers and proportions of subjects who received the treatment of interest will be summarized by preferred terms coded by the World Health Organization Drug dictionary.

[0256] Other analyses Pharmacokinetic parameters of bemarituzumab will be determined, including but not limited to AUC, Cmax, and Ctrough. Pharmacokinetic data collected from this study combined with PK data collected from other bemarituzumab studies will be used in a population PK analysis. Additional analyses will be performed to evaluate the relationship between bemarituzumab exposure and select safety or efficacy or any relevant biomarker endpoints, if data are available. Details and results of these exploratory analyses will be described in separate reports.

[0257] Example 3: Treatment of Solid Tumors with Bemarituzumab - Dose Level 1 Separate cohorts of patients with pathologically confirmed or solid tumors with FGFR2b overexpression will be treated with bemarituzumab. These cohorts will be organized based on tumor type as follows: 1. Head and neck squamous cell carcinoma 2. Triple-negative breast cancer (ER-, PR-, HER2 / neu-) 3. Intrahepatic cholangiocarcinoma 4. Lung adenocarcinoma 5. Ovarian epithelial carcinoma, including fallopian tube and primary peritoneal carcinoma 6. Endometrial adenocarcinoma 7. Cervical cancer 8.Other solid tumors

[0258] Each cohort will be treated with a regimen of an initial dose of bemarituzumab at a dose of 22 mg / kg, followed by subsequent doses of bemarituzumab at a dose of 15 mg / kg, each given 2 weeks after the initial dose and Q2W thereafter.

[0259] Bemarituzumab monotherapy is effective in treating solid tumors in these patients as measured by objective response (defined as complete response (CR) + partial response (PR)) as determined according to Response Evaluation Criteria in Solid Tumors [RECIST v1.1].

[0260] Example 4: Treatment of Solid Tumors with Bemarituzumab - Dose Level 2 Separate cohorts of patients with pathologically confirmed or solid tumors with FGFR2b overexpression will be treated with bemarituzumab. These cohorts will be organized according to tumor type as follows: 1. Head and neck squamous cell carcinoma 2. Triple-negative breast cancer (ER-, PR-, HER2 / neu-) 3. Intrahepatic cholangiocarcinoma 4. Lung adenocarcinoma 5. Ovarian epithelial carcinoma, including fallopian tube and primary peritoneal carcinoma 6. Endometrial adenocarcinoma 7. Cervical cancer 8.Other solid tumors

[0261] Each cohort will be treated with a regimen of anti-FGFR2b antibody at a dose of 15 mg / kg, followed one week after the first dose of anti-FGFR2b antibody by a single subsequent dose of anti-FGFR2b antibody at a dose of 7.5 mg / kg given every two weeks (Q2W).

[0262] Bemarituzumab monotherapy is effective in treating solid tumors in these patients as measured by objective response (defined as complete response (CR) + partial response (PR)) as determined according to Response Evaluation Criteria in Solid Tumors [RECIST v1.1].

[0263] Example 5: Treatment of Solid Tumors with Bemarituzumab - Dose Level 1 Separate cohorts of patients with pathologically confirmed or solid tumors with FGFR2b overexpression will be treated with bemarituzumab. These cohorts will be organized according to tumor type as follows: 1. Head and neck squamous cell carcinoma 2. Triple-negative breast cancer (ER-, PR-, HER2 / neu-) 3. Intrahepatic cholangiocarcinoma 4. Lung adenocarcinoma 5. Ovarian epithelial carcinoma, including fallopian tube and primary peritoneal carcinoma 6. Endometrial adenocarcinoma 7. Cervical cancer 8.Other solid tumors

[0264] Each cohort will be treated with a regimen of an initial dose of bemarituzumab at a dose of 22 mg / kg, followed by subsequent doses of bemarituzumab at a dose of 15 mg / kg, each given 2 weeks after the initial dose and Q2W thereafter.

[0265] Bemarituzumab monotherapy is effective in treating solid tumors in these patients as measured by progression-free survival and / or overall survival.

