VP10-2021: Cabozantinib (C) plus atezolizumab (A) versus sorafenib (S) as first-line systemic treatment for advanced hepatocellular carcinoma (aHCC): Results from the randomized phase III COSMIC-312 trial

Abstract

The multikinase inhibitor C has shown promising clinical activity in combination with immune checkpoint inhibitors, including A, in multiple tumor types. COSMIC-312 (NCT03755791) is evaluating C+A vs S as first-line systemic treatment for aHCC. In this open-label, global, phase 3 trial, patients (pts) were randomized 2:1:1 to C 40 mg QD plus A 1200 mg Q3W or S 400 mg BID or C 60 mg QD stratified by etiology, geographic region, and presence of extrahepatic disease and/or macrovascular invasion (EHD/MVI). Eligible pts had HCC not amenable to curative treatment or locoregional therapy, Child-Pugh class A, ECOG PS ≤1, and no prior systemic therapy for HCC. The dual primary endpoints were PFS by blinded independent review committee per RECIST 1.1 for C+A vs S in the first 372 pts randomized to these 2 arms and OS for C+A vs S in all randomized pts. The secondary endpoint was PFS for C vs S. Prespecified interim analyses of OS for C+A vs S and PFS for C vs S were performed at the primary PFS analysis. 837 pts were randomized to C+A (N=432), S (N=217), or C (N=188). 30% of pts had HBV, 31% had HCV without HBV, and 39% had non-viral etiology; 29% enrolled in Asia; and 69% had EHD/MVI. The study met the primary PFS endpoint; C+A significantly improved PFS vs S (HR 0.63, 99% CI 0.44–0.91; p=0.0012; median PFS 6.8 vs 4.2 mo). The interim analysis of OS did not show a statistically significant benefit for C+A vs S (HR 0.90, 96% CI 0.69–1.18; p=0.438). Grade 3/4 treatment-related AEs (TRAEs) occurred for 54% of pts with C+A vs 32% with S; the most common events were PPE (7.9% vs 8.2%), hypertension (7.0% vs 6.3%), AST increased (6.5% vs 2.4%), and ALT increased (6.3% vs 1.9%). Grade 5 TRAEs were 1.9% vs 0.5%. TRAEs led to discontinuations of C and A in 6.1%, C and/or A in 14%, and S in 7.7% of pts. Interim results for PFS with C vs S will also be presented. C+A showed statistically significant and clinically meaningful improvement of PFS vs S in pts with aHCC not previously treated with systemic therapy. The safety profile of C+A was manageable and consistent with the known safety profile of each agent. Follow-up for the final OS analysis is ongoing.