Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients

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.

Automated summary

This study determined the MTD, RP2D, pharmacokinetics, safety, and preliminary efficacy of EVER4010001 plus pembrolizumab in patients with advanced solid tumors. The results showed that 80 mg BID was the MTD and RP2D for EVER4010001 plus pembrolizumab.