FDA Grants Breakthrough Designation to Bemarituzumab/mFOLFOX6 Combo for Frontline FGFR2b+ Gastric/GEJ Cancer

The FDA has granted a breakthrough therapy designation to bemarituzumab plus modified fluoropyrimidine, leucovorin, and oxaliplatin as a frontline treatment for patients with FGFR2b–overexpressing and HER2-negative metastatic and locally advanced gastric and gastroesophageal adenocarcinoma.

The FDA has granted a breakthrough therapy designation to bemarituzumab plus modified fluoropyrimidine, leucovorin, and oxaliplatin (mFOLFOX6) as a frontline treatment for patients with FGFR2b–overexpressing and HER2-negative metastatic and locally advanced gastric and gastroesophageal (GEJ) adenocarcinoma.1

Bemarituzumab has showcased a survival benefit compared with placebo/FOLFOX6 in the phase 2 FIGHT trial, which evaluated bemarituzumab plus mFOLFOX6 as a first-line regimen in this patient population; data showed a 56% reduction in the risk of disease progression or death with the combination vs placebo and mFOLFOX6 (HR, 0.44; 95% CI, 0.25-0.77).2

The indication would be based on an FDA-approved companion diagnostic assay that must demonstrate at least 10% of tumor cells overexpress FGFR2b, stated Amgen, the developer of the first-in-class therapy.

"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 a frontline therapy," said David M. Reese, MD, executive vice president of Research and Development at Amgen. "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."

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. Previously, bemarituzumab monotherapy elicited an 18% objective response rate (ORR) with no dose-limiting toxicities in patients with later-line FGFR2b-positive gastric cancer.3

In the double-blind, placebo-controlled, phase 2 FIGHT study, 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 progression-free survival (PFS); secondary end points included overall survival (OS) and ORR.

In order to be eligible for enrollment, patients could not have received prior treatment, had RECIST v1.1 evaluable disease, harbored FGFR2b overexpression by immunohistochemistry (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 neoadjuvant or adjuvant or chemotherapy.

The study was initially 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.

The results of the FIGHT trial were virtually presented during the 2021 Gastrointestinal Cancers Symposium. For patients with FGFR2b overexpression via immunohistochemistry (IHC) 2+/3+ at 10% or more of the sample (n = 96), the median PFS was 14.1 months and 7.3 months for bemarituzumab/mFOLFOX6 and placebo/mFOLFOX6, respectively. The 1-year PFS rates were 56.3% and 28.6%, respectively.

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 vs 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).

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 median OS was not reached in the bemarituzumab arm vs 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.

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. 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.

Bemarituzumab is currently being explored in clinical trials of other FGFR2b-expressing malignancies, Amgen noted.


  1. Amgen's investigational targeted treatment bemarituzumab granted breakthrough therapy designation. News release. Amgen. April 19, 2021. Accessed April 20, 2021. https://bit.ly/3nbaEnW
  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; abstr 160). doi:10.1200/JCO.2021.39.3_suppl.160
  3. Catenacci DVT, Rasco D, Lee J, 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;38(21):2418-2426. doi:10.1200/JCO.19.01824