The addition of bemarituzumab, a first-in-class anti-FGFR2b antibody, to mFOLFOX6 chemotherapy significantly improved overall survival in patients with FGFR2b-overexpressing (≥ 10% tumor cell staining) unresectable, locally advanced or metastatic gastric or gastroesophageal junction cancer, according to data presented at the European Society for Medical Oncology (ESMO) Congress 2025.1 This targeted therapy binds to the fibroblast growth factor receptor 2b (FGFR2b) protein, and mFOLFOX is a modified chemotherapy regimen of oxaliplatin, leucovorin, and fluorouracil.
The phase III FORTITUDE-101 trial achieved its primary endpoint of overall survival at an interim analysis, with patients receiving bemarituzumab plus chemotherapy demonstrating a median overall survival of 17.9 months vs 12.5 months with placebo plus chemotherapy (hazard ratio [HR] = 0.61; P = .005). Although a subsequent descriptive follow-up analysis showed attenuation of this treatment effect, the trial also reported significant improvements in progression-free survival and a manageable safety profile, predominantly characterized by corneal adverse events that were reported to be largely reversible.
Sun Young Rha, MD, PhD
“Bemarituzumab demonstrated a statistically significant survival benefit at the primary analysis of this phase III trial,” said Sun Young Rha, MD, PhD, Professor of Medical Oncology and Director of the Songdang Institute for Cancer Research at the Yonsei University College of Medicine, Seoul, South Korea, who presented the findings. “However, attenuation of the treatment effect on overall survival at a subsequent descriptive analysis highlights the need for careful interpretation.”
As Dr. Rha explained, FGFR2b is overexpressed in approximately 16% of advanced gastric cancer cases and plays a critical role in cancer biology and the tumor microenvironment. Bemarituzumab is a first-in-class monoclonal antibody designed to selectively target FGFR2b, blocking oncogenic signaling and engaging antibody-dependent cell-mediated cytotoxicity. This mechanism offers a targeted approach for a subset of patients with gastric or gastroesophageal junction cancer, where chemotherapy alone has limited efficacy.
Previous phase II studies, such as the FIGHT trial, had shown survival signals with bemarituzumab plus mFOLFOX6 in FGFR2b-overexpressing, HER2-negative advanced gastric cancer, providing the rationale for this study, explained Dr. Rha.
Study Methods
The FORTITUDE-101 study was a global, randomized, double-blind trial. Eligible patients had FGFR2b-overexpressing (≥ 10% 2+/3+ tumor cell staining by central immunohistochemistry), non–HER2-positive, unresectable, locally advanced or metastatic gastric or gastroesophageal junction cancer and had not received prior first-line treatment. Patients were randomly assigned 1:1 to receive bemarituzumab (15 mg/kg every two weeks + 7.5 mg/kg on cycle 1 day 8) plus mFOLFOX6 or matched placebo plus mFOLFOX6. Treatment continued every 2 weeks until disease progression or unacceptable toxicity.
The primary endpoint was overall survival in patients with FGFR2b overexpression of at least 10%. Key secondary endpoints included progression-free survival and objective response rate in the FGFR2b ≥ 10% population and safety across all patients. The study was powered for overall survival, and an interim analysis was prespecified. Due to crossing overall survival efficacy boundaries and spending the full alpha at this interim analysis (data cutoff December 9, 2024), it served as the primary analysis. A subsequent descriptive follow-up analysis was performed at data cutoff June 20, 2025.
A total of 547 patients (68.7% male, median age 62.0 years) with FGFR2b overexpression were enrolled. The primary analysis set (FGFR2b ≥ 10% overexpression) included 159 patients in the bemarituzumab arm and 165 patients in the placebo arm. Baseline characteristics were well balanced between the treatment arms.
Longer Follow-Up Results
At the primary analysis (median follow-up of 11.8 months), overall survival was significantly improved with bemarituzumab plus mFOLFOX6 vs placebo plus mFOLFOX6 in patients with FGFR2b ≥ 10% overexpression. Median overall survival reached 17.9 months in the bemarituzumab arm vs 12.5 months in the placebo arm, which met the primary endpoint. The overall survival benefit was consistent across key prespecified subgroups. However, at the descriptive follow-up analysis (median follow-up of 19.4 months), the median overall survival was 14.5 months in the bemarituzumab arm vs 13.2 months in the placebo arm (HR = 0.82). This indicated an attenuation of the treatment effect on overall survival with longer follow-up.
Regarding key secondary endpoints in the FGFR2b ≥ 10% overexpression population, median progression-free survival was 8.6 months in the bemarituzumab arm vs 6.7 months in the placebo arm, with a hazard ratio of 0.71. Objective response rates were similar between the two arms, around 45%.
As Dr. Rha reported, the safety profile of bemarituzumab plus mFOLFOX6 was manageable. The incidence of grade ≥ 3 treatment-emergent adverse events was higher in the bemarituzumab arm (71.3%) than in the placebo arm (64.8%), primarily driven by corneal adverse events.
