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.