Cabozantinib/Atezolizumab Improves Progression-Free Survival in Hepatocellular Carcinoma

The new standard of care to treat advanced hepatocellular cancer is the combination of atezolizumab and bevacizumab. Recent studies also support first-line use of the combination of tremelimumab and durvalumab. Both of these regimens achieved superior survival compared to sorafenib. Cabozantinib, an approved agent for second- or later-line treatment of advanced hepatocellular cancer, is now being studied as an earlier-line therapy.

In an industry-sponsored, open-label, randomized, phase 3 trial researchers compared first-line use of the combination of atezolizumab and cabozantinib to sorafenib alone, and cabozantinib alone to sorafenib alone. Patients were randomized 2:1:1 to receive cabozantinib (40 mg orally daily) plus atezolizumab (1200 mg IV every 3 weeks), sorafenib (400 mg orally twice daily), or cabozantinib (60 mg orally daily). Of 837 patients, most were men with a median age of 64 years, 29% had hepatitis B and 31% had hepatitis C, and 72% had two or more sites of disease.

At a median follow up of 15.8 months, the coprimary endpoint of progression-free survival (PFS) for atezolizumab/cabozantinib compared to sorafenib showed superiority in the combination therapy arm (median, 6.8 vs. 4.2 months; hazard ratio, 0.63; P=0.0012). However, early interim analysis of the second coprimary endpoint of overall survival showed no difference for atezolizumab/cabozantinib compared to sorafenib (median, 15.4 and 15.5 months; HR, 0.90; P=0.44). A secondary endpoint of PFS for single-agent cabozantinib compared to sorafenib showed superiority for cabozantinib (median, 5.8 vs. 4.3 months; HR, 0.71; P=0.011). The response rate was higher in the combination therapy arm compared to the sorafenib arm (11% vs. 4%). Rates of grade 3 or 4 serious treatment-related adverse events were highest in the combination therapy arm (18%) followed by the cabozantinib (13%) and sorafenib arms (8%).