A New Treatment Option for Unresectable Hepatocellular Carcinoma

The new standard first-line treatment for advanced hepatocellular cancer is bevacizumab and atezolizumab, replacing prior initial use of sorafenib or lenvatinib. Alternative immunotherapy combinations are under investigation given the potential restricted use of bevacizumab in patients with esophageal varices and portal hypertension.

In an industry-sponsored, global, open-label, phase 3 trial, patients with advanced Child-Pugh class A hepatocellular cancer were randomized to one of three treatments: sorafenib, the anti-PDL-1 agent durvalumab, or the combination of a single dose of the anti-CTLA-4 agent tremelimumab followed by durvalumab. The primary endpoint was overall survival (OS) in the tremelimumab/durvalumab arm versus the sorafenib arm.

Of 1171 patients, 31% had prior hepatitis B, 27% hepatitis C; 53% had extrahepatic tumor spread; 35% had AFP elevation 400 ng/mL or greater; and 39% had PDL-1 tumor or immune cell positivity.

At a median follow-up of 33 months, OS was superior with tremelimumab/durvalumab versus sorafenib (median, 16.43 vs. 13.77 months; hazard ratio, 0.78; P=0.0035). Rates of OS were superior in the tremelimumab/durvalumab arm at 18 months (48.7% vs. 41.5%), 24 months (40.5% vs. 32.6%), and 36 months (30.7% vs. 20.2%). A secondary endpoint, noninferiority of OS for durvalumab versus sorafenib, was also achieved (median OS, 16.56 vs. 13.77; HR, 0.86). Progression-free survival trended nonsignificantly superior for tremelimumab/durvalumab versus sorafenib (HR, 0.90). Response rates were higher for tremelimumab/durvalumab (20.1%) and durvalumab (17.0%) compared to sorafenib (5.1%). Treatment-related grade 3/4 serious adverse events were similar across the three treatment arms (37.1%–50.5%). No new safety signals were observed.