Abstract
OBJECTIVE: Inhibition of fibroblast growth factor (FGF) 19-FGF Receptor 4 (FGFR4) signaling demonstrates potent anticancer activity. EVER4010001 is a highly selective FGFR4 inhibitor and pembrolizumab is approved for the treatment of several solid tumors. This study determined the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetics, safety, and preliminary efficacy of EVER4010001 plus pembrolizumab in patients with advanced solid tumors. METHODS: This Phase 1, multicenter, open-label study enrolled 19 Asian-Chinese patients (57.9% male: median age 58 years) with advanced solid tumors. For "3+3" dose escalation, 3-6 patients received treatment at each dose level (EVER4010001 40, 60, 80, or 100 mg twice daily [BID] plus pembrolizumab 200 mg every 3 weeks). RESULTS: At the data cutoff (August 12, 2021), no dose-limiting toxicities (DLTs) were reported at 40 mg-80 mg. At 100 mg, 2 (40.0%) patients had 3 DLTs within the 28-day DLT observation period after first administration. Median time to peak EVER4010001 concentration (T(max) ) was 0.55-1.03 hours. Mean terminal EVER4010001 half-life (T(1/2) ) was 4.00-4.92 hours. The area under the concentration-time curve (AUC(0-t) ) and maximum observed concentration (C(max) ) ranged from 2370.87-5475.77 hour*ng/ml and 606.07-1348.86 ng/ml, respectively. The most common EVER4010001-related treatment-emergent adverse events were diarrhea (94.7%), increased aspartate aminotransferase (57.9%), and increased alanine aminotransferase (47.4%). CONCLUSION: Eighty milligrams BID was the MTD and RP2D for EVER4010001 plus pembrolizumab. Efficacy results were promising, and no new safety risks were reported, justifying the Phase 2 portion of this study.