Cabozantinib Plus Atezolizumab Improved Progression-Free Survival in Patients with HCC Vs Sorafenib

In COSMIC-312, reduction in the risk of disease progression or death was achieved with the combination of cabozantinib Plus atezolizumab compatient with sorafenib in patient with hepatocellular carcinoma.

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) could be a possible treatment for patients with advanced hepatocellular carcinoma (HCC). The COSMIC-312 trial (NCT03755791) assessed this combination vs sorafenib (Nexavar) as first line treatment for patients with this disease.1

The median progression-free survival (PFS) was 6.8 months (99% CI, 5.6-8.3) in the combination group and was 4.2 months (99% CI, 2.8-7.0) in the sorafenib group (HR, 0.6, 99% CI 0.44-0.91, P = .0012). The median overall survival (OS) was 15.4 months (96% CI 13.7-17.7) in the combination group compared with 15.5 months (96% CI, 12·1-not estimable) in the sorafenib group (HR 0.90, 96% CI 0.69-1.18; P = .44).

This open-label, phase 3 study randomized adult patients 2:1:1 to receive 40 mg of cabozantinib twice a day plus 1200 mg atezolizumab intravenously once every 3 weeks (n = 432), 400 mg of sorafenib twice a day (n = 217), or 60 mg of cabozantinib monotherapy once per day (n = 188). The study had 2 primary end points: PFSper RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination or sorafenib (PFS intention-to-treat [ITT] population) and OS in all patients randomly assigned to the combination or sorafenib (ITT population).

Investigators excluded patients with fibrolamellar carcinoma, sarcomatoid HCC, or combined hepatocellular cholangiocarcinoma. Patients were required to have measurable disease per RESIST v 1.1, Barcelona Clinic Liver Cancer stage B or C disease, an ECOG performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A.

The median follow-up was 15.8 months (interquartile rate [IQR], 14.5-17.2) in the PFS ITT population and 13.3 months (IQR, 10.5-16.0) in the ITT population.

The 6-month PFS for patients receiving the combination was 54.5% (95% CI, 47.8%–60.7%) vs 40.0% (95% CI, 30.2%–49.6%) for patients receiving sorafenib.The 12-month PFS was 28.5% (95% CI, 22.6%–34.7%) with the combination vs 18.0% (95%CI, 10.2%–27.6%) with sorafenib.

The 6-month OS was 81.4% (95% CI, 77.3%–84.8%) in the combination group vs 76.1% (69.7%–81.3%) in the sorafenib group. The 12-month OS was 61.8% (95% CI, 56.6%–66.6%) for patients receiving the combination treatment vs 58·2% (95% CI, 50.6%–65.0%) for patients receiving sorafenib.

The most common grade 3 or 4 adverse events (AEs) for patients receiving the combination were alanine aminotransferase increase (9%), hypertension (9%), aspartate aminotransferase increase (9%), and palmar-plantar eythrodyaesthesia (8%). The sorafenib group experienced these same grade 3 or 4 events in 3% of patient, 8%, 4%, and 8%, respectively.

The cabozantinib alone group experienced these same grade 3 or 4 events in 6% of patients, 12%, 10%, and 9%, respectively. Seventy-eight patients (18%) experienced serious treatment-related AEs (TRAEs) in the combination treatment group, in 16 patients (8%) in the sorafenib group, and in 24 patients (13%) in the cabozantinib alone group. Grade 5 TRAEs occurred in 6 patients (1%) in the combination group: encephalopathy, hepatic failure, drug-induced liver injury, esophageal varices hemorrhage, multiple organ dysfunction syndrome, and tumor lysis syndrome. One patient (<1%) in the sorafenib group experienced a grade 5 TRAE (general physical health deterioration), as well as 1 (<1%) patient in the single-agent cabozantinib group (gastrointestinal hemorrhage).

Even though no evidence of improved OS was found, investigators observed a significant improvement in PFS with cabozantinib plus atezolizumab vs sorafenib. Additional research is needed to learn more about this combination within select patient populations.


Kelley 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. Published online July 4, 2022. Lancet Oncol. 2022;S1470-2045(22)00326-6. doi:10.1016/S1470-2045(22)00326-6