Regorafenib is a multikinase inhibitor that improved overall survival (OS) and time to progression (TTP) in patients with HCC who progressed during sorafenib treatment in the phase 3 RESORCE trial. This exploratory analysis evaluated the impact of SNPs on regorafenib treatment benefit (OS and TTP) and the occurrence of hand–foot skin reaction (HFSR) in the RESORCE trial.
Genotyping of 187 SNPs was performed on whole blood DNA from 330/573 (58%) patients from RESORCE using a custom NimbleGen™ kit and sequencing libraries that were made using NimbleGen™ KAPA Hyper construction kits. The prognostic and predictive effects of the SNPs, as well as the impact on the occurrence of grade ≥1 HFSR, were assessed using Cox proportional hazards regression with Breslow tie handling or logistic regression, respectively. Models were adjusted for clinical covariates as determined by Akaike information criterion (AIC)-based selection and adjusted for population stratification. P values were corrected for multiple testing using Bonferroni correction and deemed significant at an adjusted α ≤ 0.05.
The overall RESORCE and biomarker cohorts were generally similar for demographic variables (except the latter had a smaller proportion of Asian patients) and outcomes. None of the assessed SNPs were prognostic or predictive of OS. In contrast, 6 SNPs (positioned in the UGT1A1, VEGFC, and TIE2 genes) were prognostic for TTP; SNP rs4148323 in the UGT1A1 gene was predictive for TTP (HR 0.24, 95% CI 0.12–0.49; adjusted p = 0.012). The rs1547651 SNP in the VEGFA gene showed a significant prognostic effect on the occurrence of grade ≥1 HFSR (odds ratio [OR] 0.04, 95% CI 0.01–0.19; adjusted p = 0.037), while the rs114681547 SNP, also in the VEGFA gene, showed a predictive effect (OR 26.23, 95% CI 5.39–197.96; adjusted p = 0.038).
These exploratory results suggest that the detected SNP biomarkers may be candidates for future research to gain deeper understanding of the biological mechanisms determining clinical benefit of regorafenib treatment in HCC.
Clinical trial identification
Legal entity responsible for the study
Editorial assistance in the preparation of this abstract was provided by Katrin Gudmundsdottir of SuccinctChoice Medical Communications (London, UK), with financial support from Bayer.
K. Köchert, G. Meinhardt, M. Teufel: Stock ownership, Employee: Bayer. J. Bruix: Grants, Research support: Bayer; Advisory board: Bayer, AbbVie, Bristol-Myers Squibb, Novartis, Roche, Onxeo, Terumo, Sirtex and BTG; Consulting: Daiichi Sankyo, ArQule, Bayer, AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Kowa, Novartis, Roche, Onxeo, Terumo, Sirtex.