Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study
Mené dans 17 pays sur 155 patients atteints d'un adénocarcinome de l'estomac ou de la jonction oesogastrique surexprimant FGFR2b (âge médian : 60 ans ; durée médiane de suivi : 10,9 mois), cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du bémarituzumab (un anticorps anti-FGFR2b), dispensé en combinaison avec une chimiothérapie de type mFOLFOX6
Résumé en anglais
Background : Outcomes are poor in patients with HER2-negative, advanced gastric or gastro-oesophagealjunction adenocarcinomas. In this study, we investigated efficacy and safety of thefirst-in-class, afucosylated, humanised IgG1 anti-fibroblast growth factor receptor2 isoform IIb (FGFR2b) monoclonal antibody bemarituzumab with modified 5-fluorouracil,leucovorin, and oxaliplatin (mFOLFOX6) in patients with FGFR2b-selected gastric orgastro-oesophageal junction adenocarcinoma.
Methods : In the randomised, double-blind, placebo-controlled phase 2 trial (FIGHT), patientsaged 18 years and older with HER2 non-positive, FGFR2b-selected gastric or gastro-oesophagealjunction adenocarcinoma, and an Eastern Cooperative Oncology Group performance statusof 0–1 were recruited from 144 clinical sites across 17 countries. Patients with previoustreatment with any selective inhibitor of the FGF–FGFR pathway were excluded. Eligiblepatients were randomly assigned (1:1), using permuted-block randomisation (block sizeof four) and a central interactive voice-web-based response system, stratified bygeographical region, previous treatment with curative intent, and administration ofmFOLFOX6 while being screened for FGFR2b status, to either bemarituzumab (15 mg/kgof bodyweight) or matched placebo intravenously every 2 weeks. All patients also receivedmFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and 5-fluorouracil as a 400 mg/m2 bolus followed by 2400 mg/m2 over approximately 46 h) intravenously every 2 weeks. Patients were given treatmentuntil disease progression (defined by Response Evaluation Criteria in Solid Tumours[RECIST] version 1.1), unacceptable toxicity, withdrawal of consent, or death. Theprimary endpoint was progression-free survival in the intention-to-treat population(defined as all patients randomly assigned to treatment). Safety was assessed in allpatients who received at least one dose of assigned treatment. This study is registeredwith ClinicalTrials.gov, NCT03694522, and is now complete.
Findings : Between Nov 14, 2017, and May 8, 2020, 910 patients were screened and 155 were randomly assigned to the bemarituzumab (n=77) or placebo group (n=78). Median age was 60·0years (IQR 51·0–67·0), 44 (28%) participants were women, 111 (72%) were men, 89 (57%)were Asian, and 61 (39%) were White. At the time of the primary analysis and at a median follow-up of 10·9 months (IQR 6·3–14·2), median progression-free survival was9·5 months (95% CI 7·3–12·9) in the bemarituzumab group and 7·4 months (5·8–8·4) inthe placebo group (hazard ratio [HR] 0·68 [95% CI 0·44–1·04; p=0·073). Common grade3 or worse adverse events were decreased neutrophil count (23 [30%] of 76 in the bemarituzumabgroup vs 27 [35%] of 77 in the placebo group), cornea disorder (18 [24%] vs none), neutropenia (ten [13%] vs seven [9%]), stomatitis (seven [9%] vs one [1%]), and anaemia (six [8%] vs ten [13%]). Serious treatment-emergent adverse events were reported in 24 (32%) patientsin the bemarituzumab group and 28 (36%) in the placebo group. Serious mFOLFOX6 treatment-relatedadverse events occurred in nine (12%) patients in the bemarituzumab group and in 15(19%) patients in the placebo group. All-grade corneal events (adverse events of specialinterest) occurred in 51 (67%) patients in the bemarituzumab group and eight (10%)in the placebo group; grade 3 corneal events were reported only in 18 (24%) patientsin the bemarituzumab group. Treatment-related deaths occurred in three patients inthe bemarituzumab group (two due to sepsis, one due to pneumonia) and none in theplacebo group.
Interpretation : In this exploratory phase 2 study, despite no statistically significant improvementin progression-free survival, treatment with bemarituzumab showed promising clinicalefficacy. Confirmatory phase 3 trials of bemarituzumab plus mFOLFOX6 powered to demonstratestatistical significance are being investigated in patients with previously untreated,FGFR2b-overexpressing, advanced gastric or gastro-oesophageal junction adenocarcinoma.
