FDA Grants Breakthrough Therapy Designation to Bemarituzumab for Select FGFR2b+/HER2- Advanced Gastric and GEJ Cancers

The FDA has granted breakthrough therapy designation to bemarituzumab for the first-line treatment of patients with HER2-negative metastatic and locally advanced gastric and gastroesophageal adenocarcinoma who harbor FGFR2b overexpression or amplification.

FDA breakthrough therapy designation

Bemarituzumab, a novel anti-fibroblast growth factor receptor 2b (FGFR2b)–targeted antibody, was granted breakthrough therapy designation by the FDA for the frontline treatment of patients with FGFR2b-overexpressing and HER2-negative metastatic and locally advanced gastric and gastroesophageal (GEJ) adenocarcinoma in combination with the modified FOLFOX6 regimen (fluoropyrimidine, leucovorin, and oxaliplatin; mFOLFOX6), based on an FDA-approved assay showing at least 10% of tumor cells overexpressing FGFR2b.1

The use of bemarituzumab was investigated in the phase 2 FIGHT trial (NCT03694522), announced Amgen, in a press release. The study showed that the addition of bemarituzumab to mFOLFOX6 achieved clinically meaningful and statistically significant improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Most notably, bemarituzumab plus FOLFOX6 induced a 56% reduction in the risk of disease progression or death compared with placebo.1,2

"The FIGHT trial is the first study to evaluate targeting the overexpression of FGFR2b in cancer. Bemarituzumab demonstrated clinically meaningful outcomes in key endpoints for patients with advanced gastric or gastroesophageal cancer as frontline therapy," said David M. Reese, MD, executive vice president of Research and Development at Amgen, in a statement. "Amgen looks forward to further investigating the role of FGFR2b and will continue to work with regulatory agencies on next steps to bring this potential first-in-class, frontline therapy to patients."

Patients included in the double-blind, placebo-controlled FIGHT study were randomized 1:1 to receive bemarituzumab with mFOLFOX6 or placebo/mFOLFOX6, every 2 weeks. The bemarituzumab arm includes 77 patients, and the placebo arm included 76 patients. The primary end point was investigator-assessed PFS, OS, and ORR were explored as secondary end points.2

Findings from the study presented during the 2021 Gastrointestinal Cancers Symposium were for 155 patients in the intent-to-treat (ITT) population. In this population, the median PFS was 9.5 months for the combination arm versus 7.4 months for the placebo arm (HR, 0.68; 95% CI, 0.44-1.04; P = .0727). The 1-year PFS rate in the combination arm was 52.5% compared with 33.8% in the placebo arm.

There were 96 patients in the study with FGFR2b overexpression by immunohistochemistry (IHC) 2+/3+ at 10% or more of the sample, and the median PFS for this subgroups of patients was 14.1 months with bemarituzumab plus mFOLFOX6 compared with 7.3 months in the placebo arm (HR, 0.44; 95% CI, 0.25-0.77). The 1-year PFS rate observed with the combination was 57.0% and the rate for the placebo arm was 26.4%.

One-hundred eighteen patients in the study showed FGFR2b overexpression by IHC 2+/3+ in at least 5% of the sample, and in this population, the median PFS was 10.2 months with the combination versus 7.3 months with placebo (HR, 0.54; 95% CI, 0.33-0.87). The 1-year PFS rates were 56.3% and 28.6%, respectively.

In terms of OS in the ITT population, the median 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). At 1 year, the OS rates were 65.3% and 56.9%, respectively. Among patients with the IHC 2+/3+ in at least 5% of the sample, the median OS was also not reached with bemarituzumab compared with 12.5 months with the placebo arm (HR, 0.52; 95% CI, 0.30-0.91). At 1 year, the OS rate was 67.9% in the combination arm versus 55.5% in the placebo arm.

Finally, in the group of patients with IHC 2+/3+ in at least 10%, the median OS was once again not reached with bemarituzumab plus FOLFOX6 versus 11.1 months with placebo (HR, 0.41; 95% CI, 0.22-0.79).

Response data showed that a 47% ORR in the combination arm compared with a 33% ORR in the placebo arm. The median time to response was 1.84 months versus 1.67 months, respectively, and the median duration of response was 12.2 months and 7.1 months, respectively.

In the bemarituzumab/mFOLFOX6 treatment arm, 82.9% of patients experienced grade 3 or higher adverse events compared with 74.0% of the placebo arm. In both groups, stomatitis in 9.2% vs 1.3% and dry eye in 2.6% vs 0%, respectively, were the most commonly observed grade 3 or higher AEs. Additionally, grade 5 AEs were observed in 5 patients who received the combination and 4 who received placebo. Notably, serious AEs occurred in 31.6% of the bemarituzumab-containing arm versus 36.4% of the placebo arm.

In 46.1% of the combination arm, AEs led to death compared with 36.4% in the placebo arm.

The study investigators also noted occurrences of corneal-related toxicities, which are commonly observed with FGFR inhibitors like bemarituzumab. In the FIGHT study, corneal-related AEs of any grade were observed in 67.1% of the combination arm versus 10.4%, with a median time to onset being 16.1 weeks for the bemarituzumab/FOLFOX6 arm versus 11.6 weeks in the placebo arm.

Eligible patients for the FIGHT study were those who had not received prior therapy, presented with measurable disease per RECIST v1.1, harbored FGFR2b overexpression by IHC and/or FGFR2 amplification by circulating tumor DNA (ctDNA), an ECOG performance status of 0 or 1, did not show HER2-positive disease, and did not receive 1 dose of mFOLFOX6. In the study, patients meeting these characteristics were stratified by geographic region, a single dose of mFOLFOX6 during screening, and prior adjuvant or neoadjuvant chemotherapy.

Baseline characteristics showed that the cohort was well balanced. The median age of the study population was 59.7 years, and these patients were predominantly male. The study also had a large Asian population of 45 patients in each treatment arm. In terms of geographic region, 42.6% of patients were from the United States or European Union, 17.4% were from China, the remaining 40.0% were from other Asian countries. Screening found FGFR2 overexpression or amplification in 94.8% and 15.6% of those randomized to receive the bemarituzumab doublet, respectively. FGFR2 overexpression or amplification was also found in the placebo arm in 97.4% and 17.9% of patients, respectively. More than 83% of patients were IHC positive and ctDNA negative at baseline, whereas12.9% were IHC positive and ctDNA positive, and 3.9% were IHC negative and ctDNA positive.

According to Amgen, bemarituzumab is under clinical development in gastric and GEJ cancer as a targeted therapy for tumors that overexpress FGFR2b. The company is also exploring its use in other disease.1


1. Amgen's Investigational targeted treatment bemarituzumab granted breakthrough therapy designation. New release. April 19, 2021. Accessed April 20, 201. https://bit.ly/3v5jRkd

2. Wainberg ZA, Enzinge P, Kang Y, et al. A double-blind randomized study of bemarituzumab (bema) plus mFOLFOX6 versus placebo plus mFOLFOX6 as first-line treatment for advanced gastric/gastroesophageal junction cancer (FIGHT). J Clin Oncol. 2021;39(suppl 3):160. doi:10.1200/JCO.2021.39.3_suppl.160

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