David H. Ilson, MD: With the advent of genomic profiling of esophagogastric cancers, we do see that certainly for gastroesophageal junction and esophageal adenocarcinomas. About 95% of these cancers are what we call genomically unstable. That category applies to about 50% of gastric adenocarcinomas. With genomically unstable tumors, a significant percentage have amplification of receptor-associated tyrosine kinase pathways, pathways like HER2, which we know is targetable in the first line with trastuzumab. EGFR is also amplified in a small percentage of patients along with FGF [fibroblast growth factor] and MET. These are all potentially targetable pathways. The only one that has really borne fruit to date has been HER2. HER2 amplified patients’ benefit for the inclusion of trastuzumab in first-line chemotherapy. Unfortunately, the EGFR drugs did not improve outcome when added to first-line chemotherapy, but those trials were largely in patients with unselected biomarkers.

FGF is a viable target in esophagogastric cancer. There are a small percentage of patients who have abnormalities in the FGF pathway. Probably the most common would be FGF gene amplification. We see this amplification in genomically unstable tumors in esophagogastric cancers. The concern is, what’s the best biomarker? The FIGHT trial is now looking at bemarituzumab, which is an anti-FGFR receptor blocking antibody, so it blocks the receptor and potentially could show synergistic activity with chemotherapy. The trial is selecting patients with FGF receptor gene abnormalities, and patients are randomized to get a fluorinated pyrimidine-oxaliplatin with or without bemarituzumab. This is an ongoing trial. The concern is, what is the best biomarker? We are learning in other cancers that the patients most susceptible to FGF receptor–targeting drugs may be the patients with gene fusions and gene rearrangements, that amplification and gene mutation may not convey sensitivity to these drugs. We’ll see what the trial shows; our hope is that patients with activating mutations with gene amplification will be targetable with FGF receptor drugs. But what we have learned from other cancers is it’s really the patients with gene fusion and gene rearrangement who are the ones susceptible to these drugs. This certainly is an area of tremendous interest, and we await the results of the randomized trial.

I will comment that some earlier trials looking at FGF receptor tyrosine kinase inhibitors in patients with gene amplification did not show a clear benefit. But some of those trials were terminated early, and it may be because the biomarker was not the correct biomarker. Perhaps gene-amplified patients are not the right group of patients.

Transcript edited for clarity.