TW202342527A - Treatment of squamous non small cell lung cancer - Google Patents

Abstract

Methods of treating squamous cell non-small-cell lung cancer (SqNSCLC) in subjects are described. The methods may comprise administering an anti-FGFR2b antibody to the subject. The methods may further comprise administering docetaxel to the subject.

Description

Treatment of squamous non-small cell lung cancer

Embodiments herein relate to the use of antibodies against fibroblast growth factor 2 (FGFR2), including antibodies against the FGFR2 isoform FGFR2-IIIb (also known as FGFR2b), in the treatment of squamous non-small cell lung cancer (SqNSCLC). The treatment may further include administration of docetaxel.

Globally, lung cancer (small cell and non-small cell) is the most common type of cancer in men and women (WHO Statistics, 2018). It is estimated that in 2021, there will be approximately 235,760 new lung cancer cases in the United States alone (American Cancer Society, 2021). The 5-year survival rate for non-small cell lung cancer (NSCLC) is 25% (American Cancer Society, 2021). Squamous cell NSCLC accounts for 20% to 30% of all NSCLC, and while adenocarcinoma (the most common histological subtype of NSCLC) has genetic changes that are drug-targetable, the squamous cell histological subtype has extremely low drug-targeted genetic changes. Targetable genetic changes or no drug-targetable genetic changes (Rekhtman et al., 2012; Drilon et al., 2012). Therefore, although in the first-line advanced disease setting, as with adenocarcinoma, SqNSCLC is routinely treated with platinum-based chemotherapy combined with checkpoint inhibitors, there are no targeted therapy options for SqNSCLC in the second-line setting and beyond .

Members of the fibroblast growth factor (FGF) family bind four known tyrosine kinase receptors, namely fibroblast growth factor receptor 1-4 (FGFR1-4) and their isoforms, with different FGFs binding to varying degrees. Binding to different FGFRs (Zhang et al., J. Biol. Chem. 281:15694, 2006). The protein sequence of human FGFR2 is provided, for example, in GenBank locus AF487553. Each FGFR consists of an extracellular domain (ECD) containing three immunoglobulin (Ig)-like domains (D1, D2, and D3), a single transmembrane helix, and an intracellular catalytic kinase domain (Mohammadi et al., Cytokine Growth Factor Revs, 16:107, 2005). FGF binds to the receptor primarily through regions in D2 and D3 of the receptor. There is a continuous stretch of acidic amino acids in the linker between D1 and D2, called the "acid box" (AB). The region containing D1 and AB is thought to be involved in the autoinhibitory effect of the receptor, which is alleviated by binding to ligand.

FGFR is characterized by multiple alternative splicings of its mRNA, leading to various isoforms (Ornitz et al., J. Biol. Chem. 271:15292, 1996; for the sequences of FGFR2 and its isoforms, see also Swiss-Prot P21802 and isoforms P21802-1 to P21802-20). It should be noted that there are forms containing all three Ig domains (alpha isoform) or only two Ig domains D2 and D3 domains without D1 (beta isoform). In FGFR1, FGFR2, and FGFR3, all forms contain the first half of D3 (denoted IIIa), but two alternative exons can be used for the second half of D3, producing forms IIIb and IIIc. For FGFR2, these forms are denoted FGFR2-IIIb and FGFR2-IIIc (or just FGFR2b and FGFR2c, respectively); the corresponding beta forms are denoted FGFR2(β)IIIb and FGFR2(β)IIIc. The FGFR2-IIIb form of FGFR2 (also denoted K-sam-II) is a high-affinity receptor for FGF1 and KGF family members (FGF7, FGF10, and FGF22), while FGFR2-IIIc (also denoted K-sam-I) is a high-affinity receptor Binds FGF1 and FGF2 but not KGF family members (Miki et al., Proc. Natl. Acad. Sci. USA [Proc. Natl. Acad. Sci. USA] 89:246, 1992). In fact, FGFR2-IIIb is the only receptor for KGF family members (Ornitz et al., 1996, supra) and was therefore named KGFR.

FGFR and its isoforms behave differently in various tissues. FGFR2-IIIb (and the IIIb form of FGFR1 and FGFR3) is 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, cited above). Certain FGF ligands for these receptors have opposite patterns of expression. Therefore, members of the KGF subfamily, including FGF7 (KGF), FGF10, and FGF22, bind only FGFR2-IIIb (Zhang et al., supra) and are expressed in mesenchymal tissues, and thus may be paracrine effectors of epithelial cells. (Ornitz et al., 1996, op. cit.). In contrast, the FGF4 subfamily member FGF4-6 binds FGFR2-IIIc and is expressed in epithelial and mesenchymal lineages and thus may have autocrine or paracrine functions. Because of the pattern of expression of isoforms of FGFR2 and its ligands, FGFR2 plays a role in epithelial-mesenchymal interactions (Finch et al., Dev. Dyn. [Developmental Dynamics] 203:223, 1995) and, therefore, in mice It is not surprising that knockout of FGFR2-IIIb results in severe embryonic defects and lethality (De Moerlooze et al., Development 127:483, 2000).

KGF (FGF7) and KGFR (FGFR2-IIIb) are overrepresented in many pancreatic cancers (Ishiwata et al., Am. J. Pathol. 153:213, 1998), and their coexpression is associated with poor prognosis. Related (Cho et al., Am. J. Pathol. 170:1964, 2007). Somatic mutations in the FGFR2 gene are found in 12% of many endometrial (uterine) cancers and, in several tested cases, are required for tumor cell survival (Dutt et al., Proc. Natl. Acad . Sci. USA [Proceedings of the National Academy of Sciences] 105:8713, 2008). In both tumors, the same S252W substitution associated with Apert syndrome was found in FGFR2 mutations. Amplification and overexpression of FGFR2 are associated with undifferentiated, diffuse gastric cancer, which has a particularly poor prognosis, and inhibition of FGFR2 activity by small molecule compounds potently inhibits the proliferation of this cancer cell (Kunii et al., Cancer Res. [Cancer Research] ] 68:2340, 2008; Nakamura et al., Gastroenterol. [Gastroenterology] 131:1530, 2006).

This article describes methods for treating squamous non-small cell lung cancer (SqNSCLC). The method according to the following paragraphs is described:

1. In some embodiments, methods of treating squamous non-small cell lung cancer (SqNSCLC) include administering to a subject an anti-FGFR2b antibody. The method may include administering docetaxel to the subject.

2. In some embodiments, for the methods described in paragraph 1, the anti-FGFR2b antibody is administered in a Q3W regimen that includes an initial administration at a dose of at least 20 mg/kg, three weeks after the first administration, and thereafter Subsequent administrations are on a Q3W schedule with each dose being at least 10 mg/kg.

3. In some embodiments, for the methods described in paragraph 2, the anti-FGFR2b antibody is administered in a Q3W regimen that includes a first administration at a dose of 20-30 mg/kg or 20-25 mg/kg, Three weeks after the first dose, subsequent doses will be given on a Q3W schedule, with each dose being 10-19 mg/kg.

4. In some embodiments, for the methods described in paragraph 2, the anti-FGFR2b antibody is administered in a Q3W schedule that includes an initial administration at a dose of 22 mg/kg, three weeks after the first administration, and thereafter Subsequent administration of the Q3W regimen was performed at a dose of 15 mg/kg.

5. In some embodiments, for the methods described in paragraph 1, the anti-FGFR2b antibody is administered in a Q3W regimen that includes an initial administration at a dose of at least 25 mg/kg, three weeks after the first administration, and thereafter Subsequent administrations were carried out as Q3W regimen, with each dose being 15-24 mg/kg.

6. In some embodiments, for the methods described in paragraph 5, the anti-FGFR2b antibody is administered in a Q3W regimen that includes a first administration at a dose of 25-35 mg/kg or 25-30 mg/kg, Three weeks after the first dose, subsequent doses will be given on a Q3W schedule, with each dose being 20-24 mg/kg.

7. In some embodiments, for the methods described in paragraph 5, the anti-FGFR2b antibody is administered in a Q3W regimen that includes an initial administration at a dose of 30 mg/kg, three weeks after the first administration, and thereafter Subsequent administration of the Q3W regimen was performed at a dose of 22 mg/kg.

8. In some embodiments, for the methods described in paragraph 1, the anti-FGFR2b antibody is administered in a Q3W regimen that includes an initial administration at a dose of at least 15 mg/kg, three weeks after the first administration, and thereafter Subsequent administrations were carried out on the Q3W schedule, with each dose being 5-15 mg/kg.

9. In some embodiments, for the methods described in paragraph 8, the anti-FGFR2b antibody is administered in a Q3W regimen that includes a first administration at a dose of 15-25 mg/kg or 20-25 mg/kg, Three weeks after the first dose, subsequent doses will be given on a Q3W schedule, with each dose being 5-15 mg/kg.

10. In some embodiments, for the methods described in paragraph 8, the anti-FGFR2b antibody is administered in a Q3W regimen that includes a first administration at a dose of 15-25 mg/kg or 20-25 mg/kg, Three weeks after the first dose, subsequent doses will be given on a Q3W schedule, with each dose being 10-15 mg/kg.

11. In some embodiments, for the methods described in paragraph 8, the anti-FGFR2b antibody is administered in a Q3W regimen that includes an initial administration at a dose of 22 mg/kg, three weeks after the first administration, and thereafter The Q3W regimen was used for subsequent administration, with each dose being 10 mg/kg.

12. In some embodiments, for the methods described in paragraph 1, the anti-FGFR2b antibody is administered in a Q3W regimen at a dose of at least 30 mg/kg, or 25-35 mg/kg, or 30-35 mg/kg.

13. In some embodiments, for the methods described in paragraph 12, the anti-FGFR2b antibody is administered in a Q3W schedule at a dose of 30 mg/kg.

14. In some embodiments, the method of any of paragraphs 2-13, the method further comprising administering an additional dose of 7-12 mg/kg 7-10 days after the first administration of the anti-FGFR2b antibody of anti-FGFR2b antibodies.

15. In some embodiments, for the methods described in paragraph 14, the additional dose of anti-FGFR2b antibody is 7-10 mg/kg.

16. In some embodiments, for the methods described in paragraph 14, the additional dose of anti-FGFR2b antibody is 10-12 mg/kg.

17. In some embodiments, for the methods described in paragraph 16, docetaxel is administered intravenously in a Q3W regimen at a dose of at least 50 mg/m ² or in a QW regimen at a dose of at least 35 mg/m ² and.

18. In some embodiments, for the method described in paragraph 17, docetaxel is administered in a Q3W regimen at a dose of 50-100 mg/ ^m2 , or in a Q3W regimen at a dose of 60-75 mg/ ^m2 , Or administered intravenously in a QW regimen at a dose of 35-75 mg/ ^m2 .

19. In some embodiments, for the method of any of paragraphs 1-18, the anti-FGFR2b antibody is administered intravenously in a Q3W regimen, the regimen comprising a first administration at a dose of 20-30 mg/kg, Three weeks after the first dose, subsequent doses will be given on a Q3W schedule, with each dose being 10-19 mg/kg. Docetaxel can be administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m2 , such as 50-100 mg/ ^m2 in a Q3W schedule or 60-75 mg/ ^m2 in a Q3W schedule. Invest.

20. In some embodiments, for the method of any of paragraphs 1-19, the anti-FGFR2b antibody is administered intravenously in a Q3W regimen, the regimen comprising a first administration at a dose of 25-35 mg/kg, Three weeks after the first dose, subsequent doses will be given on a Q3W schedule, with each dose being 15-24 mg/kg. Docetaxel can be administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m2 , such as 50-100 mg/ ^m2 in a Q3W schedule or 60-75 mg/ ^m2 in a Q3W schedule. Invest.

21. In some embodiments, for the method of any of paragraphs 1-2 or 14-18, the anti-FGFR2b antibody is administered intravenously in a Q3W regimen, the regimen comprising a dose of 15-25 mg/kg The first dose was administered three weeks after the first dose, followed by subsequent doses on the Q3W schedule, with each dose of 5-15 mg/kg. Docetaxel is administered intravenously on a Q3W schedule at a dose of at least 50 mg/ ^m2 , such as 50-100 mg/ ^m2 on a Q3W schedule or 60-75 mg/ ^m2 on a Q3W schedule and.

22. In some embodiments, for the method of any of paragraphs 1-2 or 14-18, the anti-FGFR2b antibody is administered intravenously in a Q3W regimen, the regimen comprising a dose of 15-25 mg/kg The first dose was administered three weeks after the first dose, followed by subsequent doses in the Q3W regimen, each dose being 10-15 mg/kg. Docetaxel is administered intravenously on a Q3W schedule at a dose of at least 50 mg/ ^m2 , such as 50-100 mg/ ^m2 on a Q3W schedule or 60-75 mg/ ^m2 on a Q3W schedule and.

23. In some embodiments, for the method of any of paragraphs 1-2 or 14-18, the anti-FGFR2b antibody is administered intravenously in a Q3W regimen at a dose of 25-35 mg/kg, and dox Taxel is administered intravenously in a dose of at least 50 mg/ ^m in the Q3W regimen, such as 50-100 mg/ ^m in the Q3W regimen or 60-75 mg/ ^m in the Q3W regimen.

24. In some embodiments, for the method of any of paragraphs 1-2 or 14-18, the anti-FGFR2b antibody is administered intravenously in a Q3W regimen at a dose of 30-35 mg/kg, and dox Taxel is administered intravenously in a dose of at least 50 mg/ ^m in the Q3W regimen, such as 50-100 mg/ ^m in the Q3W regimen or 60-75 mg/ ^m in the Q3W regimen.

25. In some embodiments, a method of treating squamous non-small cell lung cancer (SqNSCLC) in a subject is described. The method may include administering to the subject an anti-FGFR2b antibody on a Q2W schedule at a dose of 15-25 mg/kg. The method may further comprise administering an additional dose of 5-10 mg/kg of the anti-FGFR2b antibody 7-10 days after the first administration of the anti-FGFR2b antibody in the Q2W schedule.

26. In some embodiments, for the methods described in paragraph 25, the anti-FGFR2b antibody is administered to the subject in a Q2W regimen at a dose of 15-22 mg/kg or 15-20 mg/kg.

27. In some embodiments, for the methods described in paragraph 25, the anti-FGFR2b antibody is administered to the subject in a Q2W schedule at a dose of 15 mg/kg.

28. In some embodiments, for the method of any of paragraphs 25-27, 7-10 days after the first administration of the anti-FGFR2b antibody in the Q2W regimen, the additional dose of the anti-FGFR2b antibody is 5-10 days. 10 mg/kg.

29. In some embodiments, for the method of any of paragraphs 25-27, 7-10 days after the first administration of the anti-FGFR2b antibody in the Q2W regimen, the additional dose of the anti-FGFR2b antibody is 7-10 days. 8 mg/kg.

30. In some embodiments, an anti-FGFR2b antibody is administered intravenously for any of the methods described herein (including the methods described in any of paragraphs 1-29).

31. In some embodiments, for any method described herein (including the method described in any of paragraphs 1-30), an anti-FGFR2b antibody comprises: a heavy chain variable region, the heavy chain variable region comprising SEQ Heavy chain complementarity determining region (HCDR) 1 of ID NO: 6, HCDR2 of SEQ ID NO: 7, and HCDR3 of SEQ ID NO: 8; and a light chain variable region comprising SEQ ID NO: Light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 10, and LCDR3 of SEQ ID NO: 11.

32. In some embodiments, for any of the methods described herein (including the methods described in paragraph 31), the anti-FGFR2b antibody system is afucosylated. For example, anti-FGFR2b antibodies can lack fucose at Asn297. For example, an anti-FGFR2b antibody can be an IgG1 or IgG3 antibody lacking fucose at Asn297.

33. In some embodiments, for the method of any of paragraphs 31-32, 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 may The variable region contains an amino acid sequence that is at least 95% identical to SEQ ID NO: 5.

34. In some embodiments, for the method of any of paragraphs 31-33, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 4, and the light chain variable region comprises SEQ ID NO: The amino acid sequence of 5.

35. In some embodiments, for the method of any of paragraphs 31-34, the anti-FGFR2b antibody comprises the heavy chain of SEQ ID NO: 1 and the light chain of SEQ ID NO: 2.

36. In some embodiments, for any of the methods described herein (including the methods described in any of paragraphs 1-35), the anti-FGFR2b antibody is bemarituzumab.

37. In some embodiments, the SqNSCLC cells express FGFR2b for any of the methods described herein, including the methods described in any of paragraphs 1-36.

38. In some embodiments, the SqNSCLC cells overexpress FGFR2b protein, overexpress FGFR2b mRNA, or comprise FGFR2b gene amplification for any method described herein (including the method described in any of paragraphs 1-37).

