Bemarituzumab, an investigational first-in-class monoclonal antibody, may extend overall survival in patients with FGFR2b-positive gastric cancer, but the benefit wanes significantly with time, according to findings from the phase 3 FORTITUDE-101 trial.

In the trial’s primary analysis, adding bemarituzumab to modified FOLFOX6 improved overall survival for patients with advanced gastric or gastroesophageal junction (GEJ) cancer with FGFR2b overexpression vs mFOLFOX6 alone — extending median overall survival by over 5 months after a median follow-up of 1 year.

That advantage was not durable, however. At a median follow-up of 19.4 months, the difference in overall survival had waned to just over 1 month.

Lead investigator Sun Young Rha, MD, PhD, Yonsei University College of Medicine, Seoul, South Korea, reported the findings at the European Society for Medical Oncology (ESMO) Annual Meeting 2025 in Berlin.

Roughly 38% of patients with gastric or GEJ cancer have tumors that overexpress the FGFR2b protein. These tumors tend to be biologically aggressive and resistant to conventional therapies.

Bemarituzumab simultaneously blocks oncogenic FGFR2b signaling and activates antibody-dependent cell-mediated cytotoxicity, which recruits immune cells to the tumor to destroy the FGFR2b-expressing cancer cells.

In the phase 2 FIGHT study, Rha said, bemarituzumab plus mFOLFOX6 showed a “promising survival signal” in FGFR2b-overexpressing, non-HER2 advanced gastric and GEJ cancers.

The follow-up FORTITUDE-101 trial enrolled 547 patients with non-HER2, locally unresectable or metastatic gastric or GEJ cancer with FGFR2b overexpression. They were randomly assigned (1:1) to bemarituzumab (15 mg/kg every 2 weeks with an additional 7.5 mg/kg on cycle 1 day 8) plus mFOLFOX6 or matched placebo plus mFOLFOX6.

In the primary analysis of overall survival, conducted after a median follow-up of 11.8 months, median overall survival was 17.9 months in the bemarituzumab group vs 12.5 months in the placebo group (hazard ratio [HR], 0.61; P = .005). Progression-free survival was also improved with the combination (median, 8.6 vs 6.7 months; HR, 0.71; P = .019).

However, in thefollow-up analysis at 19.4 months, median overall survival was 14.5 months with bemarituzumab vs 13.2 months with placebo (HR, 0.82).

“With just an additional 7.6 months follow-up…the curves converge and the difference disappears,” said discussant Yelena Janjigian, MD, gastrointestinal oncologist, Memorial Sloan Kettering Cancer Center, New York City.

Janjigian did, however, express optimism for the FORTITUDE-102 trial, which is currentlyevaluating bemarituzumab in combination with chemotherapy and the PD-1 inhibitor nivolumab (Opdivo) in patients with FGFR2b-overexpressed untreated advanced gastric or GEJ cancers.

She noted that in the current trial, about 37% of enrolled patients had a PD-1 combined positive score ≥ 5, but none received anti-PD-1 therapy, which is now the standard of care.

FORTITUDE-102, Rha said, will further characterize the benefit-risk profile of bemarituzumab in G/GEJC and explore whether immune modulation can enhance FGFR2b-targeted therapy effectiveness.

Regarding the safety profile, adverse events with bemarituzumab were mainly corneal toxicities, which is consistent with FGFR inhibition. They included reduced visual acuity, punctate keratitis, corneal epithelial defect, and dry eye. Corneal adverse events were transient and mostly reversible, Rha reported. However, 28% of patients in the bemarituzumab group vs 6% of those in the placebo group withdrew due to treatment-emergent adverse events.

Janjigian noted that ocular adverse events are a unique side effect of this treatment. “Over time,” she said, “investigators became more familiar with managing ocular toxicity, so we suspect it will be better and less of a factor in FORTITUDE-102.”

At this point, Janjigian said, FGFR2b remains an important and promising target addressing an unmet need. “But only time will tell,” she said.

The study was funded by Amgen, Inc. Rha disclosed having relationships with Amgen and other drug companies. Janjigian disclosed having relationships (advisory boards or consulting) with AbbVie, AmerisourceBergen, Arcus Biosciences, AskGene Pharma, Inc., and other companies.