Bemarituzumab combined with mFOLFOX6 demonstrated a 56% reduction in the risk of disease progression or death compared with placebo and mFOLFOX6 as a frontline treatment in select patients with FGFR2b-positive advanced gastric or gastroesophageal junction adenocarcinoma.
Zev A. Wainberg, MD
Bemarituzumab combined with mFOLFOX6 demonstrated a 56% reduction in the risk of disease progression or death compared with placebo and mFOLFOX6 as a frontline treatment in select patients with FGFR2b-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to results of the phase 2 FIGHT study that were presented during the 2021 Gastrointestinal Cancers Symposium.1
Findings showed that, for patients with FGFR2b overexpression via immunohistochemistry (IHC) 2+/3+ at 10% or more of the sample (n = 96), the median progression-free survival (PFS) was 14.1 months and 7.3 months, respectively (HR, 0.44; 95% CI, 0.25-0.77). The 1-year PFS rates were 57.0% and 26.4% in the combination and placebo arms, respectively.
In those with FGFR2b overexpression via IHC 2+/3+ in at least 5% of the sample (n = 118), the median PFS was 10.2 months in the bemarituzumab arm versus 7.3 months with the placebo arm (HR, 0.54; 95% CI, 0.33-0.87). The 1-year PFS rates were 56.3% and 28.6%, respectively.
In the intent-to-treat (ITT) population (n = 155), the median PFS was 9.5 months and 7.4 months for the combination and placebo arms, respectively (HR, 0.68; 95% CI, 0.44-1.04; P = .0727). The 1-year PFS rates were 52.5% and 33.8%, respectively.
“The FIGHT trial is the first study to evaluate targeting the overexpression of FGFR2b in any cancer, and is the first randomized dataset of any FGFR inhibitor in any malignancy,” lead study author Zev A. Wainberg, MD, co-director of the University of California, Los Angeles (UCLA) Gastrointestinal Oncology Program, director of the Early Phase Clinical Research Program, Jonsson Comprehensive Cancer Center, and associate professor of medicine and surgery at the David Geffen School of Medicine at UCLA, in a virtual presentation during the meeting. “Bemarituzumab when added to mFOLFOX6 chemotherapy led to clinically meaningful and statistically significant improvements in PFS, OS, and ORR.”
Bemarituzumab is an IgG1 antibody that is specific for FGFR2b isoform, which blocks growth factor signaling and works through an antibody-dependent cellular cytotoxicity mechanism, said Wainberg. Prior single-agent activity with bemarituzumab in later-line FGFR2b-positive gastric cancer elicited an 18% objective response rate (ORR) with no dose-limiting toxicities.2
In the double-blind, placebo-controlled, phase 2 FIGHT trial, patients with unresectable locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma were randomized 1:1 to receive bemarituzumab with mFOLFOX6 (n = 77) or placebo/mFOLFOX6 (n = 76), every 2 weeks. The primary end point was investigator-assessed PFS; secondary end points included overall survival (OS) and ORR.
To be eligible for enrollment, patients could not have received prior therapy, had RECIST v1.1 evaluable disease, harbored FGFR2b overexpression by IHC and/or FGFR2 amplification by circulating tumor DNA (ctDNA), an ECOG performance status of 0 or 1, did not harbor HER2 positivity, and could have received 1 dose of mFOLFOX6. Patients were stratified by geographic region, single dose of mFOLFOX6 during screening, and prior adjuvant or neoadjuvant chemotherapy.
Initially, the trial was designed as a registrational phase 3 trial with a planned 548 patients; however, the design was amended after enrolling 155 patients to a proof-of-concept phase 2 study with prespecified statistical assumptions.
Baseline demographics were similar between the 2 arms; overall, the median age was 59.7 years, more than half of patients were male, and about 45 patients in each arm were Asian. Patients were from the United States/European Union (42.6%), China (17.4%), or rest of Asia (40.0%). In the bemarituzumab arm, 94.8% and 15.6% of patients had FGFR2b overexpression and amplification, respectively, compared with 97.4% and 17.9% in the placebo arm. Additionally, 83.2% of patients were IHC positive and ctDNA negative; 12.9% of patients were IHC positive and ctDNA positive, and 3.9% of patients were IHC negative and ctDNA positive.
Additionally, in the ITT population, data showed that 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). The 1-year OS rates were 65.3% and 56.9%, respectively.
Similar to the PFS trends, the OS benefit with bemarituzumab increased with higher levels of FGFR2b overexpression. In the IHC 2+/3+ in at least 5% of the sample, the median OS was not reached with bemarituzumab versus 12.5 months with the placebo arm (HR, 0.52; 95% CI, 0.30-0.91). The 1-year OS rates were 67.9% and 55.5%, respectively.
In the IHC 2+/3+ in at least 10% of the sample, the median OS was not reached compared with 11.1 months with bemarituzumab and the placebo arms, respectively (HR, 0.41; 95% CI, 0.22-0.79).
The ORR in the ITT population was 47% with the combination and 33% with placebo/mFOLFOX6. For patients who had measurable disease at baseline, the ORRs were 53% and 40%, respectively, with a best change in tumor size at –41.7% and –29.9%, respectively. The median time to response was 1.84 months with bemarituzumab and 1.67 months with placebo/mFOLFOX6, and the median duration of response was 12.2 months and 7.1 months, respectively.
Regarding safety, grade 3 or higher adverse events (AEs) were observed in 82.9% of patients on bemarituzumab versus 74.0% of those on the placebo/mFOLFOX6 arm; the 2 most prominent increases in grade 3 or higher AEs with bemarituzumab included stomatitis (9.2% vs 1.3% with placebo) and dry eye (2.6% vs 0%, respectively). Grade 5 AEs occurred in 5 and 4 patients, respectively. Serious AEs occurred in 31.6% of bemarituzumab-treated patients and in 36.4% of patients on the placebo arm. AEs that led to mFOLFOX6 discontinuation occurred in 46.1% and 36.4% of patients on bemarituzumab/mFOLFOX6 and placebo/mFOLFOX6, respectively; these rates were 34.2% and 5.2% for bemarituzumab and placebo discontinuation, respectively. The duration of exposure to mFOLFOX6 was similar across the bemarituzumab (29.80 weeks) and placebo arms (26.47 weeks).
Corneal-related toxicities tend to be associated with FGFR inhibitors, Wainberg explained. All-grade and grade 3 or higher corneal-related AEs occurred in 67.1% and 23.7% of bemarituzumab-treated patients versus 10.4% and 0% of those on placebo/mFOLFOX6, respectively. The mean time to onset, of any grade, was 16.1 weeks on bemarituzumab/mFOLFOX6 and 11.6 weeks on placebo. Twenty patients discontinued bemarituzumab treatment due to corneal AEs, and 12 AEs did resolve with a median time to resolution of 27.0 weeks.
“The FIGHT trial results support a prospective randomized phase 3 study in gastric/gastroesophageal adenocarcinoma, and the evaluation of bemarituzumab in other FGFR2b-positive tumor types,” Wainberg concluded.