Bemarituzumab Plus Chemotherapy Shows Initial Overall Survival Benefit in FGFR2b-Positive Gastric Cancer
Key Insights
The phase 3 FORTITUDE-101 trial demonstrated that bemarituzumab plus mFOLFOX6 (search) significantly improved overall survival compared to placebo plus chemotherapy in patients with FGFR2b (search)-overexpressing gastric and gastroesophageal junction cancers.
At the primary analysis, median overall survival reached 17.9 months with bemarituzumab versus 12.5 months with placebo, representing a 39% reduction in death risk.
The survival benefit attenuated over time in follow-up analysis, though the combination also showed significant progression-free survival improvement.
The phase 3 FORTITUDE-101 trial met its primary endpoint, demonstrating that bemarituzumab, a first-in-class anti-FGFR2b (search) monoclonal antibody, combined with mFOLFOX6 (search) chemotherapy significantly improved overall survival compared to placebo plus chemotherapy in patients with FGFR2b-overexpressing gastric and gastroesophageal junction cancers. The results were presented by Prof. Sun Young Rha at the ESMO Congress 2025 during the Presidential Symposium.
Primary Efficacy Results
At the primary analysis with a median follow-up of 11.8 months, patients receiving bemarituzumab plus mFOLFOX6 (search) achieved a median overall survival of 17.9 months compared to 12.5 months for those receiving placebo plus mFOLFOX6. This represented a hazard ratio of 0.61 (95% CI 0.43-0.86; P = 0.005), indicating a 39% reduction in the risk of death.
The trial also met its key secondary endpoint of progression-free survival, with patients in the bemarituzumab arm achieving a median PFS of 8.6 months versus 6.7 months in the placebo arm (HR 0.71, 95% CI 0.53-0.95; P = 0.019).
However, investigators observed attenuation of the overall survival benefit at a subsequent descriptive follow-up analysis. At a median follow-up of 19.4 months, median OS was 14.5 months versus 13.2 months (HR 0.82, 95% CI 0.62-1.08), likely reflecting post-progression treatments and longer observation periods.
Study Design and Patient Population
The global, randomized, double-blind FORTITUDE-101 trial enrolled 547 patients with FGFR2b (search)-overexpressing, non-HER2-positive, unresectable or metastatic gastric and gastroesophageal junction cancer (search). Patients were randomized 1:1 to receive either bemarituzumab 15 mg/kg every 2 weeks with an additional 7.5 mg/kg on cycle 1 day 8 plus mFOLFOX6 (search), or matched placebo plus mFOLFOX6.
The primary endpoint focused on patients with FGFR2b (search) expression in ≥10% of tumor cells with 2+/3+ intensity, a biomarker-defined subgroup known to have poor prognosis and limited response to conventional chemotherapy.
Safety Profile and Management
The safety analysis revealed manageable but notable toxicities associated with bemarituzumab treatment. Any-grade treatment-emergent adverse events occurred in >99% of patients receiving bemarituzumab versus 98% receiving placebo. Grade ≥3 treatment-emergent adverse events were reported in 90% versus 79% of patients, respectively.
Treatment-related grade ≥3 adverse events occurred in 60% of bemarituzumab patients compared to 18% of placebo patients, primarily driven by corneal toxicities consistent with FGFR inhibition.
The most common grade 3 or higher treatment-emergent adverse events with bemarituzumab included reduced visual acuity (33% versus 0% with placebo), punctuate keratitis (26% versus <1%), corneal epithelium defect (14% versus 0%), and limbal stem cell deficiency (14% versus <1%).
Reversible Ocular Effects
Importantly, corneal adverse events showed a pattern of delayed onset and gradual but substantial resolution. Among patients with at least 17 weeks of ocular follow-up, 90% of grade 3 or higher corneal adverse events resolved to grade 1 or lower. The median time to onset of grade 3 or higher corneal adverse events was 24 weeks, with a median time to resolution of 17 weeks and a 70% resolution rate.
Visual acuity reduction showed faster recovery, with a median time to resolution of 8 weeks and an 83% resolution rate, despite having the same 24-week median time to onset as corneal events.
Clinical Significance and Future Directions
FGFR2b (search) overexpression is observed in a substantial proportion of gastric and gastroesophageal junction cancers and is recognized as a driver of tumor aggressiveness, higher metastatic potential, and poorer survival outcomes. The FORTITUDE-101 results establish FGFR2b as a validated therapeutic target in this population, addressing a significant unmet need for biomarker-directed targeted therapies.
Bemarituzumab simultaneously blocks oncogenic FGFR2b (search) signaling and activates antibody-dependent cell-mediated cytotoxicity, offering a novel therapeutic approach for this biomarker-defined subgroup.
The ongoing phase 3 FORTITUDE-102 trial is investigating bemarituzumab plus mFOLFOX6 (search) or CAPOX and nivolumab versus placebo plus mFOLFOX6 or CAPOX in patients with previously untreated advanced gastric/GEJ cancer with FGFR2b (search) overexpression, which will further characterize the benefit-risk profile of bemarituzumab in FGFR2b-positive gastric cancer (search).