39. In some embodiments, the SqNSCLC cells express FGFR2b protein, as determined by immunohistochemistry (IHC) for any of the methods described herein (including those described in paragraphs 37 or 38).

40. In some embodiments, the SqNSCLC cells have a FGFR2b staining intensity of 2+ or 3+ for any method described herein (including the method described in paragraph 39). That is, in some embodiments, any cell of SqNSCLC has a FGFR2b staining intensity of 2+ or 3+ for any method described herein, including the method described in paragraph 39.

41. In some embodiments, at least 5% of the cells of the SqNSCLC have an FGFR2b staining intensity of 1+, 2+, or 3+ for any of the methods described herein, including those described in paragraph 39. In some embodiments, at least 5% of the cells of the SqNSCLC have a FGFR2b staining intensity of 2+ or 3+ for any method described herein, including the method described in paragraph 39. In some embodiments, at least 10% of the cells of the SqNSCLC have a FGFR2b staining intensity of 2+ or 3+ for any method described herein, including the method described in paragraph 39.

References to related applications

This application requires U.S. Provisional Application No. 63/314,258 submitted on February 25, 2022, U.S. Provisional Application No. 63/316,382 submitted on March 3, 2022, and U.S. Provisional Application No. submitted on June 20, 2022 63/353,786, and U.S. Provisional Application No. 63/485,040 filed on February 15, 2023, each of which is hereby incorporated by reference in its entirety.

This article describes methods of treating SqNSCLC in subjects. Cells from SqNSCLC cancers can overexpress the FGFR2 isoform FGFR2-IIIb (also known as FGFR2b). Such methods may include administering to the subject an anti-FGFR2b antibody (eg, bemarituzumab). The methods may further include administering docetaxel. The anti-FGFR2b antibody can be administered in the same composition as docetaxel, or can be administered in separate compositions (sequentially or simultaneously). This article hypothesizes that anti-FGFR2b antibody administration in combination with docetaxel may be superior to administration in combination with other chemotherapy regimens. For example, an anti-FGFR2b antibody can be administered to a subject at a dose of at least 20 mg/kg (e.g., 20-30 mg/kg or 20-25 mg/kg or 25-35 mg/kg) in an initial administration, followed by Every three weeks (Q3W) at least 10 mg/kg (e.g., 10-19 mg/kg or 10-15 mg/kg or about 15 mg/kg; or 15-25 mg/kg or 15-24 mg/kg or 20 -25 mg/kg or 20-24 mg/kg or approximately 22 mg/kg). For example, an anti-FGFR2b antibody can be administered to a subject at a dose of at least 15 mg/kg (e.g., 15-25 mg/kg or 20-25 mg/kg) in an initial administration and then every three weeks (Q3W). A dose of at least 5 mg/kg (eg, 5-15 mg/kg or 10-15 mg/kg or about 10 mg/kg) is administered. For example, an anti-FGFR2b antibody can be administered to a subject at a dose of 20-30 mg/kg on the first dose, followed by at least 10 mg/kg (e.g., 10-19 mg/kg or 10 -15 mg/kg or approximately 15 mg/kg). For example, an anti-FGFR2b antibody can be administered to a subject at a dose of 25-35 mg/kg on the first dose, followed by at least 15 mg/kg every three weeks (Q3W) (e.g., 15 mg/kg or 15-25 mg/kg or 15-24 mg/kg or 20-25 mg/kg or 20-24 mg/kg or about 22 mg/kg). For example, an anti-FGFR2b antibody can be administered to a subject in a first administration at a dose of at least 30 mg/kg, or 25-35 mg/kg, or 30-35 mg/kg, or about 30 mg/kg. In this way, the anti-FGFR2b antibody administration schedule can be synchronized with the docetaxel administration schedule, thereby minimizing the number of administration courses for the subject.

Based on studies of tumor DNA, the fibroblast growth factor receptor (FGFR) family is the most commonly altered tyrosine kinase family member in SqNSCLC. By exome sequencing, FGFR 1 to 3 alterations (mutation, amplification, and translocation) were observed in 12% of SqNSCLC samples, and by fluorescent in situ hybridization (FISH), in 22% of FGFR1 amplification has been observed in SqNSCLC specimens (Hammerman et al., 2012; Weiss et al., 2010). Tumors with FGFR1 amplification or FGFR2/3 mutations (some of which result in dimerization/constitutive activation) have few other dominant oncogenic mutations, suggesting that hyperactivation of FGFR may be a genomic driver of SqNSCLC (Liao et al., 2013; Heist et al., 2012). Preliminary data on FGFR2b expression by IHC suggest that bemarituzumab's target is expressed in approximately 14% to 30% of SqNSCLC.

NSCLC is a highly lethal disease, and the SqNSCLC histological subtype, especially, often has limited treatment options after first-line therapy. In a recent phase 3 study, mPFS and median overall survival (mOS) for SqNSCLC treated second-line with docetaxel ranged from 2.7 to 2.8 months and 6.0 to 8.2 months, respectively (Brahmer et al. People, 2015; Paz-Ares et al., 2017). Genomic analysis of SqNSCLC as well as preclinical and clinical data with other FGFR TKIs indicate vulnerability to FGFR inhibition (Hashemi-Sadrai and Hanna, 2017; Brahmer et al., 2015). Preliminary data suggest that 14% to 30% of SqNSCLC overexpress FGFR2b, thus providing the basis for an approach that includes dosing bemarituzumab with and without docetaxel chemotherapy in SqNSCLC. anti- FGFR2b antibody

As used herein, "antigen binding protein" has its customary and ordinary meaning as understood by those skilled in the art in view of this disclosure. It refers to a protein that specifically binds to a specific antigen. The term covers intact antibodies and their derivatives, variants, fragments and mutants. Antigen-binding proteins also include bivalent and multivalent (polyvalent/multivalent) constructs and bispecific and multispecific (polyspecific/multispecific) constructs, as well as domain antibodies, scFv, and membrane-bound and soluble receptors. In some embodiments, the antigen binding protein comprises, consists essentially of, or consists of an antibody. In any of the methods described herein, an anti-FGFR2b antigen binding protein can be administered to a subject. For example, the antigen-binding protein may comprise or consist of an antibody (eg, bemarituzumab).

Examples of antibody-antigen-binding proteins. As used herein, "antibody" has its customary and ordinary meaning as understood by those skilled in the art in view of this disclosure. It refers to any isotype of immunoglobulin that specifically binds to a target antigen, and includes, for example, chimeric antibodies, humanized antibodies, fully human antibodies, and monoclonal antibodies. "Antibody" is thus 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 IgAl and IgA2 subtypes), IgM and IgE. Human IgG antibodies typically contain two full-length heavy chains and two full-length light chains. Antibodies may be derived from only a single source, or they may be "chimeric" antibodies, that is, different parts of the antibody may be derived from two or more different antibodies from the same or different species. It will be appreciated that once an antibody is obtained from a source, it can be further engineered, for example to enhance stability and folding. Therefore, it is understood that "human" antibodies can be obtained from sources and can undergo further engineering, for example in the Fc region. Engineered antibodies can still be called a type of human antibody. Similarly, variants of human antibodies, such as those that have undergone affinity maturation, will also be understood to be "human antibodies" unless otherwise stated. In some embodiments, the antigen binding protein comprises, consists essentially of, or consists of: a human antibody, a humanized antibody, or a chimeric monoclonal antibody.

The "heavy chain" of an antigen-binding protein (such as an antibody) consists of a variable region ("VH") and three constant regions: CH1, CH2, and CH3. The "light chain" of an antigen-binding protein (such as an antibody) includes a variable region ("VL") and a constant region ("CL"). Human light chains include kappa and lambda chains.

"Antigen-binding region" means a protein or portion of a protein that specifically binds a specific antigen. For example, the portion of an antigen-binding protein that contains amino acid residues that interact with an antigen and confer its specificity and affinity to the antigen is called an "antigen-binding region." The antigen-binding region typically includes one or more "complementary binding regions" ("CDRs") of the antibody. "CDR" is an amino acid sequence that contributes to antigen-binding specificity and affinity. The antigen-binding regions of antibody heavy and light chains usually exhibit the same overall structure, containing a relatively conserved framework region (FR) connected by three CDRs. The CDRs from the two chains of each heavy/light chain pair are typically aligned by framework regions to form a structure that specifically binds to a specific epitope on the target protein. Naturally occurring light and heavy chain variable regions typically conform to the following sequence of these elements from N-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Numbering systems have been designed to assign numbers to the amino acids occupying positions 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. [Md.] Bethesda]); or Chothia and Lesk, 1987, J. Mol. Biol. [Journal of Molecular Biology] 196:901-917; Chothia et al., 1989, Nature 342:878-883. In some embodiments, the CDRs of the antigen-binding protein are defined according to Kabat or Chothia's definitions.

Antigen-binding proteins (eg, antibodies) directed against FGFR2b can be used in the methods described herein. Antibodies can specifically bind to FGFR2b. In the methods of some embodiments, the anti-FGFR2b antigen binding protein binds FGFR2b with a higher affinity than it binds FGFR2-IIIc. For example, binding of anti-FGFR2b antibodies to FGFR-IIIc may be undetectable. In some embodiment methods, an anti-FGFR2b antigen binding protein (eg, an antibody) binds FGFR2b and blocks or inhibits signaling through the FGFR2b receptor. For example, binding of an anti-FGFR2b antigen-binding protein (eg, an antibody) to FGFR2b can inhibit the phosphorylation of FGFR2 or MAP kinase downstream of FGFR2. In methods of some embodiments, an anti-FGFR2b antigen-binding protein (e.g., an antibody) upon binding to FGFR2b inhibits the binding between FGFR2b and its FGF ligand (eg, FGF1 and/or FGF2).

Binding of an antigen-binding protein (e.g., an antibody) to FGFR2b and inhibition of the binding between FGFR2b and FGF can be analyzed, for example, by an ELISA as described in U.S. Patent No. 8,101,723 or, for example, as described in Example 2 of WO 2015/017600 This is evaluated based on wafer measurements. In some embodiments, the antibody induces ADCC activity, and in some embodiments has enhanced ADCC activity (eg, as described in WO 2015/017600). For example, ADCC activity can be determined as described in Example 3 of WO 2015/07600. In some embodiments, the antibodies can inhibit the growth of human tumors in mouse models, for example, as shown in Example 1 of WO 2017/091577. In some embodiments, an anti-FGFR2-IIIb antibody can increase PD-L1 positive cells, NK cells, CD3+T cells, CD4+T cells, CD8+T cells and The number of one or more macrophages, for example, as described in Example 2 of International Application No. WO 2017/091577.

Any anti-FGFR2b antibody described herein can 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 "fucose-deficient" refers to an IgGl or IgG3 isotype antibody that lacks fucose in its constant region glycosylation. Glycosylation of human IgG1 or IgG3 occurs at Asn297 (N297; EU numbering of Fc region residues), with core fucosylation and bibranched complex oligosaccharide glycosylation terminated by up to 2 Gal residues. In some embodiments, afucosylated antibodies lack fucose at Asn297. Depending on the number of terminal Gal residues, these structures are named G0, G1 (α1,6 or α1,3) or G2 glycan residues. See, for example, Raju, T. S., BioProcess Int. 1:44-53 (2003). CHO-type glycosylation of antibody Fc is described, for example, in Routier, F. H., Glycoconjugate J. [Journal of Glycoconjugates] 14:201-207 (1997). It will be appreciated that compositions containing monoclonal antibodies are often heterogeneous. Indeed, a method comprising administering an afucosylated anti-FGFR2 antibody described herein may further comprise administering some antibody molecule that is not afucosylated. Within a population of antibodies, an antibody was considered afucosylated if <5% of the antibodies in the population contained fucose at Asn297. For example, in some embodiments, greater than 95% of the anti-FGFR2b antibody molecules administered to the subject are afucosylated. For example, in some embodiments, at least 96%, 97%, or 99% of the anti-FGFR2b antibody molecules administered to the subject can be afucosylated. Other antibodies useful in embodiments herein include those described in U.S. Patent Publication No. 2015/0050273, which describes certain afucosylated anti-FGFR2b antibodies and is incorporated herein by reference in its entirety. .

In some embodiments, an afucosylated anti-FGFR2b antibody mediates antibody-dependent cell-mediated cytotoxicity more efficiently than a fucose-containing antibody with the same amino acid sequence in the presence of human effector cells. (ADCC). Generally, ADCC activity can be determined using the in vitro ADCC assay disclosed in US Patent Publication No. 2015/0050273, although other assays or methods of determining ADCC activity, such as in animal models and the like, are contemplated.

Figure 2A shows example sequences of anti-FGFR2b antibodies of some embodiments. In the methods of some embodiments, an 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) SEQ ID NO: 10 NO: 11 LCDR3. 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 heavy chain variable region comprising A light chain of a light chain variable region, the light chain variable region comprising LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10 and LCDR3 of SEQ ID NO: 11. In the methods of 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 the methods of 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, the heavy chain variable region comprises SEQ ID NO: 4 and the light chain variable region comprises SEQ ID NO: 5. In the methods of some embodiments, the heavy chain comprises SEQ ID NO: 2 and the light chain comprises SEQ ID NO: 3. Any anti-FGFR2 antibody described herein can be afucosylated. For example, the antibody may be an IgG1 or IgG3 antibody lacking fucose at Asn297. In the methods of some embodiments, the anti-FGFR2b antibody is bemarituzumab.

In some embodiment methods, an 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. It is further contemplated that, in some embodiments, an anti-FGFR2b antibody contains one or more substitutions, insertions, or deletions as compared to SEQ ID NO: 4 and/or SEQ ID NO: 5, and continues to bind to FGFR2b. For example, as compared to SEQ ID NO: 4 and/or SEQ ID NO: 5, an anti-FGFR2b antibody contains one or more substitutions, insertions, or deletions, can bind to FGFR2b, and has a binding affinity no greater than that of SEQ ID NO: 4 and/or SEQ ID NO: 5, as measured by surface plasmon resonance. The reference anti-FGFR2b antibody, which contains a heavy chain variable region containing SEQ ID NO: 4 and a light chain variable region containing SEQ ID NO: 5, has an order of magnitude lower affinity. In the methods of some embodiments, an anti-FGFR2b antibody comprises a heavy chain variable region and a light chain variable region that are at least 90%, 91%, 92%, 93%, identical to SEQ ID NO: 4. 94%, 95%, 96%, 97%, 98% or 99% identity, the light chain variable region having at least 90% identity with SEQ ID NO: 5. In the methods of some embodiments, an anti-FGFR2b antibody comprises a heavy chain variable region and a light chain variable region that are at least 90%, 91%, 92%, 93%, identical to SEQ ID NO: 4. 94%, 95%, 96%, 97%, 98% or 99% identity, the light chain variable region having at least 91% identity with SEQ ID NO: 5. In the methods of some embodiments, an anti-FGFR2b antibody comprises a heavy chain variable region and a light chain variable region that are at least 90%, 91%, 92%, 93%, identical to SEQ ID NO: 4. 94%, 95%, 96%, 97%, 98% or 99% identity, the light chain variable region is at least 95% identical to SEQ ID NO: 5. In the methods of some embodiments, an anti-FGFR2b antibody comprises a heavy chain variable region and a light chain variable region that are at least 90%, 91%, 92%, 93%, identical to SEQ ID NO: 4. 94%, 95%, 96%, 97%, 98% or 99% identity, the light chain variable region having at least 97% identity with SEQ ID NO: 5. In methods of some embodiments, an anti-FGFR2b antibody comprises a heavy chain variable region and a light chain variable region of SEQ ID NO: 5 that are at least 90%, 91%, or 91% identical to SEQ ID NO: 4. 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity. In methods of some embodiments, an anti-FGFR2b antibody comprises a heavy chain variable region that is at least 90% identical to SEQ ID NO: 4 and a light chain variable region that is at least 90% identical to SEQ ID NO: 4. At least 90% identical to SEQ ID NO: 5. In the methods of 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 have been substituted, inserted, and/or deleted in SEQ ID NO:4. Substitutions, insertions or deletions can occur in regions outside the CDRs (ie, in the FRs). In some embodiment methods, a total of 1 to 10, 1 to 5, or 1 to 3 amino acids have been substituted, inserted, and/or deleted in SEQ ID NO: 5. Substitutions, insertions or deletions can occur in regions outside the CDRs (ie, in the FRs). In some embodiments, a total of 1 to 10, 1 to 5, or 1 to 3 amino acids have been substituted, inserted, and/or deleted in SEQ ID NO: 4. Substitutions, insertions or deletions can occur in regions outside the CDRs (ie, in the FRs). In the methods of some embodiments, up to 10, up to 5, or up to 3 amino acids in SEQ ID NO: 5 have been substituted, inserted, and/or deleted, and in SEQ ID NO: 4 Up to 10 amino acids have been substituted, inserted and/or deleted. Substitutions, insertions or deletions can occur in regions outside the CDRs (ie, in the FRs). In the methods of some embodiments, up to 10, up to 5, or up to 3 amino acids in SEQ ID NO: 5 have been substituted, inserted, and/or deleted, and in SEQ ID NO: 4 Up to 5 amino acids have been substituted, inserted and/or deleted. Substitutions, insertions or deletions can occur in regions outside the CDRs (ie, in the FRs). In the methods of some embodiments, up to 10, up to 5, or up to 3 amino acids in SEQ ID NO: 5 have been substituted, inserted, and/or deleted, and in SEQ ID NO: 4 Up to 3 amino acids have been substituted, inserted and/or deleted. Substitutions, insertions or deletions can occur in regions outside the CDRs (ie, in the FRs). In some embodiments, a total of 1 to 10, 1 to 5, or 1 to 3 amino acids have been substituted, inserted, and/or deleted in SEQ ID NO: 4. Any anti-FGFR2 antibody described herein can be afucosylated. For example, the antibody may be an IgG1 or IgG3 antibody lacking fucose at Asn297.

