Cabozantinib Plus Atezolizumab Improves PFS, Not OS in Hepatocellular Carcinoma

Cabozantinib plus atezolizumab confers a clinical benefit in certain patients with advanced hepatocellular carcinoma (HCC), according to research published in The Lancet Oncology.

In the phase 3 COSMIC-312 trial, cabozantinib plus atezolizumab improved progression-free survival (PFS) when compared with sorafenib. However, the combination did not improve overall survival (OS).

The COSMIC-312 trial ( Identifier: NCT03755791) enrolled adults with HCC not amenable to curative treatment or locoregional therapy and previously untreated with systemic anticancer therapy. Patients were allowed to have previous resection, tumor ablation, radiotherapy, or arterial chemotherapy, as long as it was more than 28 days before randomization. 

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Patients were randomly assigned to receive cabozantinib (40 mg once daily) plus atezolizumab (1200 mg intravenously every 3 weeks), sorafenib (400 mg orally twice daily), or single-agent cabozantinib (60 mg once daily).

At the data cutoff, the analysis included the first 837 patients randomly assigned to treatment — 432 to cabozantinib plus atezolizumab, 217 to sorafenib, and 188 to cabozantinib alone. 

The study’s dual primary endpoints were PFS in the first 372 patients randomly assigned to cabozantinib-atezolizumab or sorafenib and OS in all patients randomly assigned to cabozantinib-atezolizumab or sorafenib. 

The median follow-up was 15.8 months for the PFS analysis. The median PFS was 6.8 months in the combination arm and 4.2 months in the sorafenib arm (hazard ratio [HR], 0.63; 99% CI, 0.44-0.91; P =.0012). 

The PFS benefit with combination therapy was seen in patients from Asia, the hepatitis B virus etiology subgroup, and in patients with extrahepatic disease or macrovascular invasion. A benefit was not seen in any other prespecified subgroup. 

The median follow-up for OS was 13.3 months. The median OS was 15.4 months with the combination and 15.5 months with sorafenib (HR, 0.90; 96% CI, 0.69-1.18; P =.44). OS was longer with the combination in patients with hepatitis B virus etiology but not in any other subgroups. 

The researchers also assessed PFS in the single-agent cabozantinib arm. The median PFS was significantly longer in the cabozantinib arm than in the sorafenib arm — 5.8 months and 4.3 months, respectively (HR, 0.71; 99% CI, 0.51-1.01; P =.011).

The most common grade 3-4 adverse events (with the combination, sorafenib, and cabozantinib alone, respectively) were alanine aminotransferase increase (9%, 3%, and 6%), aspartate aminotransferase increase (9%, 4%, and 10%), hypertension (9%, 8%, and 12%), and palmar-plantar erythrodysesthesia (8%, 8%, and 9%). 

Fatal treatment-related adverse events (TRAEs) occurred in 6 patients assigned to the combination. The causes of death were encephalopathy, hepatic failure, drug-induced liver injury, esophageal varices hemorrhage, multiple organ dysfunction syndrome, and tumor lysis syndrome.

There was 1 fatal TRAE in the sorafenib arm (general physical health deterioration) and 1 fatal TRAE in the cabozantinib-alone arm (gastrointestinal hemorrhage). 

“The improvement in progression-free survival with cabozantinib plus atezolizumab in this study shows that the combination confers clinical benefit for patients with advanced hepatocellular carcinoma previously untreated with systemic anticancer therapy,” the researchers wrote. “The absence of a benefit in overall survival, along with the availability of atezolizumab in combination with bevacizumab, indicates the need for additional studies to determine if cabozantinib plus atezolizumab would be an appropriate first-line treatment option in select patient populations.” 

Disclosures: This research was supported by Exelixis and Ipsen. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


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

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