Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

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

ESMO Virtual Plenary

Session date: 20 November 2021


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

Authors: R.K. Kelley, T. Yau, A.-L. Cheng...

Show all authors

Published: 20 November 2021 DOI: https://doi.org/10.1016/j.annonc.2021.10.008

Download the 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.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.