COSMIC-312: Cabozantinib Plus Atezolizumab Improves Progression-Free Survival in Advanced Hepatocellular Carcinoma

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The phase III COSMIC-312 study has met its primary endpoint, showing a significant improvement in progression-free survival with cabozantinib plus atezolizumab compared with sorafenib in treatment-naive hepatocellular carcinoma (HCC), investigators reported at a European Society for Medical Oncology (ESMO) Virtual Plenary Session in November 2021.1

For the primary endpoint, which was evaluated in the first 372 of 877 randomly assigned patients, median progression-free survival was 6.8 months with cabozantinib/atezolizumab vs 4.2 months with sorafenib (hazard ratio [HR] = 0.63; P = .0012), “with early and sustained separation of the curves,” according to Robin Kate Kelley, MD, Professor of Clinical Medicine, University of California, San Francisco. 

Robin Kate Kelley, MD

Robin Kate Kelley, MD

“There was also a higher rate of primary disease control and a lower rate of primary disease progression for the combination, collectively demonstrating meaningful clinical benefit…. This combination offers a new option for the first-line systemic treatment of patients with advanced HCC,” she said.

Dr. Kelley presented the final primary progression-free survival analysis and the interim analyses for overall survival, as well as the interim analysis of progression-free survival for the comparison of cabozantinib and sorafenib as single agents.

Across the lines of therapy for advanced HCC, she noted, clinicians can choose among agents targeting the vascular endothelial growth factor (VEGF), immune checkpoint inhibitors, and combination approaches.

She explained the rationale for combining cabozantinib and atezolizumab: cabozantinib is a standard of care after first-line sorafenib, having been shown to improve overall survival and progression-free survival vs placebo in that setting. Cabozantinib inhibits not only relevant pathways but also immunosuppressive elements of the microenvironment and has shown promising clinical activity in combination with checkpoint inhibitors in multiple tumor types.

About COSMIC-312

In this open-label phase III trial, 837 patients were randomly assigned 2:1:1 to receive cabozantinib at 40 mg daily plus atezolizumab at 1,200 mg every 3 weeks (n = 432); sorafenib at 400 mg twice daily (n = 217); or cabozantinib at 60 mg daily (n = 188).

Eligible patients had HCC not amenable to curative treatment or locoregional therapy, Child-Pugh class A, an Eastern Cooperative Oncology Group performance status ≤ 1, and no prior systemic therapy. Disease etiology was hepatitis B virus (HBV) for 30%, hepatitis C virus (HCV) without HBV for 31%, and nonviral etiology for 39%. Asian patients accounted for 29% of the population, and 69% of patients had extrahepatic disease or macrovascular invasion.

Dual primary endpoints were progression-free survival by blinded independent review for the combination vs sorafenib in the first 372 patients randomly assigned to these two arms (ITT [intention-to-treat] analysis) and overall survival for the combination vs sorafenib in all randomly assigned patients (ITT analysis). The key secondary endpoint was progression-free survival for the single agents cabozantinib vs sorafenib.

Prespecified interim analyses of overall survival for cabozantinib/atezolizumab vs sorafenib and progression-free survival for cabozantinib vs sorafenib were performed at the primary progression-free survival analysis. “Under this design, meeting either primary endpoint indicates the superiority of the combination vs sorafenib,” Dr. Kelley said.

Improvement in Progression-Free but Not Overall Survival

The ITT population for the primary analysis included 250 patients receiving combination treatment and 122 receiving sorafenib. Median follow-up was 15.8 months. For the ITT analyses of all patients, median follow-up was 13.3 months.

The risk of disease progression was reduced significantly by 37%, but no significant differences were observed for the primary overall survival endpoint in the ITT population. Median overall survival was 15.4 months with cabozantinib/atezolizumab and 15.5 months with sorafenib (HR = 0.90; P = .438). One factor leading to this may have been the exceptionally good performance of the control arm—15.5 months—“which may be the highest reported for a sorafenib control arm in a prospective randomized trial,” Dr. Kelley said.

The combination’s advantage was clear in key subgroups, with the greatest benefits in progression-free survival seen in patients from Asia (HR = 0.56), those with HBV (HR = 0.46), and those with extrahepatic spread/macrovascular invasion (HR = 0.57). For these subsets, overall survival mirrored the progression-free survival findings, with impressive hazard ratios.

By disease etiology, HBV-positive patients demonstrated the greatest improvements in both progression-free and overall survival with the combination, with 54% and 47% reductions in risk, respectively. HCV-positive patients had a “modest” improvement in progression-free survival and no improvement in overall survival. Patients with nonviral etiology derived no benefit from cabozantinib/atezolizumab for either endpoint.

For the secondary endpoint, the evaluation of progression-free survival with the single agents, median progression-free survival was 5.8 months with cabozantinib vs 4.3 months with sorafenib (HR = 0.71; P = .0107). “This did not meet the stringent P value required for significance at the interim analysis (P = .0045), but follow-up is ongoing for the final analysis of the monotherapy arms,” Dr. Kelley said.

Tumor response in the ITT population was 11% with cabozantinib/atezolizumab, 6.4% with cabozantinib, and 3.7% with sorafenib. Disease control rates were 78%, 65%, and 84%, respectively. Most patients in the combination arm had at least minor radiographic regression (70% vs 56%), she added.

Subsequent anticancer therapy (primarily other tyrosine kinase inhibitors and checkpoint inhibitors) was received by 20% of the combination arm, 37% of the sorafenib arm, and 29% of the cabozantinib arm.


  • The phase III COSMIC-312 trial demonstrated a significant improvement in progression-free survival with cabozantinib plus atezolizumab, vs sorafenib, in treatment-naive hepatocellular carcinoma.
  • Median progression-free survival was 6.8 months with cabozantinib/atezolizumab vs 4.2 months with sorafenib (HR = 0.63; P = .0012).
  • At this interim analysis, overall survival differences have not emerged. [Cabozantinib plus atezolizumab] offers a new option for the first-line systemic treatment of patients with advanced hepatocellular carcinoma.

Safety Profile

“Overall, Treatment-related adverse events were those commonly observed for tyrosine kinase inhibitors or checkpoint inhibitor therapy. They were similar between the arms, with no unexpected signals,” Dr. Kelley said.

Grade 3 or 4 toxicities emerged in 54% of patients receiving cabozantinib plus atezolizumab, 32% of those given sorafenib, and 54% of patients treated with single-agent cabozantinib (sorafenib-treated patients had a shorter duration of exposure). A total of 6.1% of patients discontinued the full combination therapy because of toxicity, and 14.0% of the combination arm stopped one of the two drugs. Dose reductions were required for 60%, 44%, and 67%, respectively.

Follow-up is ongoing for the primary endpoint of overall survival for cabozantinib/atezolizumab vs sorafenib and for the secondary endpoint of progression-free survival for the single agents. 

DISCLOSURE: Dr. Kelley has received personal consulting fees from Exact Sciences, Genentech/Roche, and Gilead as well as honoraria for continuing medical education from ASCO, Clinical Care Options, Medscape, OncLive, National Comprehensive Cancer Network, PeerView, PER, and Research to Practice.


1. Kelley RK, Yau T, Cheng AL, et al: Cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma: Results from the randomized phase III COSMIC-312 trial. ESMO Virtual Plenary 2021. Abstract VP10-2021. Presented November 20, 2021.


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