ESMO 2025 | How FGFR isoform selectivity may shape the therapeutic window
Alexandra Drakaki, MD, PhD, University of California, Los Angeles, CA, discusses the isoform selectivity of the FGFR3 inhibitor, LY3866288, and its potential to avoid off-target toxicities associated with non-selective FGFR inhibitors, such as ocular, nail, and skin toxicity. Dr Drakaki highlights that the favorable safety profile of LY3866288, with mostly grade 1 and 2 toxicities, allows for combination strategies with other agents like enfortumab vedotin and pembrolizumab, as demonstrated by preliminary data from a cohort of patients with newly diagnosed metastatic urothelial cancer. This interview took place at the European Society for Medical Oncology (ESMO) 2025 Congress in Berlin, Germany.
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Transcript
So the fact that Vepugratinib is a selective FGFR3 inhibitor that gives the opportunity to avoid off-target toxicities. So we know that pan-FGFR inhibitors have a specific range of adverse events of special interest where people develop ocular toxicity, nails, skin toxicity, diarrhea, high phosphorus levels. We don’t see significant toxicity with our drug, with Vepugratinib...
So the fact that Vepugratinib is a selective FGFR3 inhibitor that gives the opportunity to avoid off-target toxicities. So we know that pan-FGFR inhibitors have a specific range of adverse events of special interest where people develop ocular toxicity, nails, skin toxicity, diarrhea, high phosphorus levels. We don’t see significant toxicity with our drug, with Vepugratinib. And in fact, the toxicity that we see, it’s, you know, usually grade one, grade two. And that’s why the majority of patients were able to stay on treatment. So the discontinuation rate and the dose reduction rate was minimal. And so the fact that the drug is, you know, safe and effective and have that specific side effect profile, given that it’s FGFR3 selective, we’re able to combine with other agents like Enfortumab, Vidotin, and Pembrolizumab. So as part of our study, we have a preliminary data of a cohort B5, where patients with newly diagnosed metastatic urothelial, that have FGFR3 mutations or fusions, were able to combine the Vepugratinib and Enfortumab and Vidotin and Pembrolizumab. And we have already seen results from those five patients. So four out of five are responding. Three have partial response. One has complete response, which is now the basis. And we have in development and planning of the Forger 2, which is going to be a global registration study for that specific population with this three drug combination.
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