Repositioned donafenib versus standard regorafenib for second-line HCC treatment: A matched cohort study

The dominance of bevacizumab plus immunotherapy in first-line advanced hepatocellular carcinoma (HCC) has created opportunities for repositioning previously effective agents in treatment sequences. We compared donafenib, a first-line approved agent repositioned for second-line use, versus regorafenib, the established second-line standard, both combined with programmed cell death protein 1 (PD-1) inhibitors (immune checkpoint inhibitors). This retrospective matched cohort study analyzed patients with advanced HCC receiving either donafenib combined with PD-1 inhibitors or regorafenib combined with PD-1 inhibitors as second-line treatment after bevacizumab plus immunotherapy failure (2021–2024). Propensity score matching (1:1) balanced baseline characteristics. Primary endpoints were progression-free survival and overall survival. After matching, 50 patients were included (25 per group). Donafenib combined with PD-1 inhibitors achieved median progression-free survival of 9.3 months versus 7.1 months for regorafenib combined with PD-1 inhibitors (hazard ratio 1.114, 95% confidence interval: 0.581–2.134, P = .745). Median overall survival was 25.8 versus 17.4 months, respectively (hazard ratio 1.517, 95% confidence interval: 0.685–3.359, P = .304). Objective response rate was 28.0% versus 20.0% ( P = .742), and disease control rate was 56.0% versus 48.0% ( P = .778). Treatment-related adverse events occurred in 76.0% versus 84.0% of patients ( P = .725), with grade 3/4 events in 16.0% versus 24.0%. Donafenib repositioned as second-line therapy demonstrated comparable efficacy and safety to standard regorafenib-based treatment in advanced HCC following bevacizumab plus immunotherapy failure. These findings support strategic repositioning of underutilized first-line agents and provide evidence for expanding second-line treatment options in advanced HCC.