The optimal subsequent treatment and the determinants of survival after sorafenib–regorafenib failure in patients with hepatocellular carcinoma (HCC) remain unclear. The aim of this study was to delineate the determinants of response and survival after regorafenib and evaluate the post-progression outcomes in the era of multiple-line sequential systemic therapy. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure and reported the predictors of progression-free survival, overall survival, post-progression survival, as well as the next-line treatments after regorafenib failure. We showed that some well-known survival predictors of sorafenib treatment and the response to prior sorafenib also had a prognostic role in patients with HCC undergoing regorafenib treatment. Preserved liver function and subsequent systemic therapy play important roles in survival after regorafenib failure. We conclude that the survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure.

The predictors of response and survival in patients with hepatocellular carcinoma (HCC) receiving regorafenib remain unclear. This study aimed to delineate the determinants of response and survival after regorafenib and evaluate post-progression treatment and outcomes. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure. Progression-free survival (PFS), overall survival (OS), post-progression survival (PPS) and post-progression treatments were evaluated. The median PFS, OS and PPS were 3.1, 13.1 and 10.3 months, respectively. Achieving disease control by prior sorafenib, early AFP reduction and hand-foot skin reaction (HFSR) were associated with significantly better radiologic responses. By multivariate analysis, the time to progression on prior sorafenib, HFSR and early AFP reduction were associated with PFS; ALBI grade, portal vein invasion, HFSR and early AFP reduction were associated with OS. ALBI grade at disease progression, main portal vein invasion, high tumor burden and next-line therapy were associated with PPS. The median PPS was 12 months in patients who received next-line therapy, and the PPS was comparable between patients who received next-line targeted agents and immunotherapy. In conclusion, survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure.