Hepatocellular Carcinoma · Medical · Advanced / Metastatic

COSMIC-312

Clinical question: What are the efficacy and safety outcomes in first-line advanced hcc?

Registry: NCT03755791 · Open-label phase III RCT; n=837 randomized 2:1:1. Evidence cut-off: 13 November 2026.

Design, population and treatment

Eligibility

Previously untreated advanced HCC, Child-Pugh A; measurable disease.

Intervention / comparator

Cabozantinib 40 mg daily + atezolizumab 1,200 mg IV q3w versus sorafenib 400 mg twice daily; third cabozantinib-only arm.

Design

Open-label phase III RCT; n=837 randomized 2:1:1.

Primary endpoint

Dual primary PFS and OS for combination versus sorafenib.

Key efficacy outcomes

Final OS 16.5 vs 15.5 months, HR 0.98 (96% CI 0.78–1.24), p=0.87. PFS 6.9 vs 4.3 months, HR 0.74 (99% CI 0.56–0.97).

Safety and tolerability

Grade 3–4 AEs 66% vs 48%; treatment-related deaths 6 (1%) vs 1 (<1%).

Interpretation and limitations

PFS benefit did not translate into OS benefit; do not portray as a positive OS phase III result. Higher severe AE burden.

Median survival differences and hazard ratios must not be converted into NNT. Absolute-effect pictograms are only used when a fixed-time absolute event difference is defensibly reported.

Primary and supporting sources

Primary publication

Registry / follow-up source

Current-practice context · 13 November 2026

Historical trial findings are separated from current recommendations. Check current jurisdiction-specific guidelines, regulatory approval, liver function, biomarkers and patient factors before applying the evidence. Full guideline reconciliation and browser-rendered QA remain pending.