Trial in progress: Phase 1b/3 study of bemarituzumab + mFOLFOX6 + nivolumab versus mFOLFOX6 + nivolumab in previously untreated advanced gastric and gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-102).

Abstract

TPS4165 Background: Fibroblast growth factor receptor 2b (FGFR2b) is overexpressed in approximately 30% of non-human epidermal growth factor receptor 2 (non-HER2) positive gastric cancer (Wainberg, 2021). Bemarituzumab is a first-in-class monoclonal antibody that specifically blocks FGFR2b, inhibiting downstream tumor proliferation and enhancing antibody dependent cellular cytotoxicity (Catenacci, 2020; Xiang, 2021). In the phase 2 FIGHT study (Wainberg, 2021; Catenacci, 2021), progression-free survival (PFS) was improved (HR, 0.68; 95% CI, 0.44-1.04; p = 0.07) and a 5.7 month longer median overall survival (OS) was observed (19.2 months vs 13.5 months; HR, 0.60; 95% CI, 0.38-0.94) with bemarituzumab + mFOLFOX6 vs placebo + mFOLFOX6. Preclinical studies indicate that bemarituzumab modulates the tumor microenvironment to sensitize tumors to anti-PD1 monoclonal antibodies (Powers, 2016; Xiang, 2021) providing rationale for combination with nivolumab. Methods: FORTITUDE-102 (NCT05111626) is a phase 1b/3 study in patients (pts) with unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy. Part 1 is an open-label safety lead-in; Part 2 is a double-blind, placebo-controlled study to evaluate efficacy and safety. Approximately 702 pts ≥18 years will be enrolled (Part 1, ̃20; Part 2, ̃682). Key eligibility criteria include Eastern Cooperative Oncology Group performance status 0-1, evaluable disease per RECIST v1.1, adequate hematologic and organ function, and no contraindication to receive mFOLFOX6 chemotherapy or nivolumab; for part 2, IHC-confirmed FGFR2b overexpression by central testing is required and no prior treatment for metastatic or unresectable disease allowed except 1 dose of mFOLFOX6 ± nivolumab. Key exclusion criteria include positive HER2 status and untreated or symptomatic CNS metastasis and leptomeningeal disease. Pts on bemarituzumab will receive 15 mg/kg every 2 weeks (Q2W) with an additional 7.5 mg/kg dose on cycle 1 day 8. mFOLFOX6 + nivolumab will be at a fixed dose Q2W. The dose-limiting toxicity (DLT) period is 28 days; observed safety data will influence additional enrollment to Part 1, de-escalation of bemarituzumab, or the recommended phase 3 dose (RP3D). For Part 1, primary endpoints are DLTs and adverse events; secondary endpoints include OS, PFS, and objective response (OR). For Part 2, pts will be randomized 1:1 to mFOLFOX6 + nivolumab Q2W plus either bemarituzumab at RP3D or placebo. Primary endpoint for Part 2 is OS; secondary endpoints include PFS, OR, and safety. The concurrent phase 3 FORTITUDE-101 study (NCT05052801) will evaluate bemarituzumab + mFOLFOX6 vs placebo + mFOLFOX6. Clinical trial information: NCT05111626.