[0266] Example 6: Treatment of Solid Tumors with Bemarituzumab - Dose Level 2 Separate cohorts of patients with pathologically confirmed or solid tumors with FGFR2b overexpression will be treated with bemarituzumab. These cohorts will be organized according to tumor type as follows: 1. Head and neck squamous cell carcinoma 2. Triple-negative breast cancer (ER-, PR-, HER2 / neu-) 3. Intrahepatic cholangiocarcinoma 4. Lung adenocarcinoma 5. Ovarian epithelial carcinoma, including fallopian tube and primary peritoneal carcinoma 6. Endometrial adenocarcinoma 7. Cervical cancer 8.Other solid tumors

[0267] Each cohort will be treated with a regimen of anti-FGFR2b antibody at a dose of 15 mg / kg, followed one week after the first dose of anti-FGFR2b antibody by a single subsequent dose of anti-FGFR2b antibody at a dose of 7.5 mg / kg given every two weeks (Q2W).

[0268] Bemarituzumab monotherapy is effective in treating solid tumors in these patients as measured by progression-free survival and / or overall survival.

[0269] Example 7 To update the tumor cohort for this study (Table 10), we performed an FGFR2b overexpression prevalence study in sourcing tissues across 10 tumor indications selected based on TCGA data and literature. Based on these data, tumor indications with expected prescreen prevalence ≥10% (including those with 95% confidence intervals of 10%) will be recruited as defined tumor cohorts. Of note, iCCA demonstrated a prevalence of 1% (95% CI 0%–3%), but due to constraints related to the rarity of the tumor type, the majority of specimens were obtained from centers in a single country. Specimens from other tumor types were sourced in multiple countries to ensure geographic diversity. Thus, iCCA prevalence data from this study may not be representative of the broader FGFR2b prevalence as supported by published literature and early results from this study. Published literature suggests FGFR2b expression (IHC staining ≥1) in approximately 31% (19 / 62 cases) of iCCA (Junior et al., 2022). At the outset of this study, 4 iCCA specimens were received for prescreening, with 2 / 4 (50%) testing positive for any 2+3+ FGFR2b level.

[0270] [Table 17]

[0271] In addition to gastric and squamous non-small cell lung cancer (under investigation in other bemarituzumab clinical trials), data on FGFR2b expression by immunohistochemistry (IHC) suggest overexpression (defined as tumor cells with FGFR2b 2+ / 3+ membrane staining) in ovarian cancer (19%, 95% CI 14%-24%), endometrial cancer (23%, 95% CI 17%-29%), head and neck squamous cell carcinoma (22%, 95% CI 15%-29%), cervical cancer (10%, 95% CI 4%-16%), triple-negative breast cancer (8%, 95% CI 4%-13%), lung adenocarcinoma (6%, 95% CI 1%-11%), and intrahepatic cholangiocarcinoma (iCCA, 1%, 95% CI 0%-3%) (Table 10).

[0272] Example 8: Results of a Phase 1b basket study evaluating the safety, tolerability, pharmacokinetics, and efficacy of bemarituzumab monotherapy in solid tumors with FGFR2b overexpression Tumor samples from patients were determined to overexpress FGFR2b by immunohistochemistry (IHC) if they displayed any moderate (2+) to strong (3+) membrane staining according to the protocol described in Example 2. Patients with solid tumor types that overexpress FGFR2b were administered the anti-FGFR2b antibody bemarituzumab intravenously according to the protocol described in Example 2 (Part 1, Phase 1b). Patients received bemarituzumab at 22 mg / kg on cycle 1, day 1 ("C1 / D1"), followed by bemarituzumab at 15 mg / kg Q2W. Tumor types in these patients included pancreatic duct, colorectal, ovarian, and head and neck (N=1) (pharmacokinetic data are available for N=5 / 6 patients). Bemarituzumab serum concentrations were measured at prespecified time points on days 0, 1 (central PK sampling), 2, 4, 8, 15, 21, and 43. A preliminary PK profile for bemarituzumab is shown in Table 11. After cycle 1, the geometric mean bemarituzumab C max is 577μg / mL, and C trough The concentration was 96.5 μg / mL.

[0273] [Table 18]

[0274] These data indicate that, with respect to dosing and scheduling, the pharmacokinetics of bemarituzumab were consistent with clinical modeling from the gastric cancer indication and that systemic bemarituzumab concentrations exceeded the minimum predicted effective exposure threshold (60 μg / mL) derived from nonclinical data.

[0275] Based on the known safety profile of bemarituzumab, there were no new safety findings in patients.

