Breaking Down Bemarituzumab for Gastric, GEJ Cancer: Insights From the FIGHT Trial

Zev Wainberg, MD, MSc, of University of California, Los Angeles, and Nataliya Uboha, MD, PhD, of University of Wisconsin School of Medicine and Public Health, discuss updated results from the FIGHT trial, noting that bemarituzumab, targeting FGFR2b in gastric cancer, shows improved overall survival with a 10% cutoff for FGFR2b expression.

Dr. Wainberg emphasizes the need for prophylactic management of corneal toxicity and better collaboration between oncologists and ophthalmologists.

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Dr. Uboha: You recently published updated results from the FIGHT trial. Can you tell us a little about bemarituzumab, what it targets, and how it works?

Dr. Wainberg: Bemarituzumab is an FGFR2b monoclonal antibody. We published the long-term results of the FIGHT trial, a randomized phase 2 trial comparing FOLFOX with or without bemarituzumab in patients selected for FGFR2b by virtue of overexpression. Some patients were also selected based on amplification, but the majority were identified using an IHC diagnostic.

There are always 2 main reasons to publish secondary long-term analyses of these studies. The first is to achieve more maturity in the data, especially since this study transitioned from a phase 3 to a phase 2 trial midstream. Because it was placebo-controlled, we wanted to see if the results held up over a longer term, which, for the most part, they did, showing a few months of improvement in overall survival.

However, the more important aspect was the biomarker scrutiny. Initially, it was believed that a 5% cutoff would sufficiently distinguish between the placebo group and the group receiving bemarituzumab. But when we revisited the data with a new sponsor who had fresh perspectives, we found that a 10% cutoff was much more effective in distinguishing these patients. While there is some benefit at the 5% FGFR2b staining level for bemarituzumab plus FOLFOX versus FOLFOX plus placebo, the survival curves separate significantly better at the 10% level. This was the main purpose of the secondary analysis.

Dr. Uboha: How often do you see positivity for FGFR2 with a 10% cutoff?

Dr. Wainberg: It is about 20% in HER2-negative gastric cancer. The study overenrolled, so we do not know the rate in HER2-positive cases, but for HER2-negative patients, it is about 20%, down from about 30% with the 5% cutoff. By raising the cutoff to 10%, we exclude about 10% of patients from eligibility.

This change is significant because, in our ongoing phase 3 trials—one without nivolumab and one with nivolumab—the biomarker cutoff was adjusted from 5% to 10%. This adjustment has implications for patient numbers, statistical analysis, and timelines, which is why this secondary analysis was conducted.

Dr. Uboha: You are still capturing a significant proportion of patients with this agent. The updated analysis shows impressive overall survival over 2 years, is that correct?

Dr. Wainberg: Yes, that is right. In our field, we all strive to improve our biomarkers, and this updated analysis reflects that effort. We see a better separation of survival curves with the 10% cutoff compared to the original analysis. Although this makes enrollment more challenging since we need to identify the right patients, our phase 3 trials are enrolling robustly. We have two ongoing studies: one without nivolumab and one with nivolumab, both enrolling globally. We will see how these results pan out over the next year or so.

Dr. Uboha: One advantage of your study design is that it allows 1 cycle of standard chemotherapy before enrollment. This mirrors real-world practice and enables more patients to undergo testing for these biomarkers.

Can you talk a bit about adverse events? Corneal toxicity was significant in phase 2. Is there any prophylaxis built into phase 3, and what has your experience been?

Dr. Wainberg: Corneal toxicity was indeed a notable issue in phase 2 due to the expression of FGFR2b in the corneal epithelium. In phase 2, we managed it reactively, without any prophylactic measures. However, in phase 3, we have implemented prophylactic management, including the use of eye drops and other strategies to prevent dry eyes. This helps manage the initial symptoms like dry and itchy eyes and keratitis.

These prophylactic measures have been beneficial, at least in my experience. It is crucial for ophthalmologists and oncologists to communicate about ocular toxicities. As medical oncologists, we are quite removed from ophthalmology and may miss early signs of toxicity if we do not collaborate closely with ophthalmologists.

Dr. Uboha: Right. I’ll add that we are getting closer to ophthalmology because many new agents, like antibody-drug conjugates, have ocular toxicities.

Dr. Wainberg: It is true, but corneal issues are different from retinal ones. While corneal toxicity does not usually impair vision permanently, it can make activities like reading and driving very disruptive due to itchiness and keratitis. It is not fun. I agree, we need to communicate more with ophthalmologists, and over the years, we are getting closer.

Dr. Uboha: It is exciting to see these results and the nuanced approach to treating this disease with various biomarkers. Hopefully, the ongoing phase 3 trials will provide us with another tool. However, incorporating all these new biomarkers and treatments will be challenging.

Any final thoughts on this?

Dr. Wainberg: I think the next few years will be focused on how to assign biomarker-directed therapies effectively. We need a better system for obtaining IHC diagnostics for our patients. Lung cancer has a more streamlined approach, and we need to move away from a la carte IHC testing with different antibodies to a more unified readout. Figuring out how to do this would be beneficial.