The phase 1 FORAGER-1 trial tested vepugratinib (LY3866288), a selective oral FGFR3 inhibitor, in metastatic urothelial carcinoma (mUC) patients with FGFR3 alterations (15–20% of cases). Unlike older pan-FGFR inhibitors, vepugratinib targets FGFR3 specifically to reduce off-target toxicity.
As a single agent, 200 mg twice daily showed the best balance of efficacy and safety, producing a 34% overall response rate (all partial responses) and a 94% disease control rate. Grade ≥3 side effects were manageable, including diarrhea, fatigue, and liver enzyme elevation.
An early expansion cohort combining vepugratinib with enfortumab vedotin and pembrolizumab demonstrated promising first-line activity, with 3 of 5 patients showing tumor shrinkage (1 complete, 2 partial). Preclinical data suggest vepugratinib may increase NECTIN-4 expression, enhancing ADC efficacy.
These results indicate that vepugratinib is a safe, precise, and effective option for FGFR3-altered mUC, warranting further study as both monotherapy and combination therapy.