Cabozantinib Plus Atezolizumab vs Sorafenib for Advanced Hepatocellular Carcinoma: COSMIC-312 Trial

Cabozantinib plus atezolizumab shows promise as a frontline systemic treatment option for certain patients with advanced hepatocellular carcinoma; demonstrating prolonged progression-free survival (PFS) vs sorafenib in a phase 3 trial. Cabozantinib is currently approved for patients with hepatocellular carcinoma who have already been treated with sorafenib.

The multicenter, open-label, phase 3 COSMIC-312 trial enrolled 837 patients with advanced hepatocellular carcinoma who had not been previously treated with systemic cancer therapy between December 7, 2018, and August 27, 2020. Patients were randomized in a 2:1:1 ratio to either 40 mg orally of cabozantinib once daily plus 1200 mg intravenously of atezolizumab every 3 weeks (n = 432), 100 mg orally of sorafenib twice daily (n = 217), or single-agent 60 mg orally of cabozantinib once daily (n = 188).

The dual primary end points of the study were PFS in the first 372 patients randomized to either the combination therapy or sorafenib (PFS population) and overall survival (OS) in all patients randomly assigned to either the combination therapy or sorafenib. These results represent the final PFS and concurrent interim OS analyses.

At the data cut-off date of March 8, 2021, the median follow-up duration was 15.8 months for the PFS population and 13.3 months. The median PFS of the combination group was 6.8 (99% confidence interval [CI], 13.7 to 17.7) months, compared to 4.2 (99% CI, 2.8 to 7.0) months in the sorafenib group (hazard ratio [HR], 0.63; 99% CI, 0.44 to 0.91; P = .0012). In the combination group, the interim median OS was 15.4 (96% CI, 13.7 to 17.7) months compared to 15.5 (96% CI, 12.1 to not estimable) in the sorafenib group (HR, 0.90; 96% CI, 0.69 to 1.18; P = 0.44)

The most common grade 3/4 adverse events were alanine aminotransferase increase, hypertension, aspartate aminotransferase increase, and palmar-plantar erythrodysesthesia. There were serious adverse events in 78 patients in the combination group, 16 in the sorafenib group, and 24 in the single-agent cabozantinib group. There were 6 treatment-related deaths in the combination group, due to encephalopathy, hepatic failure, drug-induced liver injury, esophageal varices hemorrhage, multiple organ dysfunction syndrome, and tumor lysis syndrome. There was 1 treatment-related death each in the sorafenib and single-agent cabozantinib groups, due to general physical health deterioration and gastrointestinal hemorrhage, respectively.

“Cabozantinib plus atezolizumab significantly improved progression-free survival and showed increased disease control and lower primary progression compared with sorafenib, which are clinically meaning endpoints,” Robin Kate Kelley, MD, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, and colleagues concluded. They also noted, “additional studies are needed to determine if cabozantinib plus atezolizumab might benefit select patient populations.”

Source:

Kelly RK, Rimassa L, Cheng AL, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. Published online July 4, 2022. doi:10.1016/S1470-2045(22)00326-6