INTRODUCTION
death, tumor, pembrolizumab, cancer, HCC, tumors
CANCER, TUMOR, TUMORS, SOLID TUMORS
Despite numerous prevention and control efforts, cancer is still a major health problem and one of the leading causes of death worldwide.Fibroblast growth factors (FGFs) are structurally related polypeptides with diverse biological activities.FGF19 is an important regulator of metabolism under normal physiological conditions.In preclinical studies, inhibition of the FGF19‐FGFR4 signaling pathway has demonstrated antitumor activity and prolonged overall survival (OS) in mice with high‐expressing FGF19/FGFR4/KLB tumors at well tolerated doses.EVER4010001 (FGF401, roblitinib) is a highly selective and potent FGFR4 inhibitor, which binds the kinase domain of the adenosine triphosphate (ATP) binding‐site of FGFR4.Other FGFR4 inhibitors such as BLU‐554 and H3B‐6527 have been investigated in Phase 1 and Phase 1/2 clinical trials for HCC and displayed potent anticancer abilities.A Phase 1/2 open‐label study (CFGF401X2101 trial; NCT02325739) evaluating the safety and efficacy of FGF401 in patients with HCC or solid tumors with positive FGFR4 and KLB expression was the precursor to this study.Pembrolizumab is a humanized monoclonal immunoglobulin G4 kappa anti−PD‐1 antibody which has been tested clinically in a series of KEYNOTE studies, with promising effects.The combination of EVER4010001 and pembrolizumab in the clinical setting has not previously been investigated. However, the combined use of pembrolizumab with another FGF inhibitor, lenvatinib, has previously been studied. By blocking FGFR4, lenvatinib has reduced tumor programmed death ligand 1 (PD‐L1) levels to improve anti‐PD‐1 efficacy.Only the results from the Phase 1 dose escalation portion of this Phase 1/2 study are described here, where the safety of EVER4010001 twice daily (BID) treatment combined with pembrolizumab was evaluated in patients with advanced solid tumors to identify the maximum tolerated dose (MTD) and RP2D. We further evaluated the pharmacokinetic (PK) profile, safety, and efficacy of the treatment regimen.