Bemarituzumab, an investigational first-in-class humanized immunoglobulin G1 monoclonal antibody that selectively binds to FGFR2b, improved progression-free survival (PFS) and overall survival (OS) when added to the modified FOLFOX6 (mFOLFOX6) chemotherapy in patients with FGFR2b-positive advanced gastric or gastroesophageal junction (GEJ) cancer in the phase 2 FIGHT randomized clinical trial. The results were presented at the 2021 ASCO Gastrointestinal Cancers Symposium.
In the FIGHT study, the median PFS, the primary end point, improved from 7.4 months in the mFOLFOX6 plus placebo arm to 9.5 months in the bemarituzumab plus mFOLFOX6 arm (hazard ratio [HR], 0.68; P = .0727), announced Zev A. Wainberg, MD, MSc, Co-Director, University of California, Los Angeles Gastrointestinal Oncology Program.
The improvement in PFS was statistically significant, according to the statistical design of the trial. The HR for the bemarituzumab arm had to be ≤0.76 to demonstrate benefit, with a P value ≤.2, which was easily reached based on the results at the time of the data cutoff, Dr Wainberg said.
“The FIGHT study is the first study to evaluate targeting the overexpression of FGFR2b in any cancer, and is the first randomized data set of any FGFR inhibitor in any malignancy,” he said. “In our study, approximately 30% of patients had first-line non–HER2-positive gastric or GEJ adenocarcinoma overexpressing FGFR, using a centrally performed IHC [immunohistochemistry] test.”
FGFR2b has been shown to be overexpressed in wide variation, depending on the tumor stage and the IHC assay used to measure it.
The study included 155 patients with FGFR2b-positive advanced gastric or GEJ cancer who were randomized to first-line treatment with bemarituzumab plus mFOLFOX6 or to placebo plus mFOLFOX6. Patients were enrolled from 15 countries across Asia, the European Union, and the United States. Patients were required to have FGFR2b overexpression, based on a centrally confirmed IHC assay and/or FGFR2 gene amplification, by circulating tumor DNA (ctDNA). Patients were allowed to have 1 dose of mFOLFOX6 before study enrollment.
The median patient age was 60 years, and 57% of the patients were Asian. Approximately 95% of the patients had FGFR2b overexpression based on IHC, approximately 17% had FGFR2 amplification based on ctDNA, and 10.4% in the bemarituzumab arm and 15.4% in the placebo arm had FGFR2/b overexpression and amplification. Approximately 45% of patients in each arm received a single dose of mFOLFOX6 before randomization.
A positive correlation was found between the benefit of bemarituzumab and the percentage of FGFR2b-positive tumor cells.
For example, in patients with IHC 2+/3+ expression of FGFR2b ≥5%, the median PFS improved from 7.3 months in the placebo arm to 10.2 months in the bemarituzumab arm (HR, 0.54; 95% confidence interval [CI], 0.33-0.87). With IHC 2+/3+ expression ≥10%, the median PFS almost doubled, from 7.3 months to 14.1 months with the addition of bemarituzumab to mFOLFOX6 (HR, 0.44; 95% CI, 0.25-0.77).
“As FGFR2b overexpression increased, so too did the OS benefit in the patients who received bemarituzumab compared to placebo,” Dr Wainberg said.
In the overall study population, the median OS was not reached in the bemarituzumab arm versus 12.9 months in the placebo arm (HR, 0.58; 95% CI, 0.35-0.95; P = .0268). In the cohort with IHC 2+/3+ expression ≥5%, the median OS was not reached in patients assigned to bemarituzumab compared with 12.5 months in those assigned to placebo (HR, 0.52; 95% CI, 0.31-0.91), and in those with IHC 2+/3+ expression ≥10%, the median OS was not reached versus 11.1 months, respectively (HR, 0.41; 95% CI, 0.22-0.79).
The objective response rate was 47% in the bemarituzumab plus mFOLFOX6 arm versus 33% in the FOLFOX6 plus placebo arm. The median duration of response improved from 7.1 months with placebo to 12.2 months with bemarituzumab.
The incidence of all-grade adverse events was similar between the bemarituzumab and placebo arms (100% vs 98.7%, respectively). Ocular events are a feature of therapies targeting FGFR, and as expected, corneal events were more frequent in the bemarituzumab arm than the placebo arm (67.1% vs 10.4%), with the most common events in the bemarituzumab arm being dry eye (26.3%), keratitis (15.8%), and punctate keratitis (14.5%).
In all, 34.2% of patients discontinued bemarituzumab therapy because of an adverse event compared with 5.2% in the placebo arm. Of the 26 patients who discontinued bemarituzumab therapy, 21 discontinued because of an ocular event.
Stomatitis (31.6% vs 13.0%, respectively) and elevated transaminases (34.2% vs 19.5%, respectively) were also more common in bemarituzumab recipients compared with placebo.
