DISCUSSION
cancers, cancer initiation, HCC, diarrhea
CANCERS, SOLID TUMORS
FGF‐FGFR signaling dysregulation is reported in a wide range of cancers, specifically the FGF19‐FGFR4 pathway plays a pivotal role in cancer initiation and progression.The MTD and RP2D was declared at 80 mg BID for EVER4010001 when used in combination with pembrolizumab (200 mg, Q3W) and will be evaluated further in the indication expansion (Phase 2) part of this study. In the CFGF401X2101 trial, RP2D was established as 120 mg QD for FGF401 in combination with spartalizumab (300 mg, Q3W).Analysis of serum biomarkers (C4, total bile acid concentration, and circulating FGF19) were indicative of FGFR4 pathway suppression being achieved at all doses, therefore preliminary assessment indicated a favorable PK profile. The number of patients was also limited, therefore further research is needed to determine dose response and analyze the pharmacodynamics of EVER4010001; this will be evaluated in the Phase 2 portion of the study along with further PK investigations and biomarker analysis.In the 80 mg group, 1/6 (16.7%) patients experienced a partial response, with ORR and DCR at 16.7% and 50.0%, respectively. This is similar to the CFGF401X2101 trial, where DCR was reported as 50.0% in each cohort receiving combined FGF401 and spartalizumab therapy.Preliminary clinical data suggest EVER4010001 has a manageable safety profile that is consistent with FGF19 pathway inhibition and the safety profile reported in the CFGF401X2101 trial.Similarly, while the overall incidence of drug‐related TEAEs (irrespective of grade) was similar across the four dosing groups in this study, more EVER4010001‐related TEAEs were observed with the 100 mg BID group versus the other three dosing groups.The most common TEAEs related to EVER4010001 (diarrhea, increased AST, and increased ALT) were the same as the CFGF401X2101 trial treating HCC and solid tumors with EVER4010001 monotherapy and EVER4010001 plus spartalizumab combination therapy.Most AEs were Grade 1 or 2, with the most frequently observed AE, diarrhea, being an anticipated on‐target AE consistent with inhibition of the FGF19‐FGFR4 pathway and its role in bile synthesis.In this study, increased AST was reported in 57.9% of patients as a TEAE related to EVER4010001, and in 10.5% of patients as a Grade ≥3 TEAE. This is similar to the CFGF401X2101 trial where increased AST was present in 47.5% of patients, and 18.8% of patients as a Grade ≥3 TEAE.The CFGF401X2101 trial also investigated FGF401 combined with the anti‐PD‐1 antibody, spartalizumab, where diarrhea, increased AST, and increased ALT were present in 58.3%, 50.0%, and 33.3% of the 12 patients, respectively.Overall, there were no significant changes in the knowledge of risks and benefits of EVER4010001 and pembrolizumab. Therefore, the overall risk‐benefit remains positive and justifies the continuation of the development program. EVER4010001 and the combination regimen will continue to be evaluated in the Phase 2 part of this study to further refine patient selection.