[0276] References Each of the following references is incorporated herein by reference in its entirety. 2020-2021 Basic and Clinical Science Course(TM)(BCSC); Section 3 - Clinical Optics. Ophthalmology. https: / / www.aao.org / bcscsnippetdetail.aspx?id=3550b1ca-1740-4e7f-8712-70905c99eb26. 30 June 2020. Ahn S, Lee J, Hong M, et al. FGFR2 in gastric cancer:protein overexpression predicts gene amplification and high H-index predicts poor survival. Mod Pathol. 2016; 29(9):1095-1103. Andre F, Ranson M, Dean E, et al. Abstract LB-145:Results of a Phase I Study of AZD4547, an Inhibitor of Fibroblast Growth Factor Receptor (FGFR), in Patients with Advanced Solid Tumors. AACR 104th Annual Meeting 2013, Washington, DC, American Association of Cancer Research. BALVERSA® US Prescribing Information, 2020. https: / / www.janssenlabels.com / package-insert / product-monograph / prescribing-information / BALVERSA-pi.pdf Bemarituzumab Investigator's Brochure. Thousand Oaks, CA. Amgen Inc. Brands RC, Knierim LM, De Donno F, et al. Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro. Oncology Reports. 2017; 38:1877-1885. Brookmeyer R and Crowley J. A Confidence Interval for the Median Survival Time. Biometrics. 1982; 2984; 38:29-41. Brown AP, Courtney CL, King LM, et al. Cartilage Dysplasia and Tissue Mineralization in the Rat Following Administration of a FGF Receptor Tyrosine Kinase Inhibitor. Toxicologic Pathology. 2005; 33:449-455. 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. Catenacci DVT, Kang Y-K, Saeed A, et al. FIGHT:A randomized, double-blind, placebo-controlled, phase II study of bemarituzumab (bema) combined with modified FOLFOX6 in 1L FGFR2b+ advanced gastric / gastroesophageal junction adenocarcinoma (GC) [Abstract]. 2021. J Clin Onc. 2021; 39(no 15_supp):4010. Churi CR, Shroff R, Wang Y. Mutation Profiling in Cholangiocarcinoma:Prognostic and Therapeutic Implications. Plos One. 2014; 9(12):e115383. The Common Terminology Criteria for Adverse Events, version 5.0:http: / / ctep.cancer.gov / protocolDevelopment / electronic_applications / ctc.htm Clopper CJ and Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the Binomial. Biometrika. 1934; 26:404-413. 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. Dutt A, Salvesen HB, Chen T-H, et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci U S A. 2008; 105(25):8713-8717. 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. Gatius S, Velasco A, Azueta A, et al. FGFR2 alterations in endometrial carcinoma. Modern Pathology. 2011; 24:1500-1510. Gemo A, Deshpande A, Palencia S, et al. FPA144:A Therapeutic Antibody for Treating Patients with Gastric Cancers Bearing FGFR2 Gene Amplification. AACR 105th Annual Meeting 2014, San Diego California. Han X, Xiao Z, and Quarles LD. Membrane and integrative nuclear fibroblastic growth factor receptor (FGFR) regulation of FGF-23. J Biol Chem. 2021; 290(16):10447-10459. International Committee of Medical Journal Editors, Uniform Requirements for Manuscripts Submitted to Biomedical Journals:Writing and Editing for Biomedical Publication. 2013. http: / / www.icmje.org / Kang X, Lin Z, Xu M, et al. Deciphering role of FGFR signalling pathway in pancreatic cancer. Cell Proliferation. 2019; 52:e12605. Kato H, Arao T, Matsumoto K, et al. Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma. In J Oncol. 2013; 42:1152-1158. Katoh and Katoh. FGF signaling network in the gastrointestinal tract (review). Int J Oncol. 2006; 29(1):163-168. Kalbfleisch JD and Prentice, RL. The Statistical Analysis of Failure Time Data, New York:John Wiley & Sons (1980) Li P, Huang T, Zou Q, et al. FGFR2 Promotes Expression of PD-L1 in Colorectal cancer via the JAK / STAT3 Signaling Pathway. J Immunol. 2019; 202:3065-3075. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5(6):649-655. PEMAZYRE® US Prescribing Information, 2021. https: / / www.pemazyre.com / pdf / prescribing-information.pdf Reintjes N, Li Y, Becker A, et al. Activating Somatic FGFR2 Mutations in Breast Cancer. Plos One. 2013; 8(3):e60264. 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. 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. Sun Y, Cheng Y, Zhang Y, et al. MicroRNA-889-3p targets FGFR2 to inhibit cervical cancer cell viability and invasion. Experimental and Therapeutic Medicine. 2019; 18:1440-1448. 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. Tyulyandina A, Demidova I, Gikalo M, et al. Role of FGFR2 amplification in prognosis of patients with ovarian cancer. 2018; 29(8):viii354-viii355. Wu Y-M, Su F, Kalyana-Sundaram, et al. Identification of Targetable FGFR Gene Fusions in Diverse Cancers. Cancer Discovery. 2013; 3(6):636-647. Xiang H, Chan AH, Ahene A, et al. Preclinical characterization of bemarituzumab, an FGFR2b antibody for the treatment of cancer. MAbs. 2021; 13(1):1981202.

