Donafenib versus sorafenib as first-line therapy in advanced hepatocellular carcinoma: An open-label, randomized, multicenter phase II/III trial.

4506 Background: Sorafenib is still the standard first-line therapy for advanced hepatocellular carcinoma (HCC). Donafenib, a novel multikinase inhibitor, showed potential benefits in a previous phase Ib study in HCC. Methods: In this open-label, randomized phase II/III trial (ZGDH3), patients with unresectable or metastatic HCC, a Child-Pugh liver function score ≤ 7, and no prior systemic therapy were enrolled from 37 sites across China and randomized (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). Efficacy analysis was primarily based on the full analysis set (FAS). Results: Between March 2016 and April 2018, 668 patients were randomized (donafenib, 334; sorafenib, 334) and included in the intention-to-treat (ITT) set, of whom 659 were analysed by FAS (328 vs 331). Donafenib was associated with a significantly longer median OS than sorafenib in both FAS (12.1 months vs 10.3 months, hazard ratio 0.831, 95% confidence interval 0.699–0.988, p = 0.0363) and ITT (12.0 months vs 10.1 months, 0.839, 0.706–0.996, p = 0.0446). There were no significant differences in median progression-free survival (3.7 months vs 3.6 months, p = 0.2824), objective response rate (4.6% vs 2.7%, p = 0.2448), and disease control rate (30.8% vs 28.7%, p = 0.5532). Grade 3 or worse adverse events (AEs) occurred in 191 (57.4%) and 224 (67.5%) patients ( p = 0.0082), respectively, and AEs of special interest and those leading to treatment interruption occurred in 287 (86.2%) vs 309 (93.1%, p = 0.0049) and 101 (30.3%) vs 141 (42.5%, p = 0.0013). A numerically lower number of patients reported serious AEs (55 [16.5%] vs 67 [20.2%], p = 0.2307) with donafenib. Common AEs with donafenib included hand-foot skin reaction (50.5%), aspartate aminotransferase increased (40.5%), blood bilirubin increased (39.0%), platelet count decreased (37.8%), and diarrhea (36.6%). Conclusions: Donafenib significantly improves OS over sorafenib with favourable safety and tolerability. Donafenib is a promising superior first-line therapy for advanced HCC. Funding: Zelgen. Clinical trial information: NCT02645981 .