This is the report of a randomized phase 3 trial assessing the efficacy and safety of first-line cabozantinib plus atezolizumab versus sorafenib in patients with unresectable HCC. 837 patients were randomized 2:1:1 to receive cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg i.v. every 3 weeks (N=432), sorafenib 400 mg orally twice daily (N=217) or single-agent cabozantinib 60 mg orally once daily (=188). Dual primary endpoints were progression-free survival (PFS) per RECIST 1.1 assessed by a blinded independent radiology committee (BIRC) in the first 372 patients assigned to the combination, and overall survival (OS) in all patients assigned to cabozantinib plus atezolizumab or sorafenib. Median PFS (final analysis) was 6.8 months (99%CI 5.6–8.3) in the combination group versus 4.2 months (2.8–7.0) in the sorafenib group (HR 0.63, 99%CI 0.44–0.91, p=0·0012). Median OS (interim analysis) was 15.4 months (96% CI 13.7–17.7) in the combination treatment group versus 15.5 months (12.1–not estimable) in the sorafenib group (HR 0.90, 96% CI 0.69–1.18, p=0.44). The secondary endpoint was PFS per RECIST 1.1 assessed by BIRC for single-agent cabozantinib versus sorafenib. Additional predefined endpoints included objective response rate, duration of response, time to progression, and safety. The most common grade 3-4 adverse events (AEs) were ALT increase (9% in the combination group vs 3% in the sorafenib group vs 6% in the single-agent cabozantinib group), hypertension (9% vs 8% vs 12%), AST increase (9% vs 4% vs 10%), and palmar-plantar erythrodysesthesia (8% vs 8% vs 9%); serious treatment-related AEs occurred in 18% patients in the combination treatment group, 8% patients in the sorafenib group, and 13% in the single-agent cabozantinib group.

(Kelley, RK. et al., – Lancet Oncol., July 2022)

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