Other examples of anti-FGFR2b antibodies are the HuGAL-FR21, GAL-FR22 and GAL-FR23 antibodies described in US Patent No. 8,101,723 B2, which is incorporated herein by reference in its entirety. Figures 13 and 14 of U.S. Patent No. 8,101,723 B2 show the amino acid sequences of the variable region and full-length mature antibody chain of HuGAL-FR21 and are incorporated herein by reference. The heavy chain variable region sequence of antibody HuGAL-FR21 is underlined in Figure 13 of U.S. Patent No. 8,101,723 B2 and is expressly incorporated herein by reference. The light and heavy chain variable regions of GAL-FR22 are provided as, for example, SEQ ID NOs: 7 and 8 in Patent No. 8,101,723 B2, and the Kabat CDRs and light and heavy chain variable regions are also provided in that patent. Figure 16 is incorporated herein by reference. The fusionoma-generating GAL-FR21, GAL-FR22, and GAL-FR23 were deposited with the American Type Culture Collection under ATCC numbers 9586, 9587, and 9408 on November 6, 2008, and August 12, 2008, respectively. American Type Culture Collection, PO Box 1549, Manassas VA, USA, 20108. Thus, in some embodiments, the FGFR2 antibody system comprises an antibody derived from the amino acid sequence of an antibody obtained from one of these three fusionoma strains.

Bemarituzumab is an afucosylated, humanized monoclonal antibody that targets fibroblast growth factor (FGF) receptor isotype 2b (FGFR2b) and exhibits FGF binding inhibition and antibody-dependent Dual mechanisms of cytotoxicity. The anti-FGFR2b antibody of any of the methods described herein can be bemarituzumab. Bemarituzumab contains the heavy chain of SEQ ID NO: 2 and the light chain of SEQ ID NO: 3. In the methods of some embodiments, the anti-FGFR2 antibody comprises the heavy chain of SEQ ID NO: 2 and the light chain of SEQ ID NO: 3 and is afucosylated. In the methods of some embodiments, the anti-FGFR2b antibody is bemarituzumab. In the methods of some embodiments, the anti-FGFR2b antibody comprises HCDR1-3 and LCDR1-3 of bemarituzumab. Bemarituzumab can be produced in a Chinese hamster ovary cell line that lacks the FUT8 gene, so the antibody produced is glycosylated but lacks the core fucose in the polysaccharide portion of the antibody. The deletion of core fucose results in higher affinity for the Fc receptor FcγRIIIa compared to fucosylated molecules and potentially enhances immune cell-mediated tumor cell killing.

Bemarituzumab inhibited FGF ligand-stimulated FGFR2b phosphorylation and cell proliferation in cell cultures of FGFR2b-overexpressing gastric and breast cancer cell lines. Bemarituzumab also inhibits tumor growth in FGFR2b overexpressing gastric and breast xenograft models. Without being bound by theory, it is conceivable that the mechanism of action of bemarituzumab may include blocking ligand binding and downstream signaling, reducing FGFR2b kinesin expression, and/or enhancing ADCC. Furthermore, without being bound by theory, it is conceivable that because bemarituzumab is specific for the FGFR2b receptor, it would 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, the use of bemarituzumab to treat hyperphosphatemia associated with FGFR TKIs is not relevant (Catenacci et al., 2020; Dienstmann et al., 2014; Sequist et al., 2014; Andre et al., 2013; Brown et al., 2005).

Bemarituzumab has been studied as monotherapy in a phase 1 dose-finding study (FPA144-001) and in combination with mFOLFOX6 chemotherapy in FGFR2b-positive gastric cancer in the FIGHT study. The efficacy of bemarituzumab correlates with the degree of FGFR2b overexpression in gastric cancer detected by immunohistochemistry (IHC) and has demonstrated a manageable safety profile in combination with mFOLFOX6. Genomic and IHC data suggest that other cancers, including SqNSCLC, may also have significant rates of FGFR2b overexpression.

Bemarituzumab blocks FGFR2b phosphorylation, downregulates the receptor, and inhibits downstream signaling. The impact on downstream signaling was measured by studying the phosphorylation of proteins directly phosphorylated by the FGFR2 protein, FGFR substrate-2 (FRS2). Each of these mechanisms has been explored in vitro and in vivo and, without being bound by theory, appears to contribute to the antitumor activity of bemarituzumab. In an FGFR2b-overexpressing human tumor xenograft model, bemarituzumab showed dose-related antitumor activity, with regression and complete responses at well-tolerated doses.

Bemarituzumab exhibited consistent pharmacokinetic (PK) behavior following intravenous (IV) administration in rats and stone crab macaques, and the PK profile observed across all studies was consistent. The half-life was dose-dependent, ranging from 0.8 days at the lowest dose (1 to 1.5 mg/kg) to at least 8 days at the highest dose (100 to 150 mg/kg) tested in stone crab macaques. Bemarituzumab exhibits dose-dependent nonlinear PK marked by faster clearance at the end of the plasma concentration-time profile and increasing exposure (area under the concentration-time curve [AUC]) with increasing dose A greater than dose-proportional increase occurs. Target-mediated clearance is saturated, as indicated by a dose-proportional increase in exposure at doses above this level when administered at weekly intervals. PK studies supporting toxicokinetic studies show a dose-dependent increase in exposure (AUC) supporting the reliability of these studies in assessing toxicity. From prenatal and postnatal development studies, significant reproductive and developmental toxicity was observed in embryo-fetal development at all dose levels (5 to 100 mg/kg/dose). Thus, it is contemplated that in some embodiments, a subject treated with bemarituzumab does not become pregnant.

Bemarituzumab has demonstrated an acceptable safety profile. Identified risks when used in combination with mFOLFOX6 include corneal toxicity, infusion-related reactions, gastrointestinal toxicity (stomatitis and mucosal inflammation), nail toxicity, and increases in AST and ALT. Corneal events are very common with bemarituzumab treatment, with the most common adverse event being dry eye. Although nearly all events have been non-serious, grade 3 events (eg, ulcerative keratitis and punctate keratitis) have been observed, resulting in decreased visual acuity. Most corneal events usually resolve with interruption or discontinuation of treatment and standard of care intervention for the corneal event. As such, it is contemplated that, in some embodiments, subjects treated with bemarituzumab further receive ocular lubricant treatment. Ocular lubricants may be administered prophylactically to reduce the risk of corneal events.

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

Anti-FGFR2b antibodies (such as bemarituzumab) can be administered intravenously as described herein. docetaxel

Docetaxel is considered a single agent for the treatment of patients with locally advanced or metastatic NSCLC after failure of platinum-based chemotherapy. For example, docetaxel is commercially available as ^Taxotere® (see ^Taxotere® United States Prescribing Information [USPI] 2019). For cancers that have progressed after treatment with checkpoint inhibitors and platinum-based chemotherapy, according to treatment guidelines from the US National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) For patients with the disease, taxanes (such as docetaxel) are the recommended treatment when no other "actionable" mutations are found.

Docetaxel can be administered intravenously as described herein.

Subjects receiving docetaxel may be premedicated with an oral corticosteroid, such as 8 mg dicortisol twice daily for 3 days, starting 1 day before docetaxel administration (or according to local guidelines). Consider this May reduce the incidence and severity of fluid retention and the severity of hypersensitivity reactions. Methods of treating SqNSCLC include methods of administering anti -FGFR2b antibodies

This article describes methods to treat subjects with squamous non-small cell lung cancer (SqNSCLC). Such methods may include administering to the subject an anti-FGFR2b antibody on a Q2W schedule at a dose of 15-25 mg/kg. The methods may further include administering an additional dose of 5-10 mg/kg of the anti-FGFR2b antibody 7-10 days after the first administration of the anti-FGFR2b antibody in the Q2W schedule. The additional dose may be called an "intervention" dose. In some methods, the anti-FGFR2b antibody is administered to the subject in a Q2W schedule at a dose of 15-22 mg/kg or 15-20 mg/kg. In some methods, the Q2W regimen is administered at a dose of about 15 mg/kg, about 17 mg/kg, about 20 mg/kg, about 22 mg/kg, or about 25 mg/kg, including any two of the listed values. ranges between, for example, 15-17 mg/kg, 17-20 mg/kg, 17-22 mg/kg, 17-25 mg/kg, 20-22 mg/kg, 20-25 mg/kg, or 22- 25 mg/kg) were administered to subjects with anti-FGFR2b antibodies. In some methods, the subject is administered an anti-FGFR2b antibody at a dose of 15 mg/kg on a Q2W schedule. According to some methods described herein, additional or "intervention" doses may be 5-10 mg/kg and may be administered 7-10 days after the first administration of the anti-FGFR2b antibody in a Q2W schedule. According to some methods described herein, the additional or "intervention" dose may be 7-8 mg/kg and may be administered 7-10 days after the first administration of the anti-FGFR2b antibody in a Q2W schedule. For example, 7-10 days after the first administration of an anti-FGFR2b antibody in a Q2W regimen, the additional or "intervention" dose may be about 7 mg/kg, about 7.5 mg/kg, or about 8 mg/kg. . For any of the methods described herein, the anti-FGFR2b antibody can be bemarituzumab. For example, treatment of Sq NSCLC may include progression-free survival, overall survival, partial response, complete response, objective response (complete response + partial response (PR)), or a combination of two or more of the listed items.

Depicted in Figure IB are methods of treating SqNSCLC in a subject according to some embodiments. The method may include 15-25 mg/kg (e.g., 15-22 mg/kg, or 15-20 mg/kg, 15-17 mg/kg, 17-20 mg/kg, 17-22 mg) in a Q2W schedule /kg, 17-25 mg/kg, 20-22 mg/kg, 20-25 mg/kg, 22-25 mg/kg, about 15 mg/kg, about 17 mg/kg, about 20 mg/kg, about The anti-FGFR2b antibody 100 was administered to the subject at a dose of 22 mg/kg, or about 25 mg/kg). The method may further comprise administering to the subject 5-10 mg/kg (e.g., 8 mg/kg, 7-7.5 mg/kg, 7.5-8 mg) 7-10 days after the first administration of the anti-FGFR2b antibody /kg, 7.5-9 mg/kg, or 7.5-10 mg/kg, 7-9 mg/kg, 7-10 mg/kg, 10-12 mg/kg, about 7 mg/kg, about 7.5 mg/kg , about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg) an additional dose of anti-FGFR2b antibody 105 .

It has been observed that the Phase 1 portion of study FPA144-004 indicates: All patients receiving PK data for treatment at 15 mg/kg in the Q2W regimen with 1 additional dose of 7.5 mg/kg on Day 8 of Cycle 1 Subjects reached target C _trough concentrations on Day 15, and C _peaks were within the range observed in Study FPA144-001. Therefore, without being bound by theory, it is conceivable to add a single intervention dose as described herein (e.g., 5-10 mg/kg on day 8 of cycle 1, e.g. 7.5 mg on day 8 of cycle 1 /kg) can minimize the time to reach the target C _trough without increasing the subject's C _peak . Methods including administering anti -FGFR2b antibodies and docetaxel

This article describes methods to treat subjects with squamous non-small cell lung cancer (SqNSCLC). The method can include administering to the subject an anti-FGFR2b antibody. The method may further comprise administering docetaxel to the subject. For any of the methods described herein, the anti-FGFR2b antibody can be bemarituzumab.

Depicted in Figure 1C are methods of treating SqNSCLC in a subject according to some embodiments. The method may include administering at least 15 mg/kg (eg, at least 20 mg/kg, 25 mg/kg, at least 30 mg/kg, or 20-25 mg/kg, 20-30 mg/kg, or 25-35 mg/kg). The subjects were first administered an anti-FGFR2b antibody at a dose of 110 kg). Anti-FGFR2b antibodies can be administered intravenously. The method may comprise administering docetaxel 120 to the subject on a Q3W schedule, such as intravenously administering docetaxel to the subject on a Q3W schedule at ^a dose of at least 35 mg/m. For example, docetaxel can be administered at a dose of at least 50 mg/ ^m in Q3W, 50-100 mg/ ^m in Q3W, 60-75 mg/m in Q3W, or 60-75 mg/ ^m in Q3W. Administer intravenously at a dose of 35 – 75 mg/ ^m2 . Optionally, the method may further comprise administering to the subject 7-12 mg/kg (e.g., 8 mg/kg, 7-7.5 mg/kg, 7-10 days after the first administration of the anti-FGFR2b antibody). 7.5-8 mg/kg, 7.5-9 mg/kg, or 7.5-10 mg/kg, 7-9 mg/kg, 7-10 mg/kg, 10-12 mg/kg, about 7 mg/kg, about 130 . In some methods, block 130 is omitted. Referring to Box 140 , three weeks after the first dose of 110 , the method may include administering a Q3W regimen of at least 10 mg/kg (e.g., 10-19 mg/kg, 10-15 mg/kg, 15-19 mg/kg, approximately The subject was administered the anti-FGFR2b antibody 140 at a dose of 10 mg/kg, about 15 mg/kg, or about 19 mg/kg). Optionally, docetaxel and the anti-FGFR2b antibody can be administered simultaneously in a Q3W regimen, eg, in a single composition or in separate compositions. Alternatively, referring to Box 141 , three weeks after the first dose of 110 , the method may include administering 5-15 mg/kg (e.g., 5-10 mg/kg, 10-15 mg/kg, or about 10 mg) in a Q3W regimen /kg), the anti-FGFR2b antibody was administered to the subject.

Depicted in Figure ID are methods of treating SqNSCLC in a subject according to some embodiments. The method may include administering to the subject a dose of at least 25 mg/kg, such as at least 30 mg/kg, about 30 mg/kg, or 25-35 mg/kg, 30-35 mg/kg, or 25-30 mg/kg. Subjects were administered anti-FGFR2b antibody for the first time 115 . Anti-FGFR2b antibodies can be administered intravenously. The method may include administering docetaxel to the subject on a Q3W schedule 125 , such as intravenously administering docetaxel to the subject on a Q3W schedule at a dose of at least 35 mg/m ² . For example, docetaxel can be administered intravenously at 50-100 mg/m ² on a Q3W schedule, 60-75 mg/m ² on a Q3W schedule, or 35 – 75 mg/m ² on a Q3W schedule. Invest. Optionally, the method may further comprise administering to the subject 7-12 mg/kg (e.g., 8 mg/kg, 7-7.5 mg/kg, 7-10 days after the first administration of the anti-FGFR2b antibody). 7.5-8 mg/kg, 7.5-9 mg/kg, or 7.5-10 mg/kg, 7-9 mg/kg, 7-10 mg/kg, 10-12 mg/kg, about 7 mg/kg, about 135 . In some methods, box 135 is omitted. Referring to Box 145 , three weeks after the first dose of 115 , the method may include at least 15 mg/kg (e.g., 15-25 mg/kg, 15-24 mg/kg, 20-25 mg/kg, 20 -Administering an anti-FGFR2b antibody to a subject at a dose of 24 mg/kg, 15-20 mg/kg, about 15 mg/kg, about 20 mg/kg, about 22 mg/kg, or about 24 mg/kg) 145 . Optionally, docetaxel and the anti-FGFR2b antibody can be administered simultaneously in a Q3W regimen, eg, in a single composition or in separate compositions.