Other common treatment-emergent adverse events (any grade) in the bemarituzumab arm included pruritus, alopecia, and diarrhea. Corneal adverse events, such as punctate keratitis, corneal epithelium defect, and visual acuity reduction, were notably more frequent with bemarituzumab. Although these events could be grade 3 or higher, said Dr. Rha, visual acuity reduction typically resolved earlier (median 8 weeks) than corneal adverse events (median 17 weeks). At data cutoff, 70% of grade 3 or higher corneal adverse events and 83% of visual acuity reductions had resolved. Treatment withdrawals due to bemarituzumab-related adverse events occurred in 28% of patients.
“Although the safety profile (primarily characterized by manageable and largely reversible corneal adverse events) was acceptable, further characterization of the benefit-risk profile of bemarituzumab in gastric or gastroesophageal junction cancer will be explored in the upcoming FORTITUDE-102 study,” Dr. Rha concluded.
DISCLOSURE: Dr. Rha reported financial relationships with Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, BeOne Medicines (formerly BeiGene), Daiichi Sankyo, Eisai, Indivumed, Jazz Pharmaceuticals, LG Chem, MSD Oncology, Ono Pharmaceutical, Toray, Bristol Myers Squibb, Eli Lilly, Roche/Genentech, Sillajen, and Taiho Pharmaceutical.
REFERENCE
1. Rha SY, Pazo Cid RA, Montes AF, et al: Bemarituzumab plus chemotherapy for advanced or metastatic FGFR2b-overexpressing gastric or gastroesophageal junction cancer: FORTITUDE-101 phase III study results. ESMO Congress 2025. Abstract LBA10. Presented October 20, 2025.
EXPERT POINT OF VIEW
Invited discussant Yelena Y. Janjigian, MD, FASCO, Chief Attending Physician at Memorial Sloan Kettering Cancer Center, New York, offered a critical discussion of the FORTITUDE-101 trial, framing it within the complex landscape of targeting gastroesophageal adenocarcinomas, which she described as overwhelmingly p53-mutant and prone to gaining new alterations.
Cautious Optimism
Dr. Janjigian acknowledged that FGFR2b represents an important unmet need in HER2-negative, claudin-negative gastric and gastroesophageal junction cancers, noting the 10% immunohistochemistry (IHC) 2+/3+ cutoff used in the study identifies approximately 16% of tumors. However, she immediately raised concerns about the trial’s methodology and the transient nature of the observed benefit. She highlighted that the comparator arm, mFOLFOX6 alone, is not the current standard of care for many patients, as it lacked PD-1 blockade. She also noted that a significant proportion of patients (40%) were enrolled late in the trial, leading to early censoring at the interim analysis.
Yelena Y. Janjigian, MD, FASCO
A central point of Dr. Janjigian’s discussion was the “Kaplan-Meier overall survival drift.” She explained that although the primary analysis (at 11.8 months’ median follow-up) showed a statistically significant overall survival benefit (hazard ratio = 0.61, delta 5.4 months) that was initially “very enthusiastic,” this difference converged with longer follow-up. At 19.4 months’ median follow-up, the hazard ratio attenuated to 0.82, and the delta was a nonmeaningful 1.3 months. She attributed this convergence to factors including late censoring, biomarker heterogeneity (suggesting the 10% cutoff might be “too liberal” and that fluorescent in situ hybridization for IHC 2+ patients could be beneficial), and potentially ocular adverse events.
Dr. Janjigian also discussed the unique ocular adverse events associated with bemarituzumab, noting that 28% of patients withdrew due to ocular toxicity, with a typical onset around 6 months. She speculated that these early treatment discontinuations might have contributed to the convergence of the progression-free survival curves. Although investigators became more adept at managing ocular toxicity over time, said Dr. Janjigian, it remains a notable side effect.
Ultimately, Dr. Janjigian concluded that FORTITUDE-101 demonstrated “biologic activity,”but it was “not practice changing” due to the omission of PD-1 blockade in the control arm and the lack of a meaningful difference in median or 2-year overall survival at the updated analysis.
“FGFR2b remains a promising target, but its clinical implementation requires further refinement,” said Dr. Janjigian, who noted that the upcoming FORTITUDE-102 trial is anticipated to provide a more definitive assessment, though she cautioned that the continued use of a 10% FGFR2b cutoff might still be problematic. “There is a need for future strategies to overcome biomarker heterogeneity and explore more stringent selection criteria.”
DISCLOSURE: Dr. Janjigian reported financial relationships with AbbVie, Amerisource Bergen, Amgen, Arcus Biosciences, Ask-Gene Pharma, Astellas Pharma, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol Myers Squibb, Clinical Care Options, Cycle for Survival, Daiichi Sankyo, Eli Lilly, Fred’s Team, Geneos Therapeutics, Genentech/Roche, GlaxoSmithKline, Guardant Health, Imedex, Imugene, Inspira, Jazz Pharmaceuticals, LG Chem, Lynx Health, MacroGenics, Mashup Media, Medscape, MEDiSTRAVA, Merck, Merck Serono, Mersana Therapeutics, Michael J. Hennessy Associates, Natera, Ono Pharmaceutical, OncoDaily, Paradigm Medical Communications, PeerView Institute, Pfizer, Research to Practice, Inspirna (formerly Rgenix), Roche/Genentech, RTP, Seagen, Samsung Bioepis, Silverback Therapeutics, Sillajen, SignifyMD, Sutro Biopharma, Taiho Pharmaceutical, Toray, Touch Oncology, Tyra Biosciences, UpToDate, and Zymeworks.