[0277] 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.

[0278] In the context of describing the invention (particularly in the context of the claims below), use of the terms "a," "an," "the," "at least one," and similar referents should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Use of the term "at least one" when 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 selected from the listed items (A or B) 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 "comprising," "having," "including," and "containing" should be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise noted. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each individual value falling within the range, and each individual value is incorporated herein as if it were individually set forth herein, unless otherwise indicated herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. Any examples provided herein, or the use of illustrative language (e.g., "etc.") are intended merely to further clarify the invention, and do not impose limitations on the scope of the invention unless specifically claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0279] 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 of ordinary skill in the art upon reading the foregoing description. The inventors expect that those of ordinary skill in the art will employ such variations as necessary, and the inventors intend for the invention to be practiced otherwise than as 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 otherwise clearly contradicted by context.

Claims

1. A composition comprising an anti-FGFR2b antibody for use in a method of treating a target solid tumor as monotherapy, wherein the method involves, (a) A regimen of initial administration of the anti-FGFR2b antibody at a dose greater than 20 mg / kg but less than or equal to 30 mg / kg, followed by subsequent administrations of the anti-FGFR2b antibody at a dose of 12 to 20 mg / kg, two weeks after the initial administration and every two weeks thereafter (Q2W), wherein the dose of the subsequent administration is lower than that of the initial administration; or (b) A regimen administered every two weeks (Q2W) consisting of the anti-FGFR2b antibody at a dose greater than 10 mg / kg but less than or equal to 20 mg / kg, followed by a single subsequent dose of the anti-FGFR2b antibody at a dose of 5 to 10 mg / kg, one week after the initial dose of the anti-FGFR2b antibody. Administer using one of the following methods. Includes, The administration of the anti-FGFR2b antibody is a second-line or later therapy for the solid tumor. composition.

2. The composition according to claim 1, wherein the solid tumor is selected from the group consisting of squamous cell carcinoma, ER-PR-HER2 / neu- ("triple-negative") breast cancer, pancreatic ductal adenocarcinoma, intrahepatic cholangiocarcinoma, colorectal adenocarcinoma, gynecological malignancy, and lung adenocarcinoma.

3. The squamous cell carcinoma is head and neck cancer, squamous cell esophageal cancer, or head and neck squamous cell carcinoma, The composition according to claim 2, wherein the gynecological malignancy is selected from the group consisting of ovarian epithelial carcinoma (such as fallopian tube cancer or primary peritoneal cancer), endometrial cancer, and cervical cancer.

4. The squamous cell carcinoma is after platinum-based chemotherapy and / or PD-1 inhibitor therapy, The aforementioned triple-negative breast cancer is present after chemotherapy, PARPi (in the case of BRCA mutations), PD-1 inhibitor therapy, and / or anti-trop-2 therapy. The aforementioned pancreatic ductal adenocarcinoma has undergone platinum-based chemotherapy. If the aforementioned intrahepatic cholangiocarcinoma is eligible for targeted therapy, then it is after platinum-based chemotherapy and after targeted therapy. The colorectal adenocarcinoma is following bevacizumab therapy, oxaliplatin-based chemotherapy, irinotecan-based chemotherapy, and / or additional prior therapy based on RAS, BRAF, and dMMR / MSI-H status, and / or The composition according to claim 2, wherein the gynecological malignancy is post-platinum-based chemotherapy and / or is resistant to platinum chemotherapy.