Depicted in Figure IE are methods of treating SqNSCLC in a subject according to some embodiments. The method may include at least 25 mg/kg (eg, 25-35 mg/kg, 30-35 mg/kg, 25-30 mg/kg, at least 30 mg/kg, or about 30 mg/kg) in a Q3W regimen Dosage Subjects were administered anti-FGFR2b antibody 117 . Anti-FGFR2b antibodies can be administered intravenously. The method may include administering docetaxel to the subject on a Q3W schedule, 127 such as administering docetaxel intravenously to the subject on a Q3W schedule at ^a dose of at least 35 mg/m. For example, docetaxel can be administered intravenously at 50-100 mg/m ² on a Q3W schedule, 60-75 mg/m ² on a Q3W schedule, or 35 – 75 mg/m ² on a Q3W schedule. Invest. Optionally, docetaxel and the anti-FGFR2b antibody can be administered simultaneously in a Q3W regimen, eg, in a single composition or in separate compositions. In some methods, see Box 117 , an anti-FGFR2b antibody is administered intravenously in a Q3W schedule at a dose of 25-35 mg/kg, and see Box 127 , docetaxel in a Q3W schedule at a dose of at least 50 mg/ ^m Administer intravenously, e.g., at a dose of 50-100 mg/ ^m2 with the Q3W regimen or 60-75 mg/m2 with the Q3W regimen. In some methods, see Box 117 , an anti-FGFR2b antibody is administered intravenously in a Q3W schedule at a dose of 30-35 mg/kg, and see Box 127 , docetaxel in a Q3W schedule at a dose of at least 50 mg/ ^m Administer intravenously, e.g., at a dose of 50-100 mg/ ^m2 with the Q3W regimen or 60-75 mg/ ^m2 with the Q3W regimen. In some methods, see Box 117 , an anti-FGFR2b antibody is administered intravenously in a Q3W schedule at a dose of 25-30 mg/kg, and see Box 127 , docetaxel in a Q3W schedule at a dose of at least 50 mg/ ^m Administer intravenously, e.g., at a dose of 50-100 mg/ ^m2 with the Q3W regimen or 60-75 mg/m2 with the Q3W regimen. In some methods, refer to Box 117 , an anti-FGFR2b antibody is administered intravenously in a Q3W schedule at a dose of at least 30 mg/kg, and refer to Box 127 , docetaxel is administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m Administration, such as intravenous administration at a dose of 50-100 mg/ ^m2 with the Q3W regimen or 60-75 mg/ ^m2 with the Q3W regimen. In some methods, refer to Box 117 , an anti-FGFR2b antibody is administered intravenously in a Q3W schedule at a dose of 30 mg/kg, and refer to Box 127 , docetaxel is administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m Administer, e.g., intravenously at ^a dose of 50-100 mg/m with the Q3W regimen or 60-75 mg/ ^m with the Q3W regimen.

In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule that includes an initial administration at a dose of at least 20 mg/kg three weeks after the first administration, followed by subsequent administrations in a Q3W schedule at each dose At least 10 mg/kg. For example, docetaxel can be administered intravenously at a dose of at least 75 mg/m ² on a Q3W schedule, at least 50 mg/m ² on a Q3W schedule, or at least 35 mg/m ² on a Q3W schedule. Docetaxel can be administered concurrently with the anti-FGFR2b antibody, eg, in a single composition or in separate compositions, in a Q3W regimen. In some methods of treating SqNSCLC, the first dose administered can be at least 20 mg/kg, 25 mg/kg, or 30 mg/kg, including a range between any two of the listed values, such as 20-25 mg /kg, 20-30 mg/kg, 25-30 mg/kg or 25-35 mg/kg. Docetaxel can be administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m2 . In some methods of treating SqNSCLC, the first dose administered can be at least 20 mg/kg, 25 mg/kg, or 30 mg/kg, including a range between any two of the listed values, such as 25-30 mg/kg. kg. Docetaxel can be administered intravenously in a Q3W regimen at a dose of at least 35 mg/ ^m2 . For example, the anti-FGFR2b antibody can be bemarituzumab.

For any method of treating SqNSCLC described herein, the anti-FGFR2b antibody can be administered intravenously. The anti-FGFR2b antibody can be bemarituzumab.

For any method of treating SqNSCLC described herein, docetaxel can be administered at least 35 mg/m ² in Q3W, or at least 50 mg/m ² in Q3W, or at least 75 mg/m ² in Q3W. The dose is administered intravenously. For example, docetaxel can be administered as 50-100 mg/m ² in the Q3W regimen, or 75-100 mg/m ² in the Q3W regimen, or 60-75 mg/m ² in the Q3W regimen, or 60-75 mg/m 2 in the Q3W regimen. Doses of 35 – 75 mg/ ^m2 are administered intravenously.

In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule, which includes an initial administration at a dose of 20-30 mg/kg or 20-25 mg/kg, three weeks after the first administration, and thereafter in a Q3W schedule For subsequent administrations, each dose is 10-19 mg/kg. For example, docetaxel can be administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m2 . In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule, which includes an initial administration at a dose of 20-30 mg/kg or 20-25 mg/kg, three weeks after the first administration, and thereafter in a Q3W schedule For subsequent administrations, each dose is 10-19 mg/kg. For example, docetaxel can be administered intravenously in a Q3W regimen at a dose of at least 35 mg/ ^m2 . For example, the anti-FGFR2b antibody can be bemarituzumab.

In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule that includes an initial administration at a dose of about 22 mg/kg three weeks after the first administration, followed by subsequent administrations in a Q3W schedule at each dose of About 15 mg/kg. For example, docetaxel can be administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m2 . The initial dose may be 22 mg/kg, and subsequent doses may be 15 mg/kg each. In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule that includes an initial administration at a dose of about 22 mg/kg three weeks after the first administration, followed by subsequent administrations in a Q3W schedule at each dose of About 15 mg/kg. For example, docetaxel can be administered intravenously in a Q3W regimen at a dose of at least 35 mg/ ^m2 . The initial dose may be 22 mg/kg, and subsequent doses may be 15 mg/kg each. For example, the anti-FGFR2b antibody can be bemarituzumab.

In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule that includes an initial administration at a dose of at least 25 mg/kg three weeks after the first administration, followed by subsequent administrations in a Q3W schedule at each dose 15-24 mg/kg. For example, docetaxel can be administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m2 . In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule that includes an initial administration at a dose of at least 25 mg/kg three weeks after the first administration, followed by subsequent administrations in a Q3W schedule at each dose 15-24 mg/kg. For example, docetaxel can be administered intravenously in a Q3W regimen at a dose of at least 35 mg/ ^m2 . For example, the anti-FGFR2b antibody can be bemarituzumab.

In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule, which includes an initial administration at a dose of 25-35 mg/kg or 25-30 mg/kg, three weeks after the first administration, and thereafter in a Q3W schedule For subsequent administrations, each dose will be 20-25 mg/kg (e.g., approximately 22 mg/kg). For example, docetaxel can be administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m2 . In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule, which includes an initial administration at a dose of 25-35 mg/kg or 25-30 mg/kg, three weeks after the first administration, and thereafter in a Q3W schedule For subsequent administrations, each dose will be 20-25 mg/kg (e.g., approximately 22 mg/kg). For example, docetaxel can be administered intravenously in a Q3W regimen at a dose of at least 35 mg/ ^m2 . For example, the anti-FGFR2b antibody can be bemarituzumab.

In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule that includes an initial administration of 30 mg/kg three weeks after the first administration, followed by subsequent administrations in a Q3W schedule of 22 mg/kg. For example, docetaxel can be administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m2 . In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule that includes an initial administration of 30 mg/kg three weeks after the first administration, followed by subsequent administrations in a Q3W schedule of 22 mg/kg. For example, docetaxel can be administered intravenously in a Q3W regimen at a dose of at least 35 mg/ ^m2 . For example, the anti-FGFR2b antibody can be bemarituzumab.

In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule, which includes an initial administration at a dose of 15-20 mg/kg or 15-25 mg/kg, three weeks after the first administration, and thereafter in a Q3W schedule For subsequent administrations, each dose is 10-19 mg/kg (e.g., 15-19 mg/kg or about 15 mg/kg). For example, docetaxel can be administered intravenously in a Q3W schedule at a dose of at least 50 mg/ ^m2 . In some methods, the anti-FGFR2b antibody is administered in a Q3W schedule, which includes an initial administration at a dose of 20-30 mg/kg or 20-25 mg/kg, three weeks after the first administration, and thereafter in a Q3W schedule For subsequent administrations, each dose is 10-19 mg/kg. For example, docetaxel can be administered intravenously in a Q3W regimen at a dose of at least 35 mg/ ^m2 . For example, the anti-FGFR2b antibody can be bemarituzumab.

For any method of treating SqNSCLC described herein, the method may further comprise administering an additional or "intervention" dose of 7-12 mg/kg of an anti-FGFR2b antibody 7-10 days after the first administration of the anti-FGFR2b antibody. For example, additional doses may be 7-8 mg/kg, 7-9 mg/kg, 7-10 mg/kg, or 10-12 mg/kg. For example, the additional dose may be about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg, including between any two of the listed values. range, such as 7-7.5 mg/kg, 7.5-8 mg/kg, 7.5-9 mg/kg or 7.5-10 mg/kg. For example, the anti-FGFR2b antibody can be bemarituzumab.

For any method of treating SqNSCLC described herein, the anti-FGFR2b antibody can be administered intravenously in a Q3W regimen, which consists of an initial dose of 20-30 mg/kg, three weeks after the first dose, and Q3W thereafter. Subsequent administrations are planned for each dose at 10-19 mg/kg, 10-15 mg/kg, 15-19 mg/kg, about 10 mg/kg, about 15 mg/kg, or about 19 mg/kg. Docetaxel can be administered intravenously at a dose of at least 35 mg/ ^m2 , such as at least 50 mg/ ^m2 with the Q3W regimen, 35-100 mg/ ^m2 with the Q3W regimen, 50-100 mg/m2 with the Q3W regimen mg/m ² , 35-75 mg/m ² on the Q3W regimen, or 60-75 mg/m ² on the Q3W regimen. For example, docetaxel can be administered intravenously on a Q3W schedule at a dose of at least 50 mg/ ^m2 , such as 50-100 mg/ ^m2 on a Q3W schedule or 60-75 mg/ ^m2 on a Q3W schedule Administer intravenously. For example, the anti-FGFR2b antibody can be bemarituzumab.

For any method of treating SqNSCLC described herein, the anti-FGFR2b antibody can be administered intravenously in a Q3W regimen, which consists of an initial dose of 25-35 mg/kg, three weeks after the first dose, and Q3W thereafter. Schedule subsequent administrations at doses of 15-24 mg/kg (e.g., 20-24 mg/kg). Docetaxel can be administered intravenously at a dose of at least 35 mg/ ^m2 or at least 50 mg/ ^m2 on a Q3W schedule, e.g., 35-100 mg/ ^m2 on a Q3W schedule, 50-100 mg on a Q3W schedule /m ² , administered intravenously at 35-75 mg/m ² in the Q3W regimen, or 60-75 mg/m ² in the Q3W regimen. For example, docetaxel can be administered intravenously on a Q3W schedule at a dose of at least 50 mg/ ^m2 , such as 50-100 mg/ ^m2 on a Q3W schedule or 60-75 mg/ ^m2 on a Q3W schedule Administer intravenously. For example, the anti-FGFR2b antibody can be bemarituzumab.

Methods according to some embodiments describe a study to evaluate the safety, tolerability, and efficacy of bemarituzumab monotherapy and in combination with docetaxel after first-line treatment. This study may further explore the established efficacy of bemarituzumab combined with docetaxel in FGFR2b+ selected SqNSCLC. The study may include dosing and timing of bemarituzumab and docetaxel as described in Example 1.

For any method of treating SqNSCLC described herein, the subject's SqNSCLC cells may express FGFR2b. For example, the subject's SqNSCLC cells may overexpress FGFR2b protein, overexpress FGFR2b mRNA, or contain FGFR2b gene amplification. In some methods, SqNSCLC cells express FGFR2b protein, as determined by immunohistochemistry (IHC). For example, a subject's SqNSCLC cells may have a FGFR2b staining intensity of 2+ or 3+. For example, at least 5% of SqNSCLC cells may have a FGFR2b staining intensity of 1+, 2+, or 3+. For example, at least 10% of SqNSCLC cells may have a FGFR2b staining intensity of 1+, 2+, or 3+. If the subject's SqNSCLC cells can have an FGFR2b staining intensity of 1+, 2+, or 3+, or if at least 5% or at least 10% of the SqNSCLC cells can have an FGFR2b staining intensity of 1+, 2+, or 3+, then It is believed that the subject's SqNSCLC overexpressed FGFR2b. In some methods, if any cells of the subject's SqNSCLC have a FGFR2b staining intensity of 2+ or 3+, or if at least 5% or at least 10% of the SqNSCLC cells have a FGFR2b staining intensity of 2+ or 3+, then It is believed that the subject's SqNSCLC overexpressed FGFR2b. It is contemplated that subjects with SqNSCLC overexpressing FGFR2b may be particularly likely to benefit from treatments involving administration of an anti-FGFR2b antibody described herein (eg, bemarituzumab). Optionally, SqNSCLC cells are also evaluated for PD-L1 expression, eg, by IHC.

In some methods described herein, the subject's SqNSCLC is treated if any of the SqNSCLC cells has an FGFR2b staining intensity of at least 2+ or 3+. In some methods described herein, the subject is treated for SqNSCLC if at least 5% of the SqNSCLC cells have an FGFR2b staining intensity of at least 2+ or 3+. In some methods described herein, the subject is treated for SqNSCLC if at least 10% of the SqNSCLC cells have an FGFR2b staining intensity of at least 2+ or 3+. Example 1 : Administration of Bemarituzumab to Lung Cancer Cell Lines

In vitro measurement of ADCC activity of bemarituzumab in squamous lung cancer cell lines expressing FGFR2b as determined by flow cytometry. Evaluation of FGFR2b mRNA expression [ENST00000457416.6 [FPKQ]] and surface expression of FGFR2b protein in squamous lung cancer cell lines KNS-62, LC1F, HARA, EPLC-272H, SW900, NCIH2170, LUDLU1, and SW1573 by flow cytometry analysis . As positive controls, the gastric cancer cell lines SNU16-Luc, SNU16 and KATOIII were also evaluated. In flow cytometry experiments, cells were incubated with bemarituzumab or a control antibody of the same isotype, and 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, the squamous lung cancer cell lines KNS-62, EPLC-272H, LC1F, HARA, SW900 and LUDLU1 have an MFI of at least 10, as do the triple-negative breast cancer (TNBC) cell lines HCC1569 and HCC1806.

The effect of bemarituzumab on antibody-dependent cellular cytotoxicity (ADCC) was evaluated in each cell line. Cancer cell lines were cocultured 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 h. ADCC was assessed using Promega's ADCC Reporter Biometer (G7018), which uses luminescence readouts. ADCC curves are summarized in Figure 3A-D . ADCC activity was observed in every squamous lung cancer cell line with surface expression of FGFR2b above 10 MFI. Therefore, it can be concluded that bemarituzumab can induce ADCC in FGFR2b-positive squamous lung cancer cells. [ Table 1] Tumor type cell lines FGFR2b mRNA ( ENST00000457416.6 ) [FPKQ] Average fluorescence intensity determined by flow cytometry ADCC activity Tumor Type Squamous Lung Cancer KNS-62 8.9 572 ++ EPLC-272H 7.9 759.2 ++ LC1F 3.2 123 - HARA 3.2 401.1 + SW900 1.6 10.3 - NCIH2170 1.1 152.9 ++ LUDLU1 0.9 638.5 + SW1573 0.1 -1.2 - stomach cancer SNU16 548.3 7799.3 ++ SNU16-Luc 548.3 7962.5 ++ KATOIII 410.4 20375.2 Not tested Example 2 : Phase 1b study of bemarituzumab monotherapy and docetaxel combination therapy in FGFR2b overexpressing SqNSCLC

This example describes a phase 1b, open-label, multicenter study evaluating bemarituzumab monotherapy and the combination of bemarituzumab and docetaxel in patients with previously treated metastatic or metastatic disease. Safety, tolerability, pharmacokinetics (PK), and efficacy in subjects with locally advanced SqNSCLC.

The study includes a pre-screening period (Parts 2 and 3 only) to collect tissue for FGFR2b testing, a 28-day screening period, a treatment period, a safety follow-up (SFU) visit, and a long-term follow-up (LTFU) period. Subjects who discontinue all study treatment for any reason other than withdrawal of consent will receive SFU approximately 28 (+3) days after the last dose of study treatment. In addition, subjects will undergo survival LTFU starting with the first dose of bemarituzumab and approximately every 3 months (±1 month) for up to 2 years.

