The FGFR2b inhibitor bemarituzumab was effective in high-FGFR2b gastroesophageal adenocarcinoma.
Major Finding: The FGFR2b inhibitor bemarituzumab was effective in FGFR2b-high gastroesophageal adenocarcinoma.
Approach: This phase I trial stratified patients with advanced-stage disease by FGFR2b expression level.
Impact: Bemarituzumab warrants further study and is being tested with chemotherapy in a first-line setting.
Overexpression of FGFR2b, an FGFR2 splice variant, occurs in some gastroesophageal adenocarcinomas (GEA) as a result of amplification or upregulation of FGFR2. Catenacci and colleagues conducted a phase I, open-label clinical trial of bemarituzumab, a first-in-class humanized afucosylated IgG1 monoclonal antibody to FGFR2b, in 79 patients with advanced solid tumors. The trial was divided into three parts: part 1a, a dose-escalation study including 19 patients with recurrent solid tumors of a variety of types; part 1b, a dose-escalation study including eight patients with advanced-stage GEA; and part 2, a dose-expansion study including 52 patients with advanced-stage GEA or bladder cancer stratified by FGFR2b expression level. Bemarituzumab was generally well tolerated, with no patients exhibiting dose-limiting toxicities; however, serious ocular adverse events (ulcerative keratitis, limbal stem-cell deficiency, or corneal dystrophy) occurred in three patients (3.8%) and low-grade ocular side effects occurred in 23 patients (29.1%). Ocular side effects may be attributable to inhibition of FGF10, which is involved in healing of the corneal epithelium. The objective response rate in the 52 patients in the dose-expansion study (part 2 of the trial) was best in patients with GEA with high FGFR2b overexpression, all with FGFR2 amplification, with 17.9% of patients exhibiting an objective partial response over a median duration of 12.6 weeks. In contrast, no patients with low FGFR2b expression responded to bemarituzumab, nor did any patients with bladder cancer. This study indicates that bemarituzumab has single-agent antitumor activity as a late-line therapy in advanced-stage GEA overexpressing FGFR2b, a finding warranting further study. The authors also recently reported safety of bemarituzumab in combination with oxaliplatin, fluorouracil, and leucovorin (mFOLFOX6) chemotherapy. Given these findings, and because only approximately 50% of patients proceed to second-line therapy and 30% to third-line therapy due to declining performance status, bemarituzumab is now being investigated in combination with mFOLFOX6 in newly diagnosed advanced-stage GEA in a phase III clinical trial, underscoring the potential utility of bemarituzumab in this disease.
Catenacci DVT, Rasco D, Lee J, Rha SY, Lee KW, Bang YJ, et al. Phase I escalation and expansion study of bemarituzumab (FPA144) in patients with advanced solid tumors and FGFR2b-selected gastroesophageal adenocarcinoma. J Clin Oncol 2020 Mar 13 [Epub ahead of print].
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