5. The composition according to claim 2, wherein the cells of the solid tumor overexpress FGFR2b mRNA or protein, or include FGFR2 gene amplification, and / or the solid tumor overexpresses FGFR2b as determined by immunohistochemistry (IHC).

6. The cells of the solid tumor are FGFR2b positive when determined by IHC, or The composition according to claim 5, wherein the cells of the solid tumor exhibit 2+ and / or 3+ FFFR2b staining when determined by IHC.

7. The cells of the solid tumor are FGFR2b positive as determined by IHC, and at least 5%, 10%, or 20% of the cells are FGFR2b positive as determined by IHC, The composition according to claim 5, wherein the cells of the solid tumor exhibit 2+ and / or 3+ FFFR2b staining when determined by IHC, and at least 5%, 10%, or 20% of the cells exhibit FFFR2b staining.

8. (a) The initial dose of the anti-FGFR2b antibody is greater than 20 mg / kg but less than or equal to 25 mg / kg, and subsequent doses of the anti-FGFR2b antibody are administered at doses of 12 to 17 mg / kg, two weeks after the initial dose and then at Q2W; The initial dose of the anti-FGFR2b antibody is 22-25 mg / kg, followed by subsequent doses of 12-17 mg / kg of the anti-FGFR2b antibody two weeks after the initial dose and then at Q2W; or The composition according to claim 1, wherein the initial dose of the anti-FGFR2b antibody is 22 mg / kg, and subsequent doses of the anti-FGFR2b antibody are administered at doses of 15 mg / kg each, two weeks after the initial dose and then at Q2W.

9. (b) The Q2W regimen of the anti-FGFR2b antibody is administered at a dose of 12 to 17 mg / kg, and the subsequent single dose of the anti-FGFR2b antibody administered one week after the initial dose is administered at a dose of 7 to 8 mg / kg; The composition according to claim 1, wherein the Q2W regimen of the anti-FFFR2b antibody is administered at a dose of 15 mg / kg, and the subsequent single dose of the anti-FFFR2b antibody administered one week after the initial dose is administered at a dose of 7.5 mg / kg.

10. The composition according to claim 1, wherein the anti-FFFR2b antibody is administered intravenously.

11. The anti-FGFR2b antibody is Heavy chain variable regions including heavy chain complementarity determination region (HCDR) 1 of SEQ ID NO: 6, HCDR 2 of SEQ ID NO: 7, and HCDR 3 of SEQ ID NO: 8; and Light chain variable region including light chain complementarity determination region (LCDR) 1 of SEQ ID NO: 9, LCDR 2 of SEQ ID NO: 10, and LCDR 3 of SEQ ID NO: 11 The composition according to claim 1, comprising:

12. The composition according to claim 1, wherein the anti-FGFR2b antibody is unfucosylated.

13. The heavy chain variable region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 4, and the light chain variable region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 5; or The composition according to claim 11, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 4, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

5.

14. The composition according to claim 13, wherein the anti-FGFR2b antibody comprises the heavy chain of SEQ ID NO: 1 and the light chain of SEQ ID NO: 2, and the anti-FGFR2b antibody lacks fucose of Asn297 (EU numbering).

15. The composition according to claim 1, wherein the anti-FGFR2b antibody is bemarituzumab.

16. The bemarituzumab is administered intravenously, (a) The initial dose is greater than 20 mg / kg but less than or equal to 25 mg / kg, and subsequent doses of bemarituzumab are administered at doses of 12 to 17 mg / kg, two weeks after the initial dose and then at Q2W; The initial dose is 22-25 mg / kg, followed by subsequent doses of bemarituzumab at doses of 12-17 mg / kg, two weeks after the initial dose and then at Q2W; or The initial dose is 22 mg / kg, followed by subsequent doses of bemarituzumab at 15 mg / kg each, two weeks after the initial dose and then at Q2W; (b) The Q2W regimen of bemarituzumab is administered at a dose of 12–17 mg / kg, and the subsequent single dose of bemarituzumab administered one week after the initial dose is administered at a dose of 7–8 mg / kg; or The composition according to claim 15, wherein the Q2W regimen of bemarituzumab is administered at a dose of 15 mg / kg, and the subsequent single dose of bemarituzumab administered one week after the initial dose of bemarituzumab is administered at a dose of 7.5 mg / kg.

17. The composition according to any one of claims 1 to 16, wherein the solid tumor is PD-L1 positive when determined by IHC staining.

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