Investigators performed radiographic assessments according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 every 6 weeks (±7 days) through week 56 and then every 12 weeks (±14 days). After discontinuation of study treatment for reasons other than radiographic disease progression or withdrawal of consent, tumor evaluation will continue until radiographic progression is detected or additional anticancer therapy is initiated. The study consists of 3 parts: Part 1: Combination dose escalation Part 2: Combination Dose Expansion Part 3: Monotherapy

Subjects are required to have FGFR2b expression in their tumor samples before entering Parts 2 and 3 of this study (but not Part 1). The primary objectives of the study include: • Evaluating the safety and tolerability of bemarituzumab monotherapy and in combination with docetaxel; and • Determining the safety and tolerability of bemarituzumab monotherapy and in combination with docetaxel; The recommended Phase 3 doses of combination therapy with primary and secondary goals and endpoints are summarized in Table 2 below: [ Table 2] Target end point main • Assess the safety and tolerability of bemarituzumab monotherapy and in combination with docetaxel • Determine recommended phase 3 doses of bemarituzumab monotherapy and in combination with docetaxel • Dose-limiting toxicities (DLTs), treatment-emergent adverse events, and clinically significant changes in vital signs, physical examination, electrocardiogram, clinical laboratory tests, and visual acuity secondary • Characterizing the pharmacokinetics (PK) of bemarituzumab monotherapy and in combination with docetaxel • PK parameters of bemarituzumab include, but are not limited to, area under the concentration-time curve (AUC), maximum observed concentration (C _peak ), and observed concentration at the end of the dose interval (C _trough ) • Evaluate the preliminary anti-tumor activity of bemarituzumab monotherapy and in combination with docetaxel • Objective response [defined as complete response (CR) + partial response (PR)] (determined by investigator based on Response Evaluation Criteria in Solid Tumors [RECIST v1.1]) • Duration of response defined as from first response to disease Time to progression (determined by investigator per RECIST v1.1) or death from any cause, whichever comes first • Disease control defined as CR + PR + stable disease (SD) • Progression-free survival (PFS), Defined as the time from inclusion to disease progression or death from any cause. Subjects who were alive and progression-free were censored at the time of last evaluable disease assessment. Progress is based on investigator assessment according to RECIST v1.1. • Overall survival (OS), defined as the time from inclusion to death from any cause. Surviving subjects were censored on the most recent date known to be alive. part 1 _

Part 1 of this study will explore the coadministration of bemarituzumab and docetaxel. During the dose escalation process, subjects were enrolled into groups with 3 to 6 subjects evaluable for dose-limiting toxicities (DLTs) per cohort, and escalation was primarily guided by safety responses to different doses.

The recommended Phase 2 dose of bemarituzumab plus mFOLFOX6 (evaluated in Study FPA144-004) was established as 15 mg/kg intravenously (IV) every two weeks (Q2W), with a dose of The single dose for 8 days is 7.5 mg/kg. In Parts 1 and 2 of this study, the dosing interval was increased from Q2W to Q3W to be consistent with the docetaxel once-every-three-weeks (Q3W) dosing schedule. At dose level 1, a dose of 15 mg/kg was tested, but compared to FAP144-004, in a Q3W schedule instead of a Q2W schedule, with an additional dose of 7.5 mg/kg on day 8 replaced on the first dosing day Give 1 loading dose of 22 mg/kg IV. Dose Level 2 will result in a proportional increase in bemarituzumab doses (including the loading dose) from those administered in the Q2W regimen studied in FPA144-004 to account for the increased Q3W dosing interval. A treatment cycle is 21 days. For Part 1, prospective tumor assessment of FGFR2b expression was not required for enrollment, and a maximum of approximately 18 subjects could be enrolled. Dosage levels are: Dose Level 1: Bemarituzumab 22 mg/kg IV on Day 1 of Cycle 1, then 15 mg/kg IV on Day 22, followed by Q3W regimen Dose Level 2: Bemarituzumab 30 mg/kg IV on Day 1 of Cycle 1, then 22 mg/kg IV on Day 22, followed by Q3W regimen

If dose tapering from dose level 1 is necessary, an additional dose level 1a of bemarituzumab 15 mg/kg IV Q3W plus 1 additional dose of 7.5 mg/kg only on Day 8 of Cycle 1 may be explored. Docetaxel was administered at 75 mg/m ² IV Q3W (or 60 mg/m ² IV Q3W for subjects at the Japanese site) at each dose level and on each scheduled dosing day.

Part 1 begins with dose level 1. The study DLT period is 21 days after the first dose. Once 3 to 6 subjects enrolled at a specific dose level have completed 21 days of safety follow-up, a Dose Level Review Team (DLRT) meeting is held. DLRT evaluates all available safety, laboratory and PK data, as well as rules generated by the modified toxicity probability interval design (mTPI-2) (Guo et al., 2017), to guide their dose finding recommendations. The panel may make recommendations such as escalating to the next planned dose, continuing at the current dose level, tapering to a lower dose, terminating the study, or initiating enrollment in Part 2 of the study at the evaluated dose level. The mTPI-2 escalation/decrement guidelines for each dose cohort were derived with a target toxicity probability of 0.30 and an acceptable toxicity probability interval of (0.25, 0.33). If the estimated probability of a dose level exceeding the target DLT (i.e., elimination boundary) is 95% or greater, that dose level will be considered unsafe and no additional subjects will be enrolled at that dose level. Dose exploration continues until: Part 1 has reached a maximum of 18 subjects; or 9 subjects have been treated at a specific dose level; or the lowest dose level exceeds the elimination boundary in Part 2

Once the DLRT declares the dose level safe, the dose level can move into Part 2 of the study. Part 2 inclusion is limited to subjects with possible FGFR2b manifestations. In Part 2, treat a minimum of 10 response-evaluable subjects and a maximum of 30 response-evaluable subjects at each dose level to better understand the safety profile of the combination at the recommended phase 3 dose (RP3D) and initial efficacy. In Part 2 of the study, it can be expanded to up to 2 dose levels, each consisting of 10 to 30 subjects. Part 3 _

Part 3 of the study explored bemarituzumab monotherapy at the dose evaluated in Study FPA144-004, which was 15 mg/kg IV Q2W plus 1 additional dose on Day 8 of Cycle 1 7.5 mg/kg. A treatment cycle lasts for 14 days. Part 3 inclusion is limited to subjects with possible tumor manifestations of FGFR2b. A minimum of 10 and a maximum of 30 response-evaluable subjects were treated in Part 3 to better understand the safety profile of bemarituzumab monotherapy in FGFR2b+ SqNSCLC, PK and preliminary efficacy. Part 3 may enroll subjects at the same time as Parts 1 and 2. Bemarituzumab dosing rationale:

Study FPA144-004 demonstrated clinically meaningful and statistically significant improvements in PFS, OS and ORR in FGFR2b-positive, non-human epithelial growth factor receptor 2 (HER2)-positive frontline advanced GC and GEJ subjects using 15 mg/kg IV Q2W with one additional dose of 7.5 mg/kg on day 8 of cycle 1 has a controllable safety profile. In this trial, the same dose and schedule were tested on the monotherapy Part 3 group. Dose level 1 of bemarituzumab in combination with docetaxel is proposed to be a dose of 15 mg/kg administered as a Q3W schedule rather than a Q2W schedule in order to comply with the Q3W docetaxel schedule. Dose Level 1 will also explore removing the additional dose on Day 8 of Cycle 1 and adding a loading dose of 22 mg/kg administered once on Day 1 of Cycle 1. Dose Level 2 will result in a proportional increase in bemarituzumab doses (including the loading dose) from those administered in the Q2W regimen studied in FPA144-004 to account for the increased Q3W dosing interval. due to late

NSCLC is an aggressive disease, and standard chemotherapy only provides a median disease control of approximately 7 months, so loading doses are recommended. Shortening the time to reach target C _trough levels may help maximize the potential benefit of bemarituzumab.

Based on the following data, study FPA144-004 selected the following regimen of bemarituzumab: 15 mg/kg Q2W with one additional dose of 7.5 mg/kg on Day 8 of Cycle 1.

In a Phase 1 monotherapy dose-escalation study of FPA144-001, bemarituzumab demonstrated linear clearance from 1 mg/kg to 15 mg/kg in subjects with solid tumors, including gastric cancer. Within the linear dose range, the maximum observed serum concentration ( _peak C) and AUC scale proportionally with increasing dose. The estimated half-life at 1 mg/kg to 15 mg/kg was 6.01 to 11.7 days by non-compartment analysis, which supports dosing once every 2 weeks or less frequently.

The target _Ctrough of bemarituzumab ≥ 60 μg/mL was derived from nonclinical studies, including binding affinity, in vitro receptor occupancy, and in vivo efficacy studies on human FGFR2b-Fc and human FcγRIIIa (V158).

Supporting the hypothesis that ≥ 60 μg/mL should be the target minimum C _trough , all FGFR2b overexpressing subjects who showed a partial response (PR) in the FIH FPA144-001 trial, regardless of dose level, achieved ≥ 60 μg /mL target _{Ctrough ,ss} . Among all subjects treated with the 15 mg/kg Q2W regimen in Study FPA144-001, 23 of 51 subjects achieved target C _trough concentrations on Day 15. At week 8 (steady state), 14 of 16 subjects achieved target C _trough ≥ 60 μg/mL at the same dose.

Observed PK data from the Phase 1 portion of study FPA144-004 indicate: all treatments at 15 mg/kg in the Q2W regimen with 1 additional dose of 7.5 mg/kg on Day 8 of Cycle 1 Subjects with PK data achieved target C _trough concentrations on Day 15 and C _peaks were within the range observed in Study FPA144-001. Therefore, adding a single dose of 7.5 mg/kg on Day 8 of Cycle 1 minimizes the time to target C _trough without increasing C _peak . Docetaxel dosing rationale

According to the U.S. and European Union (EU) prescribing information for docetaxel (EU Summary of Product Characteristics [SPC], USPI), the docetaxel dose for U.S. and EU subjects in this study was 75 mg/m ² every 3 weeks Administer intravenously over 1 hour at a time. According to the regional prescribing information for docetaxel and the terms of the docetaxel dosage approved in Japan, the docetaxel dose for Japanese subjects is 60 mg/m ² administered intravenously over 1 hour every 3 weeks ( Abe et al., 2015; Kudoh et al., 2006). number of subjects

It is contemplated that up to 108 subjects will be included in this study, consisting of a maximum of 18 subjects in Part 1 and a total of a maximum of 90 response-evaluable subjects in Parts 2 and 3. 90 response evaluable subjects including the possibility of having two cohorts in Part 2 of 10 to 30 subjects each, administering 2 doses of bemarituzumab plus docetaxel level. Projected areas for this study will include North America, Asia, Europe, and Australia. Summary of Subject Eligibility Criteria

Subjects were ≥18 years of age at the time of informed consent, had histologically documented SqNSCLC, and had received at least 1 prior systemic therapy (Parts 1 and 2) or at least 2 prior systemic therapies (Part 3) To treat locally advanced, unresectable or metastatic disease at or after progression or experiencing disease recurrence. For Parts 1 and 2, subjects must be candidates for docetaxel therapy, and for Parts 2 and 3, subjects must have FGFR2b overexpression, as determined by centrally conducted IHC testing . All subjects must have measurable disease according to RECIST v1.1. treatment

For Parts 1 and 2, bemarituzumab was administered intravenously every 21 days on day (D1) of each cycle, along with docetaxel 75 mg/m ² (or docetaxel at the Japanese study site Subjects were dosed 60 mg/m ² ). The doses of bemarituzumab indicated in the dose finding were administered intravenously via peripheral vein or central venous catheter as an intravenous infusion over approximately 30 minutes (±10 minutes). Docetaxel at a dose of 75 mg/ ^m2 (or 60 mg/ ^m2 for subjects at the Japanese study site) was administered over 60 minutes via peripheral vein or central venous catheter only. A treatment cycle is 21 days.

For Part 3, bemarituzumab was administered intravenously every 14 days on day (D1) of each cycle. Bemarituzumab (dosage regimen of 15 mg/kg IV Q2W and a single 7.5 mg/kg dose on cycle 1 day 8) is administered via intravenous infusion through a peripheral vein or central venous catheter over approximately 30 minutes (± 10 minutes). A treatment cycle lasts for 14 days. Statistical Considerations Sample Size Considerations

Among 3, 6, or 9 subjects in the dose level cohort in Part 1, if the true DLT rate was 25%, there would be a 58%, 82%, and 93% probability, respectively, of observing at least 1 DLT.

In a minimum of 10 subjects each in Parts 2 and 3, there is at least an approximately 95% probability of observing at least 1 DLT if the lower limit of the acceptable toxicity interval for the true DLT rate is 25%. In dose expansion parts 2 and 3, up to 30 response-evaluable subjects per dose level will be included to obtain further safety and preliminary efficacy data.

Part 3 may be included at the same time as Parts 1 and 2, so the timing of the DLRT meeting may be adjusted so that data from multiple study parts can be reviewed in one meeting. Analytical method

Descriptive statistics are provided for selected demographic, safety, PK, efficacy, and biomarker data. Descriptive statistics for continuous data will include mean, median, standard deviation, and range, while categorical data is summarized using frequency counts and percentages. Response rates are presented with 95% exact CI. Time-to-event endpoints were summarized using the Kaplan-Meier (KM) method.

Statistical hypotheses were not tested in this study. research community

Eligibility criteria will be assessed during screening. Appropriate written informed consent will be obtained prior to any research specific activities/procedures. Inclusion Criteria Subjects will be eligible for inclusion in the study only if all of the following criteria apply: Subject has provided informed consent/assent prior to the commencement of any study-specific activities/procedures Aged ≥ 18 years at the time of signing the Informed Consent Form (ICF) Years of age (or legal adult in the country, whichever is older) Pathologically confirmed squamous cell lung cancer with unresectable, locally advanced or metastatic disease (incurable) Parts 2 and 3 only: by Centralized IHC testing confirms FGFR2b overexpression

Subjects must have had a tumor tissue sample on file prior to inclusion (formalin-fixed, paraffin-embedded [FFPE] specimen [resection, core needle, or fine-needle aspiration FFPE]) or be willing to undergo a pretreatment tumor biopsy (resection , core needle or fine needle aspiration).

Subjects must have progressed or relapsed after at least 1 prior systemic therapy (Parts 1 and 2 only) or at least 2 prior systemic therapies (Part 3 only) for locally advanced, unresectable or metastatic disease . Prior treatment must include platinum-based dual chemotherapy and checkpoint inhibitors for advanced or metastatic disease, which may be given as a line of therapy or as separate lines of therapy, unless the subject has a medical contraindication to one of the required therapies (must be included in the eCRF record). Additionally, if a subject's tumor was previously identified as having a driver mutation (according to local standard of care or guidelines, e.g., KRAS G12C, NTRK) and has an approved therapy, and the subject is eligible and has To qualify for this therapy, subjects must have received the approved therapy in a previous line of treatment.

For Parts 1 and 3, subjects may have received prior docetaxel therapy if they did not meet any prior therapy exclusion criteria.

Adjuvant therapy was counted as a treatment line if the subject progressed at or within 6 months of adjuvant therapy administration.

In locally advanced and unresectable NSCLC, disease progression at or within 6 months of completion of prior multimodal therapy with curative intent was counted as a prior line of therapy.

Maintenance therapy after platinum-based doublet chemotherapy is not considered a separate line of therapy.

Measurable disease according to RECIST v1.1 criteria.

Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1. Adequate organ function as follows: Absolute neutrophil count ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Heme ≥ 9 g/dL

Creatinine clearance ≥ 50 mL/min. Creatinine clearance was calculated using the Cockcroft-Gault formula. A 24-hour urine collection is not required but allowed. International normalized ratio (INR) or prothrombin time (PT) < 1.5 × upper limit of normal (ULN), except for subjects receiving anticoagulant therapy, who must have received stable doses of anticoagulant therapy for 6 weeks before inclusion, only Part 1 and Part 2: AST and ALT ≤ 2.5 times ULN, unless alkaline phosphatase > 2.5 times ULN, then AST and/or ALT must be ≤ 1.5 times ULN Total bilirubin ≤ 1.0 × ULN Part 3 only:

AST and ALT <3 x ULN (or <5 x ULN if liver is involved). Total bilirubin <1.5 x ULN (or <2 x ULN if liver is involved); except in subjects with Gilbert's disease) Part 1 and 2 only:

Subjects must be candidates to receive docetaxel. Exclusion Criteria Subjects were excluded from the study if any of the following criteria applied: Relevant disease Mixed small cell lung cancer or mixed NSCLC Histology Untreated or symptomatic central nervous system (CNS) metastases or leptomeningeal disease Asymptomatic CNS Subjects with metastases are eligible if they are clinically stable for at least 4 weeks and do not require intervention (including the use of corticosteroids) Subjects with treated brain metastases are eligible if they meet the following criteria: At first count Complete definitive therapy at least 2 weeks before the planned dose of study treatment (stereotactic radiosurgery at least 7 days before the first planned dose of study treatment) At least 7 days before the first dose of study treatment: Any CNS disease in the clinic are stable, the subject discontinues steroids for CNS disease (unless the reason for steroid use is unrelated to CNS disease), and the subject discontinues or takes stable doses of antiepileptic drugs

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures more frequently than once a month. Subjects with PleurX™ catheter placement will only be considered for inclusion in this study if approved by the medical supervisor. Other medical conditions Impaired heart function or clinically significant heart disease, including:

Unstable angina within 6 months before the first dose of study treatment, acute myocardial infarction within 6 months before the first dose of study treatment, New York Heart Association (NYHA) class II-IV congestive heart disease Failure, uncontrolled hypertension (defined as mean systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg despite optimal treatment (according to the European Society for Hypertension/European Society of Cardiology) of Cardiology, ESH/ESC] 2013 Guideline Measurement), uncontrolled arrhythmia requiring antiarrhythmic therapy other than beta-blockers or digitonin, active coronary artery disease, Fridericia correction Formula (QTc) ≥ 470. Grade 2 or higher peripheral sensory neuropathy Active infection requiring systemic therapy or prior to first dose of study treatment Any uncontrolled infection within 14 days Human immunodeficiency virus (HIV) infection, hepatitis C infection with a known CD4+ T cell (CD4+) count <350 cells/µL (Hepatitis C subjects with sustained virologic response after antiviral therapy are allowed ), or hepatitis B infection (allowing for sustained virological response after antiviral therapy for hepatitis B

Subjects with hepatitis B surface antigen or core antibodies). History of interstitial lung disease History of systemic disease or ophthalmic disorder requiring long-term use of ophthalmic corticosteroids Evidence of any ongoing acute (within 4 weeks) or actively progressing ophthalmic abnormalities or symptoms Unwillingness to avoid contact lens use during study treatment

Recent (within 6 months) corneal surgery or ophthalmic laser treatment, or recent (within 6 months) history or evidence of corneal defect, corneal ulcer, keratitis or keratoconus, or other known condition that may increase the risk of corneal ulcer Corneal abnormalities. Prior/concomitant therapy

Part 1 only: Subjects have experienced toxicity or hypersensitivity reactions requiring discontinuation of prior docetaxel treatment.

Part 1 only: Subjects with disease progression on prior docetaxel therapy.

Part 2 only: Subjects previously treated with docetaxel in the unresectable or metastatic setting (includes subjects previously treated with docetaxel in the first line for metastatic disease, but does not include subjects who have received docetaxel in the first line after completion of therapy 6 Subjects who have received prior neoadjuvant or adjuvant docetaxel treatment within months and have not progressed).

Previous treatment with any selective inhibitor of the FGF-FGFR pathway. Any anti-cancer therapy or immunotherapy within 4 weeks before inclusion; Palliative radiotherapy is allowed provided it is completed more than 14 days before the first dose of study treatment All treatment-related toxicities need to resolve to grade ≤ 1 before the first dose of study treatment, except for alopecia or toxicity considered irreversible (defined as present and stable for >21 days) not otherwise stated in the exclusion criteria Previous/current clinical research experience

218 Currently receiving treatment in another investigational device or drug study, or less than 30 days after ending treatment in another investigational device or drug study. Participation in other research procedures concurrent with this study was excluded. Other exclusions Major surgical procedure within 28 days before first dose of study treatment

Minor surgery requiring local/epidural anesthesia must be completed more than 72 hours before the first dose of study treatment. In all cases, the subject must be fully recovered and stable before treatment can be administered. History of other malignancies within the past 2 years, except for the following: • Curative treatment of non-melanoma cutaneous malignancies • Cervical cancer in situ • Uterine cancer stage I with curative treatment • Ductal or lobular breast cancer in situ treated curatively and not currently receiving any systemic therapy • Localized prostate cancer treated with surgery that is curative and presumed curative

Female subjects of childbearing potential who are unwilling to use a protocol-specified method of contraception during treatment and for an additional 6 months after the last dose of protocol-specified therapy.

Female subjects who are breast-feeding or plan to breast-feed during the study period and up to 3 months after the last dose of regimen-specified therapy.

Female subjects who plan to become pregnant during the study period and up to 6 months after the last dose of protocol-specified therapy.

Female subjects of childbearing potential who have a positive pregnancy test as assessed by a highly sensitive urine or serum pregnancy test at screening.

Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (avoidance of heterosexual intercourse) or use contraception during treatment and for an additional 3 months after the last dose of protocol-specified therapy.

Male subjects who are unwilling to give up sperm donation during treatment and for an additional 3 months after the last dose of protocol-specified therapy.

Known allergy, hypersensitivity, or contraindication to docetaxel (Parts 1 and 2 only) or components of bemarituzumab or docetaxel formulations (including polysorbates).

To the best of the subject's and investigator's knowledge, a subject may not be able to complete all protocol-required study visits or procedures and/or comply with all required study procedures (e.g., assessment of clinical outcomes).

History or evidence of any other clinically significant disorder, condition, or disease (other than those outlined above) that would pose a risk to subject safety or interfere with study evaluation, procedures, or completion.

FGFR2b-negative subjects may be exposed to an additional identified safety risk of corneal toxicity, but this risk is likely to be much lower than in FPA-144-04 due to the expected shorter treatment duration (a scenario that does not benefit from bemarituzumab) . The mPFS for SqNSCLC treated second-line with docetaxel was 2.7 to 2.8 months, which is much shorter than the median time to onset of grade 2 or 3 ocular events of 5.0 months in FPA 144-04. Parts 2 and 3 will select subjects with overexpressing FGFR2b.

Additionally, in part 3, where bemarituzumab monotherapy was explored, subjects had to have failed second-line therapy to be eligible and therefore had exhausted available therapies.

In addition to the eligibility criteria to exclude subjects with severe organ dysfunction, the following precautions were taken in this study:

Monitor subjects closely for infusion-related reactions, which are known potential toxicities of bemarituzumab. The investigator may decide at his or her discretion to reduce the bemarituzumab infusion based on the occurrence of an infusion-related reaction (e.g., changes in vital signs, nausea, vomiting, or other systemic symptoms, or allergic reactions occurring during the infusion or up to 2 hours after the infusion is stopped). Rate.

Routine premedication is generally not applicable with the initial dose of bemarituzumab; subjects who experience infusion-related adverse events may be premedicated before subsequent infusions of bemarituzumab at the discretion of the investigator.

Subcutaneous epinephrine, intravenous diphenhydramine (or equivalent), and any other medications and resuscitation equipment used in the emergency management of anaphylaxis must be available in the infusion room.

The protocol includes standard antiemetic therapy, close clinical monitoring, and medication changes and discontinuations. Additionally, the Dose Level Review Team (DLRT) will monitor the study for safety and toxicity. The most common adverse reactions of docetaxel are infection, neutropenia, anemia, febrile neutropenia, hypersensitivity reactions, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, and anorexia symptoms, nail disorders, fluid retention, weakness, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions and myalgias. Bemarituzumab and docetaxel

Information about bemarituzumab and docetaxel in this study, including dosing and administration instructions, is shown in Tables 1.1, 1.2, and 1.3 below: [Table 1.1]: Investigational Product: Bemarituzumab and its investment Dosage preparation Bemarituzumab is a sterile, aqueous, colorless to slightly yellow, pyrogen-free solution supplied in disposable glass vials. The final drug product is provided in solution form, which should be stored refrigerated (2°C to 8°C), protected from light, and in liquid form, which should be refrigerated and protected from light, and diluted for administration. Unit dose intensity/dose level Part 1: Dose Level 1: 22 mg/kg IV on Day 1 of Cycle 1, then 15 mg/kg IV on Day 22, thereafter Q3W regimen Dose Level 2: 30 mg/kg on Day 1 of Cycle 1 IV, then 22 mg/kg IV on Day 22, thereafter Q3W protocol Part 2: Dose levels determined in Part 2 Part 3: 15 mg/kg Q2W IV on Day 1 of each cycle, Cycle 1 Additional dose of 7.5 mg/kg on day 8 Investment channels intravenous infusion Dosing Instructions Bemarituzumab is administered as an intravenous infusion via a peripheral vein or central venous catheter over approximately 30 minutes (±10 minutes) under medical supervision. Intravenous administration devices used for bemarituzumab infusion must contain a 0.22 µm in-line filter. eCRF = electronic case report form; Q2W = every 2 weeks; Q3W = every 3 weeks [Table 1.2]: Bemarituzumab groups and dose levels group title part 1 _ part 2 _ Part 3 _ Group type Combination dose escalation Combination dose expansion monotherapy Group description Dose Level 1: Participants will receive bemarituzumab 22 mg/kg intravenously on Day 1 of Cycle 1, followed by 15 mg/kg intravenously on Day 22, and Q3W thereafter with, in addition, docetaxel 75 mg/m ² IV Q3W (or for subjects at the Japanese site, 60 mg/m ² IV Q3W). Dose Level 2: Participants will receive bemarituzumab 30 mg/kg intravenously on Day 1 of Cycle 1, followed by 22 mg/kg intravenously on Day 22, and Q3W thereafter with, in addition, docetaxel 75 mg/m ² IV Q3W (or for subjects at the Japanese site, 60 mg/m ² IV Q3W). Dosage and schedule of bemarituzumab and docetaxel are determined in Part 1. Bemarituzumab 15 mg/kg IV Q2W, and a single 7.5 mg/kg dose on Day 8 of Cycle 1. IV = intravenous; Q2W = every 2 weeks; Q3W = every 3 weeks [Table 1.3]: Docetaxel dosage formulation and administration Dosage preparation Docetaxel is supplied from a commercial supply that is clinically labeled according to relevant local guidelines. Unit dose intensity/dose level Subjects in all countries were administered 75 mg/m ² every 3 weeks except Japan; subjects in Japan were administered 60 mg/m ² . Investment channels intravenous infusion Responsibility Planned dose, total volume of formulation, batch number (unless unable to be recorded due to local prescribing procedures in countries where the standard of care is considered non-investigational), concentration of formulation, volume to be administered, start date/time, stop date/time, total volume Reasons for changes or refusals of administration, reasons for delays in administration, and reasons for interruptions in infusion should be documented on each subject's eCRF. Dosing Instructions Docetaxel is administered in the clinic by qualified staff over a 1-hour infusion time frame (additional administration times are allowed according to local guidelines). Dose level determination

Recommended only if one or more prior dosing regimens are found to be reasonably tolerated based on findings from available study data in 3 to 6 subjects over a 21-day DLT period and by consensus of the Dose Level Review Team (DLRT) members Escalate to higher dose cohorts. Available data from previous subject groups will also be considered. Dose levels are recommended on a treatment cohort basis (rather than on an individual basis).

Part 1 begins with dose level 1. The study DLT period is 21 days after the first dose. Once 3 to 6 subjects enrolled at a specific dose level have completed 21 days of safety follow-up, a Dose Level Review Team (DLRT) meeting is held. The DLRT will evaluate all available safety, laboratory, and PK data, as well as rules generated by the modified Toxicity Probability Interval Method (mTPI-2) (Guo et al., 2017), to guide their dose finding recommendations. The panel may make recommendations such as escalating to the next planned dose, continuing at the current dose level, tapering to a lower dose, terminating the study, or initiating enrollment in Part 2 of the study at the evaluated dose level. The mTPI-2 escalation/decrement guidelines for each dose cohort were derived with a target toxicity probability of 0.30 and an acceptable toxicity probability interval of (0.25, 0.33). If the estimated probability of a dose level exceeding the target DLT (i.e., elimination boundary) is 95% or greater, that dose level will be considered unsafe and no additional subjects will be enrolled at that dose level. In Part 1, DLRT will use guidelines based on the mTPI-2 design as follows:

Subjects in the first cohort were treated at dose level 1. To allocate doses to the next cohort of subjects, use the guidelines in Table 2. In Table 2 (Dose escalation/tapering rules for mTPI-2 design), note the following:

“Elimination” means the elimination of current and higher doses from a trial to prevent any future subjects from being treated at those doses because they are too toxic. When a dose is eliminated, it is tapered to the next lower dose level. When the lowest dose is eliminated, the trial is stopped for safety reasons.

If no action (increment, decrement, or elimination) is triggered, treat the new subject at the current dose.

If the current dose is the lowest dose and the rules indicate dose tapering, new subjects will be treated with the lowest dose unless the number of DLTs reaches the elimination boundary, at which point the trial is stopped for safety reasons.

Repeat step 2 until the maximum sample size of 18 is reached or the number of subjects treated at the current dose reaches 9, and the current dose is maintained according to the decision system of Table 2. [Table 2] Dose escalation/decrement rules for mTPI-2 design Subjects treated with current dose 1 2 3 4 5 6 7 8 9 If #≤ of DLT, increment 0 0 0 0 1 1 1 1 2 If #≥ of DLT, decrement 1 1 1 2 2 2 3 3 3 If #≥ of DLT, eliminate NA NA 3 3 4 4 5 5 5 DLT = dose-limiting toxicity; NA = not applicable; mTPI = modified toxicity probability interval for DLT # is the number of subjects with at least 1 DLT. When no action (i.e., increment, decrement, or elimination) is triggered, the next cohort of subjects is treated at the current dose. “NA” means the dose cannot be eliminated before treating 3 subjects. Dose-Limiting Toxicity A dose-limiting toxicity during Part 1 was defined as any of the following adverse events deemed by the investigator to be related to protocol-required therapy: Grade 4 neutropenia of any duration Febrile neutropenia Grade 4 thrombocytopenia Grade 3 thrombocytopenia, >Grade 2 bleeding or persistent >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 7 days Grade 4 Ophthalmic Adverse Events Any Grade 4 laboratory value Grade 4 vomiting or diarrhea Grade 3 vomiting or Grade 3 diarrhea that persists for more than 3 days despite best medical support >Grade 3 nausea that persists for more than 3 days despite best medical support or more days with grade 3 fatigue lasting 1 week or longer

Any subject meeting Hy's Law case criteria (severe drug-induced liver injury [DILI]) is considered a DLT. A Heidegger's Law case is defined as an AST or ALT value ≥ 3 x ULN and a serum TBIL level > 2 x ULN, or an international normalized ratio (INR) > 1.5, without signs of cholestasis, and no other clear alternative cause to explain the observation Liver-related laboratory abnormalities. Any other adverse event of grade ≥ 3, except for the following: DLT Waiver: Asymptomatic grade 3 electrolyte abnormalities lasting <72 hours that are not clinically complex and resolve spontaneously or respond to medical intervention DLT Waiver: Other options for laboratory abnormalities that appear clinically unrelated or not harmful to the subject (e.g., grade 3 lymphopenia, grade 3 hypoalbuminemia), and/or can be corrected with replacement or modification DLT Waiver: Transient (resolved to ≤ Grade 1 within 6 hours of onset) Grade 3 infusion-related adverse events

If an adverse event is clearly attributable to docetaxel and does not exceed expected severity, then that specific adverse event may be considered exempt from becoming a DLT. Bemarituzumab dose adjustment, delay, suspension or restart, permanent discontinuation rules

Bemarituzumab dose-sustaining adverse events may be associated with bemarituzumab doses based on the guidelines outlined in Table 6-5. Reasons for bemarituzumab dose delays should be documented on one or more CRFs for each subject. Docetaxel administration may continue regardless of bemarituzumab dose delay.

After Cycle 1, bemarituzumab dose should be recalculated only if body weight changes >10% based on weight on Day 1 of Cycle 1. If the dose is recalculated due to >10% change in body weight from Day 1 of Cycle 1, the body weight used for the dose recalculation should be used as the new baseline for subsequent dose recalculation evaluations.

Cycles may be delayed to control toxicity. Cycle delays beyond 28 days should be discussed with the medical supervisor prior to reactivation.

Corneal Events: Any subject who develops a corneal event within 100 days of the last dose of bemarituzumab (whether or not considered related to bemarituzumab) should be evaluated by an ophthalmologist. Any subject reporting eye pain or irritation or changes in vision should be evaluated by an ophthalmologist. Rules for Docetaxel Dose Adjustment, Delay, Suspension or Restart, and Permanent Suspension

Initial dose of 75 mg/ ^m2 and febrile neutropenia, less than 500 cells/ ^mm3 for more than 1 week, severe or cumulative cutaneous disease during docetaxel treatment Subjects who experience a reaction or other Grade 3 or 4 non-hematologic toxicity should have treatment withheld until the toxicity resolves, then resume treatment at a dose of 55 mg/ ^m2 . Subjects who develop ≥ grade 3 peripheral neuropathy should discontinue docetaxel treatment.

Concomitant use of docetaxel with drugs that inhibit CYP3A4 may increase docetaxel exposure and should be avoided. In subjects receiving docetaxel (Parts 1 and 2), if systemic administration of strong CYP3A4 inhibitors cannot be avoided, close monitoring for toxicity and docetaxel dose reduction should be considered.

See regional prescribing information for docetaxel for more information. Discontinuation of study treatment

A subject (or legally authorized representative) may refuse to continue receiving the investigational product and/or other protocol-required therapies and/or procedures at any time during the study but may continue to participate in the study. Subjects who discontinue investigational product and/or other protocol-required therapies and/or procedures should not be automatically withdrawn from the study. Subjects' continued participation in the study is necessary to ensure safe monitoring and/or collection of outcome data when safe and feasible. Reasons for early withdrawal from one or more evaluations of an investigational product or procedure required by the protocol may include any of the following: • At the discretion of the trial sponsor • Loss to follow-up • Death • Adverse events • Subject requirements • Determination of ineligibility • Protocol Deviations • Noncompliance • Disease progression • Need for alternative therapies • Pregnancy outcome assessment Radiologic Imaging Assessment

Disease extent was assessed by contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI) according to RECIST v1.1. In order to reduce the subject's radiation exposure, low-dose CT should be used whenever possible. Filter scan:

The screening scan should be performed within 28 days before Cycle 1 Day 1 (scan can be performed within 31 days) and include clinical examination and appropriate imaging techniques (preferably performed according to RECIST v1.1 with appropriate sectioning Thickness CT scan; MRI acceptable). If there are multiple screening scans, the one closest to the inclusion date will be used as the baseline.

Radiologic evaluation included CT/MRI of the chest, abdomen, and pelvis, as well as evaluation of all other known disease sites. Investigators performed tumor response assessments according to RECIST v1.1 guidelines.

All subjects with brain metastases must have an MRI of the brain. All brain scans in subjects with brain metastases are required to be MRI, and unless MRI is contraindicated, CT with contrast agent is acceptable. If signs or symptoms suggestive of CNS metastasis are present, brain imaging (MRI or CT) should be performed. Follow-up scans:

All subsequent scans should be performed in the same manner as at screening (e.g., with the same contrast, MRI field strength), preferably on the same scanner.

Radiographic imaging of the chest, abdomen, pelvis, and all other sites of known disease was performed during treatment and follow-up, independent of the treatment periods specified in the activity plan. If clinically necessary, imaging may also be performed more frequently at the discretion of the attending physician. Radiographic imaging and tumor evaluation were performed until initiation of new anticancer therapy, disease progression, death, withdrawal of consent, or study end, whichever occurred first.

Disease response determinations for clinical control and response assessment were performed at the clinical site in accordance with RECIST v1.1. Scan results can be submitted to the central imaging core laboratory for archiving and, if needed, response assessment (including RECIST v1.1) and/or exploratory analysis (e.g., volume and viable tumor measurements). biomarkers

Biomarkers are indicators that objectively measure and evaluate normal biological processes, pathogenic processes, or pharmacological responses to therapeutic interventions.

PD-L1 testing was performed on remaining archived pre-processed tissue, if available.

Plasma cell-free tumor DNA (circulating tumor DNA [ctDNA]) will be assessed for DNA changes before dosing and during treatment. In addition, subjects who consent to this evaluation will undergo optional tumor biopsies for exploratory biomarker testing to study pre-treatment, on-treatment and progression changes in tumor biomarkers. Biomarker assessment to determine eligibility

Subjects in Study Parts 2 and 3 will need to provide archived, formalin-fixed, paraffin-embedded (or fresh biopsy if archived samples are not available) tumor biopsy/resection (excluding bone biopsies examination and cytology samples) for FGFR2b performance pre-screening testing by IHC, and subjects must consent to tumor tissue analysis. For Part 1, FGFR2b performance testing was performed retrospectively. Primary tumors and metastatic sites for specimen collection are allowed.

Subjects in Parts 2 and 3 were selected for inclusion based on FGFR2b overexpression, as determined by investigational in vitro diagnostic (IVD) IHC assays. The investigational IVD used to select subjects was the VENTANA FGFR2b (FPR2D) RxDx assay, an IHC test used to detect FGFR2b protein in tumor tissue. The percentage of FGFR2b-positive tumor cells was analyzed and the H score was calculated.

Subjects without confirmed FGFR2b overexpression using IHC will not be eligible for inclusion. Once the tumor specimen is received, it will be analyzed as efficiently as possible and FGFR2b performance status results will be reported back to the investigator or designee.

Blood and tissue were collected for biomarker analysis if allowed by local regulations and agreed by the Ethics Committee (EC)/Institutional Review Board (IRB). Blood samples were collected to assess the potential association of circulating tumor/cell-free DNA mutation profiles with clinical endpoints. Circulating tumor/cell-free DNA (ctDNA) assessment for analysis of somatic mutations. Tumor samples are used to detect protein expression, including FGFR2b, PD-L1, and other potential biomarkers. Protein expression may include gene expression or somatic (tumor) mutation analysis. None of these samples were used for screening for genetic traits. Statistical Considerations Statistical Assumptions

No statistical hypotheses will be tested. Sample size determined

It is expected that up to 108 subjects will be enrolled in this study, consisting of a maximum of 18 subjects in Part 1 and a total of up to 90 response-evaluable subjects in Parts 2 and 3. 90 response evaluable subjects including the possibility of having two cohorts in Part 2 of 10 to 30 subjects each, administering 2 doses of bemarituzumab plus docetaxel level. An additional 3 to 6 Japanese subjects will be included at each dose level in Part 1 and/or Part 2, either as part of the initial dose level assessment or as backfill after RP3D is determined.

Among 3, 6, or 9 subjects in the dose level cohort in Part 1, if the true DLT rate was 25%, there would be a 58%, 82%, and 93% probability, respectively, of observing at least 1 DLT.

In a minimum of 10 subjects each in Parts 2 and 3, there is at least an approximately 95% probability of observing at least 1 DLT if the lower limit of the acceptable toxicity interval for the true DLT rate is 25%. In dose expansion parts 2 and 3, up to 30 response-evaluable subjects per dose level will be included to obtain further safety and preliminary efficacy data. The following groups are defined: [Table 3.1] group instruction incorporate Include all subjects. safety All subjects who received at least 1 dose of bemarituzumab. DLT Enroll all subjects in Part 1 who receive at least one dose of bemarituzumab and docetaxel and meet any of the following requirements: 1) experience a DLT, or 2) after the first dose of study product Study was conducted for 21 days. common variables

Relationships between covariates and endpoints can be explored and specified (if applicable) in the statistical analysis plan. Group

Groupings can be explored and specified (if applicable) in the statistical analysis plan. Analytical method

Data are summarized by study section and dose level in Part 1. Descriptive statistics for continuous data will include mean, median, standard deviation, and range, while categorical data is summarized using frequency counts and percentages. Data are summarized using the safety analysis set unless otherwise specified.

Confidence intervals (CI) for proportions were estimated using the exact method proposed by Clopper-Pearson (Clopper and Pearson, 1934). The Kaplan-Meier (KM) method was used to estimate the median and percentile of time to event endpoint, and CI was calculated using the Brookmeyer and Crowley method (Brookmeyer and Crowley, 1982). The Kaplan-Meier method was used to estimate time-to-event endpoint markers (e.g., 1-year OS), and the Greenwood formula (Kalbfleisch and Prentice, 1980) was used to estimate the standard error used in CI calculations. [Table 3.2]: Efficacy analysis endpoint / estimate Statistical analysis methods main Not applicable secondary A list of secondary efficacy endpoints was generated for all subjects. The proportion of subjects with objective responses was estimated along with 95% CI. The same approach was used to summarize disease control rates. For subjects treated with RP3D, KM curves at each landmark time point, KM quartiles with 95% CI, and KM estimates with 95% CI were estimated for the following endpoints: Objective duration of response (responders only subjects), PFS and OS. [Table 3.3]: Safety analysis: analysis of one or more primary safety endpoints end point Statistical analysis methods main The occurrence of DLTs, TEAEs, clinical laboratory abnormalities, vital signs, and corneal findings was tabulated. Subject occurrences of DLTs were tabulated by planned dose levels in Part 1. Other analysis

Bemarituzumab serum concentrations and bemarituzumab pharmacokinetic parameters (including, but not limited to, AUC, C- _peak , and C- _trough ) were determined and tabulated. Pharmacokinetic data collected from this study were used in population PK analysis together with PK data collected from other bemarituzumab studies. Additional analyzes were performed to evaluate the relationship between bemarituzumab exposure and selected safety or efficacy or any relevant biomarker endpoints. The details and results of these exploratory analyzes will be described in a separate report. Example 3A : Treatment of Patients with SqNSCLC (Dose Level 1 )

A cohort of patients with pathologically confirmed SqNSCLC received bemarituzumab at a dose of 22 mg/kg intravenously on day 1 of cycle 1, followed by 15 mg/kg intravenously on day 22 , and then implement the Q3W plan. In addition, these patients were treated with docetaxel on the following regimen: 75 mg/m ² IV Q3W or 60 mg/m ² IV Q3W.

As measured by objective response (defined as complete response (CR) + partial response (PR)], determined according to Response Evaluation Criteria in Solid Tumors [RECIST v1.1], bemarituzumab and docetaxel The combination can effectively treat SqNSCLC in these patients. Example 3B : Treatment of Patients with SqNSCLC (Dose Level 1 )

A cohort of patients with pathologically confirmed SqNSCLC received bemarituzumab at a dose of 22 mg/kg intravenously on day 1 of cycle 1, followed by 15 mg/kg intravenously on day 22 , and then implement the Q3W plan. In addition, these patients were treated with docetaxel on the following regimen: 75 mg/m ² IV Q3W or 60 mg/m ² IV Q3W.

The combination of bemarituzumab and docetaxel was effective in treating SqNSCLC in these patients, as measured by progression-free survival and/or overall survival. Example 4A : Treatment of Patients with SqNSCLC (Dose Level 2 )

A cohort of patients with pathologically confirmed squamous cell lung cancer received bemarituzumab at a dose of 30 mg/kg intravenously on day 1 of cycle 1, followed by 22 intravenously on day 22 mg/kg, and then implement the Q3W plan. In addition, these patients were treated with docetaxel on the following regimen: 75 mg/m ² IV Q3W or 60 mg/m ² IV Q3W.

As measured by objective response (defined as complete response (CR) + partial response (PR)], determined according to Response Evaluation Criteria in Solid Tumors [RECIST v1.1], bemarituzumab and docetaxel The combination can effectively treat SqNSCLC in these patients. Example 4B : Treatment of Patients with SqNSCLC (Dose Level 2 )

A cohort of patients with pathologically confirmed SqNSCLC received bemarituzumab as follows: 30 mg/kg intravenously on day 1 of cycle 1, followed by 22 mg/kg intravenously on day 22 , and then implement the Q3W plan. In addition, these patients were treated with docetaxel on the following regimen: 75 mg/m ² IV Q3W or 60 mg/m ² IV Q3W.

The combination of bemarituzumab and docetaxel was effective in treating SqNSCLC in these patients, as measured by progression-free survival and/or overall survival. Example 5A : Treatment of patients with SqNSCLC (bemarituzumab monotherapy)

A cohort of patients with pathologically confirmed SqNSCLC received monotherapy with bemarituzumab as follows: 15 mg/kg administered intravenously on a Q2W schedule, followed by a single dose of 7.5 mg/kg on day 8 of cycle 1 mg/kg.

Bemarituzumab is effective in treating these patients as measured by objective response (defined as complete response (CR) + partial response (PR)] as determined by Response Evaluation Criteria in Solid Tumors [RECIST v1.1] SqNSCLC in patients. Example 5B : Treatment of patients with SqNSCLC (bemarituzumab monotherapy)

A cohort of patients with pathologically confirmed SqNSCLC received monotherapy with bemarituzumab as follows: 15 mg/kg administered intravenously on a Q2W schedule, followed by a single dose of 7.5 mg/kg on day 8 of cycle 1 mg/kg.

Bemarituzumab was effective in treating SqNSCLC in these patients, as measured by progression-free survival and/or overall survival. Example 6 : Treatment of patients with SqNSCLC

A cohort of patients with pathologically confirmed squamous cell lung cancer received bemarituzumab at a dose of 22 mg/kg intravenously on day 1 of cycle 1, followed by 10 mg/kg intravenously on day 22 mg/kg, and then implement the Q3W plan. In addition, these patients were treated with docetaxel on the following regimen: 75 mg/m ² IV Q3W or 60 mg/m ² IV Q3W.

As measured by objective response (defined as complete response (CR) + partial response (PR)], determined according to Response Evaluation Criteria in Solid Tumors [RECIST v1.1], bemarituzumab and docetaxel The combination can effectively treat SqNSCLC in these patients. Example 7 : Treatment of patients with SqNSCLC

A cohort of patients with pathologically confirmed SqNSCLC received monotherapy with bemarituzumab as follows: 30 mg/kg administered intravenously as a Q3W regimen. In addition, these patients were treated with docetaxel on the following regimen: 75 mg/m ² IV Q3W or 60 mg/m ² IV Q3W.

The combination of bemarituzumab and docetaxel was effective in treating SqNSCLC in these patients, as measured by progression-free survival and/or overall survival. Example 8 : Treatment of patients with SqNSCLC

A cohort of patients with pathologically confirmed squamous cell lung cancer received bemarituzumab at a dose of 22 mg/kg intravenously on day 1 of cycle 1, followed by 15 mg/kg intravenously on day 22 mg/kg, and then implement the Q3W plan. In addition, these patients were treated with docetaxel at 75 mg/m ² IV Q3W (or 60 mg/m 2 IV Q3W for subjects at the Japanese study site).

As measured by objective response (defined as complete response (CR) + partial response (PR)], determined according to Response Evaluation Criteria in Solid Tumors [RECIST v1.1], bemarituzumab and docetaxel The combination can effectively treat SqNSCLC in these patients. Example 9 : Treatment of patients with SqNSCLC

A cohort of patients with pathologically confirmed SqNSCLC received bemarituzumab as follows: 30 mg/kg intravenously on day 1 of cycle 1, followed by 22 mg/kg intravenously on day 22 , and then implement the Q3W plan. In addition, these patients were treated with docetaxel at 75 mg/m ² IV Q3W (or 60 mg/m 2 IV Q3W for subjects at the Japanese study site).

The combination of bemarituzumab and docetaxel was effective in treating SqNSCLC in these patients, as measured by progression-free survival and/or overall survival. Example 10 : Results of a Phase 1b study evaluating the safety, tolerability, pharmacokinetics, and efficacy of bemarituzumab alone and in combination with other anticancer therapies in subjects with squamous non-small cell lung cancer

The anti-FGFR2b antibody bemarituzumab was administered intravenously to patients with SqNSCLC in combination with docetaxel according to the protocol described in Example 1 (Part 1). Docetaxel was administered intravenously at a dose of 75 mg/ ^m2 Q3W (or 60 mg/ ^m2 IV Q3W for subjects at the Japanese site). Cohort 1 administered bemarituzumab 22 mg/kg on Day 1 of Cycle 1 (“C1/D1”), followed by bemarituzumab 15 mg/kg in the Q3W schedule (Pharmacokinetic data available for N = 4/4 patients). Cohort 2 administered bemarituzumab 30 mg/kg on C1/D1 followed by 22 mg/kg bemarituzumab Q3W (N = 8/9 for cycle 1 Pharmacokinetic data are available for N = 5/9 patients and for N = 5/9 patients in Cycle 2). Bemarital was measured at prespecified time points on Day 0, Day 1 (enhanced PK sampling), Day 2, Day 4, Day 8, Day 15, Day 22, Day 43, and Day 85 Serum concentrations of lizumab. The preliminary PK summary of bemarituzumab administered in combination with docetaxel is shown in Table 4 . The bemarituzumab C _peak for Cohort 1 was 590 ug/mL and the C _peak for Cohort 2 was 765 ug/mL. The bemarituzumab C _trough concentration for Cohort 1 was 66.9 ug/mL, and the C _trough concentration for Cohort 2 was 127 ug/mL. [Table 4] Observed bemarituzumab exposure (geometric mean: C _peak and C _trough ) based on available PK data from sq-NSCLC study 20210102 (data cutoff: January 31, 2023) group Bemarituzumab dosage _Peak C (µg/mL) C _valley (µg/mL) Group 1 (N = 4) 22 mg/kg C1D1; subsequently 15 mg/kg Q3W 590 66.9 Cohort 2 (Cycle 1, N = 8; Cycle 2, N = 5) 30 mg/kg C11D1; subsequently 22 mg/kg Q3W 765 127

These data demonstrate that, for the dosing and timing of each of Cohorts 1 and 2, the pharmacokinetics of bemarituzumab are consistent with clinical modeling for the gastric cancer indication and based on gastric cancer studies Based on the information, systemic bemarituzumab concentrations were within the predicted effective exposure range. Bemarituzumab exposure increased approximately in a dose-proportional manner between cohorts.

Based on the known safety profile of bemarituzumab, there were no new safety findings in patients in Cohorts 1 and 2.

Patients included in cohorts 1 and 2 were not selected for FGR2b expression. Overexpression of FGFR2b in the tumor samples was then determined by immunohistochemistry (IHC). Samples considered positive for FGFR2b overexpression status exhibited any moderate (2+) to strong (3+) membrane staining in tumor cells; samples were considered FGFR2b overexpression in the absence of moderate to strong membrane staining. Status is negative. Among the 9 patients who received the combination of bemarituzumab and docetaxel in Cohort 2, a partial response was observed in one FGFR2b overexpression-positive patient and in one FGFR2b overexpression-negative patient to partial response. Of note, these are the results of two patients in an ongoing study. References

Each of the following references is incorporated herein by reference in its entirety.

Abe T, Takeda K, Oh Y, et al. Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non-small cell lung cancer: the intergroup trial JCOG0803/WJOG4307L. J Clin Oncol . 2015;33(6):575-581.

American Cancer Society 2021. Cancer Facts & Figures 2021. Accessible on the world wide web at www dot cancer dot org/content/dam/cancer-org/research/cancer-facts-andstatistics/annual-cancer-facts-and-figures/ 2021/cancer-facts-and-figures-2021.pdf

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 104 ^th Annual Meeting 2013, Washington, DC, American Association of Cancer Research.

BALVERSA US Prescribing Information, 2020. Accessible on the world wide web at www dot janssenlabels dot com/packageinsert/product-monograph/prescribing-information/BALVERSA-pi.pdf

Bemarituzimab Investigator’s Brochure. Thousand Oaks, CA. Amgen Inc.

Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in Advanced Squamous-cell Non-small-cell Lung Cancer. N Eng J Med. 2015;373:123-135.

Bron AJ, Evans VE, and Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea. 2003;22(7):640-650.

Brookmeyer R and Crowley J. A Confidence Interval for the Median Survival Time. Biometrics. 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.

The Common Terminology Criteria for Adverse Events, version 5.0: Accessible on the world wide web at ctep dot cancer dot 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.

Drilon A, Rekhtman N, Ladyani M, and Paik P. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol. 2012;13(10):e418-e426.

Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

Gemo A, Deshpande A, Palencia S, et al. FPA144: A Therapeutic Antibody for Treating Ptients with Gastric Cancers Bearing FGFR2 Gene Amplification. AACR 105th Annual Meeting 2014, San Diego California.

Guo W, Wang SJ, Yang S, et al. A Bayesian interval dose-finding design addressing Ockham's razor: mTPI-2. Contemp Clin Trials . 2017;58:23-33.

Hammerman PS, Sos ML, Ramos AH, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011;1(1):7889.

Heist RS, Mino-Kenudson M, Sequist LV, et al. FGFR1 amplification in squamous cell carcinoma of the lung. J Thorac Oncol . 2012;7(12)1775-1780.

International Committee of Medical Journal Editors, Uniform Requirements for

Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication. 2013. Accessible on the world wide web at www dot icmje dot org

Kalbfleisch, J.D. and Prentice, R.L. (1980) The Statistical Analysis of Failure Time Data, New York: John Wiley & Sons.

Kudoh S, Takeda K, Nakagawa K, et al. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol . 2006; 24(22):3657-3663.

Liao RG, Jung J, Tchaicha J, Wilkerson MD, et al. Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma. Cancer Res. 2013;73(16):51955205.

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.

Paz-Ares LG, Perol M, Ciuleanu TE, et al. Treatment outcomes by histology in REVEL: A randomized phase III trial of Ramucirumab plus docetaxel for advanced non-small cell lung cancer. Lung Cancer . 2017;112:126-133.

Pemazyre ^□□ US Prescribing Information, 2021. Accessible on the world wide web at www dot pemazyre dot com/pdf/prescribing-information.pdf

Rekhtman N, Paik PK, Arcila ME, et al. Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of the lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Canc Res . 2012;18( 4):1167-1176.

Hashemi-Sadraei N and Hanna N. Targeting FGFR in Squamous Cell Carcinoma of the Lung. Target Oncol. 2017;12(6):741-755.

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.

Taxotere Summary of Product Characteristics 2019: Accessible on the world wide web at www dot ema dot europa dot eu/en/documents/product-information/taxotere-epar-productinformation_en.pdf

Taxotere US Prescribing Information: Accessible on the world wide web at www dot accessdata dot fda dot gov/drugsatfda_docs/label/2019/020449s080s082lbl.pdf

Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Trans Med. 2010;2(62):62ra93.

World Health Statistics 2018. Accessible on the world wide web at www dot who dot int/docs/default-source/ghodocuments/world-health-statistic-reports/6-june-18108-world-health-statistics-2018.pdf.

All references (including publications, patent applications, and patents) cited herein are hereby incorporated by reference to the same extent as if each reference was individually and expressly indicated to be incorporated by reference and in its entirety was set forth herein. .

Unless otherwise indicated herein or clearly contradicted by context, the terms "a/an" and "the" are used in the context of describing the present disclosure (especially in the context of the following claims) and "the" Similar referents will be deemed to cover both the singular and the plural. Unless stated otherwise, the terms "includes," "has," "includes," and "contains" are to be considered open-ended terms (i.e., meaning "including but not limited to").

Ranges of values recited herein are intended only as a shorthand method of individually referring to each individual value falling within that range and each endpoint, unless otherwise stated herein, and each individual value and endpoint is incorporated into this specification as if they were individually cited in this article.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (eg, "such as") provided herein is intended merely to better describe the disclosure and does not limit the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as necessary to practice the disclosure.

For each method described herein that involves the administration of one or more compositions, the corresponding medical use of the one or more compositions is also contemplated. For example, for methods that include administering an anti-FGFR2b antibody to treat SqNSCLC, the use of the anti-FGFR2b antibody to treat SqNSCLC is also contemplated, as is the use of the anti-FGFR2b antibody to prepare a medicament for the treatment of SqNSCLC. Wherever "methods to treat SqNSCLC" are described in this article, "methods to suppress SqNSCLC," "methods to improve SqNSCLC," and "methods to reduce the severity of SqNSCLC" are also explicitly considered. So no matter where the method is.

Preferred embodiments of the disclosure are described herein, including the best way known to the inventors for carrying out the disclosure. Variations of the preferred embodiments will be apparent to those skilled in the art upon reading the above description. The inventors anticipate that skilled artisans will employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Furthermore, the disclosure encompasses any combination of the elements described herein in all possible variations thereof unless otherwise indicated herein or otherwise clearly contradicted by context.

without

[ Figure 1A-E] are diagrams of methods of treating SqNSCLC according to some embodiments.

[ Fig. 2A-B] is a diagram of an amino acid sequence. Figure 2A depicts the amino acid sequences of some embodiments of anti-FGFR2b antibodies. Figure 2B depicts the amino acid sequence of FGFR2 of some embodiments.

[ Figures 3A-D] are graphs showing the ADCC response of cells treated with bemarituzumab, according to some embodiments.

without

Claims (42)

A method of treating squamous non-small cell lung cancer (SqNSCLC) in a subject, the method comprising: administering an anti-FGFR2b antibody to the subject; and The subject was administered docetaxel. The method of claim 1, wherein the anti-FGFR2b antibody is administered in a Q3W regimen, which regimen includes an initial administration at a dose of at least 20 mg/kg, three weeks after the first administration, and subsequent administration in a Q3W regimen. with, each dose is at least 10 mg/kg. The method of claim 2, wherein the anti-FGFR2b antibody is administered in a Q3W regimen, which regimen includes a first administration at a dose of 20-30 mg/kg or 20-25 mg/kg, three weeks after the first administration , and then follow-up administration is carried out with the Q3W regimen, with each dose being 10-19 mg/kg. The method of claim 2, wherein the anti-FGFR2b antibody is administered in a Q3W regimen, which regimen includes an initial administration at a dose of 22 mg/kg, three weeks after the first administration, and subsequent administrations in a Q3W regimen. , each dose is 15 mg/kg. The method of claim 1, wherein the anti-FGFR2b antibody is administered in a Q3W regimen, the regimen comprising an initial administration at a dose of at least 25 mg/kg, three weeks after the first administration, and subsequent administration in a Q3W regimen. With, each dose is 15-24 mg/kg. The method of claim 5, wherein the anti-FGFR2b antibody is administered in a Q3W regimen, which regimen includes a first administration at a dose of 25-35 mg/kg or 25-30 mg/kg, three weeks after the first administration , and then follow-up administration is carried out with the Q3W regimen, with each dose being 20-24 mg/kg. The method of claim 5, wherein the anti-FGFR2b antibody is administered in a Q3W regimen, which regimen includes an initial administration at a dose of 30 mg/kg, three weeks after the first administration, and subsequent administrations in a Q3W regimen. , each dose is 22 mg/kg. The method of claim 1, wherein the anti-FGFR2b antibody is administered in a Q3W regimen, which regimen includes an initial administration at a dose of at least 15 mg/kg, three weeks after the first administration, and subsequent administration in a Q3W regimen. With, each dose is 5-15 mg/kg. The method of claim 8, wherein the anti-FGFR2b antibody is administered in a Q3W regimen, which regimen includes a first administration at a dose of 15-25 mg/kg or 20-25 mg/kg, three weeks after the first administration , and then follow-up administration is carried out with the Q3W regimen, with each dose being 5-15 mg/kg. The method of claim 8, wherein the anti-FGFR2b antibody is administered in a Q3W regimen, which regimen includes a first administration at a dose of 15-25 mg/kg or 20-25 mg/kg, three weeks after the first administration , and then follow-up administration is carried out with the Q3W regimen, with each dose being 10-15 mg/kg. The method of claim 8, wherein the anti-FGFR2b antibody is administered in a Q3W regimen, which regimen includes an initial administration at a dose of 22 mg/kg, three weeks after the first administration, and subsequent administrations in a Q3W regimen. , each dose is 10 mg/kg. The method of claim 1, wherein the anti-FGFR2b antibody is administered in a Q3W schedule at a dose of at least 30 mg/kg, or 25-35 mg/kg, or 30-35 mg/kg. The method of claim 12, wherein the anti-FGFR2b antibody is administered at a dose of 30 mg/kg in a Q3W schedule. The method of any one of claims 2-13, further comprising administering an additional dose of 7-12 mg/kg of the anti-FGFR2b antibody 7-10 days after the first administration of the anti-FGFR2b antibody. The method of claim 14, wherein the additional dose of the anti-FGFR2b antibody is 7-10 mg/kg. The method of claim 14, wherein the additional dose of the anti-FGFR2b antibody is 10-12 mg/kg. The method of any one of claims 1-16, wherein the docetaxel is administered intravenously in a Q3W regimen at a dose of at least 50 mg/ ^m2 , or in a QW regimen at a dose of at least 35 mg/ ^m2 and. The method of claim 17, wherein the docetaxel is administered in a Q3W regimen at a dose of 50-100 mg/ ^m2 , or in a Q3W regimen at a dose of 60-75 mg/ ^m2 , or in a QW regimen at a dose of 35 -A dose of 75 mg/ ^m2 is administered intravenously. The method of any one of claims 1-2 or 14-18, wherein the anti-FGFR2b antibody is administered intravenously in a Q3W regimen, which includes a first administration at a dose of 20-30 mg/kg, and the first administration Three weeks after administration, followed by subsequent administrations in a Q3W schedule at doses of 10-19 mg/kg each time, and wherein the docetaxel is administered intravenously in ^a Q3W schedule at a dose of at least 50 mg/m , if administered intravenously at a dose of 50-100 mg/ ^m in the Q3W regimen or 60-75 mg/ ^m in the Q3W regimen. The method of any one of claims 1-2 or 14-18, wherein the anti-FGFR2b antibody is administered intravenously in a Q3W regimen, which includes a first administration at a dose of 25-35 mg/kg, and the first administration Three weeks after administration, followed by subsequent administrations in a Q3W schedule at doses of 15-24 mg/kg each time, and wherein the docetaxel is administered intravenously in ^a Q3W schedule at a dose of at least 50 mg/m , if administered intravenously at a dose of 50-100 mg/ ^m in the Q3W regimen or 60-75 mg/ ^m in the Q3W regimen. The method of any one of claims 1-2 or 14-18, wherein the anti-FGFR2b antibody is administered intravenously in a Q3W regimen, which includes a first administration at a dose of 15-25 mg/kg, the first administration Three weeks after administration, followed by subsequent administrations on a Q3W schedule at doses of 5-15 mg/kg each, and wherein the docetaxel is administered intravenously on ^a Q3W schedule at a dose of at least 50 mg/m , if administered intravenously at a dose of 50-100 mg/ ^m in the Q3W regimen or 60-75 mg/ ^m in the Q3W regimen. The method of any one of claims 1-2 or 14-18, wherein the anti-FGFR2b antibody is administered intravenously in a Q3W regimen, which includes a first administration at a dose of 15-25 mg/kg, the first administration Three weeks after administration, followed by subsequent administrations in a Q3W schedule at doses of 10-15 mg/kg each time, and wherein the docetaxel is administered intravenously in ^a Q3W schedule at a dose of at least 50 mg/m , if administered intravenously at a dose of 50-100 mg/ ^m in the Q3W regimen or 60-75 mg/ ^m in the Q3W regimen. The method of any one of claims 1-2 or 14-18, wherein the anti-FGFR2b antibody is administered intravenously in a Q3W regimen at a dose of 25-35 mg/kg, wherein the docetaxel is administered in a Q3W regimen The regimen is administered intravenously at a dose of at least 50 mg/ ^m2 , such as 50-100 mg/ ^m2 with the Q3W regimen or 60-75 mg/ ^m2 with the Q3W regimen. The method of any one of claims 1-2 or 14-18, wherein the anti-FGFR2b antibody is administered intravenously in a Q3W regimen at a dose of 30-35 mg/kg, wherein the docetaxel is administered in a Q3W regimen The regimen is administered intravenously at a dose of at least 50 mg/ ^m2 , such as 50-100 mg/ ^m2 with the Q3W regimen or 60-75 mg/ ^m2 with the Q3W regimen. A method of treating squamous non-small cell lung cancer (SqNSCLC) in a subject, the method comprising: Administer an anti-FGFR2b antibody to the subject at a dose of 15-25 mg/kg on a Q2W schedule; and Further comprising: administering an additional dose of 5-10 mg/kg of the anti-FGFR2b antibody 7-10 days after the first administration of the anti-FGFR2b antibody in a Q2W schedule. The method of claim 25, wherein the anti-FGFR2b antibody is administered to the subject at a dose of 15-22 mg/kg or 15-20 mg/kg in a Q2W schedule. The method of claim 25, wherein the anti-FGFR2b antibody is administered to the subject at a dose of 15 mg/kg in a Q2W schedule. The method of any one of claims 25-28, wherein the additional dose of the anti-FGFR2b antibody is 5-10 mg/kg 7-10 days after the first administration of the anti-FGFR2b antibody in a Q2W schedule . The method of any one of claims 25-28, wherein the additional dose of the anti-FGFR2b antibody is 7-8 mg/kg 7-10 days after the first administration of the anti-FGFR2b antibody in a Q2W schedule . The method of any one of claims 1-29, wherein the anti-FGFR2b antibody is administered intravenously. The method according to any one of the preceding claims, wherein the anti-FGFR2b antibody comprises: A heavy chain variable region comprising the heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, and HCDR3 of SEQ ID NO: 8; and The light chain variable region includes the light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 9, the LCDR2 of SEQ ID NO: 10, and the LCDR3 of SEQ ID NO: 11. The method of claim 31, wherein the anti-FGFR2b antibody is afucosylated. The method of any one of claims 31-32, wherein the heavy chain variable region comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 4, and wherein the light chain variable region Comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 5. The method of any one of claims 31-32, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 4, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 5 Amino acid sequence. The method of any one of claims 31-34, wherein the anti-FGFR2b antibody comprises the heavy chain of SEQ ID NO: 1 and the light chain of SEQ ID NO: 2. The method of any one of the preceding claims, wherein the anti-FGFR2b antibody is bemarituzumab. The method of any one of the preceding claims, wherein the SqNSCLC cells express FGFR2b. The method according to any one of the preceding claims, wherein the SqNSCLC cell overexpresses FGFR2b protein, overexpresses FGFR2b mRNA, or contains FGFR2b gene amplification. The method of claim 37 or 38, wherein the SqNSCLC cells express FGFR2b protein as determined by immunohistochemistry (IHC). The method of claim 39, wherein any cell of the SqNSCLC has a FGFR2b staining intensity of 2+ or 3+. The method of claim 39, wherein at least 5% of the cells of the SqNSCLC have an FGFR2b staining intensity of 1+, 2+ or 3+, such as 2+ or 3+. The method of claim 39, wherein at least 10% of the cells of the SqNSCLC have an FGFR2b staining intensity of 1+, 2+ or 3+, such as 2+ or 3+.