KEY TAKEAWAYS
- Phase 3 COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line treatment for advanced hepatocellular carcinoma (HCC).
- The dual primary endpoints were PFS per RECIST 1.1 and OS in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib.
- Patients were enrolled from 178 centers in 32 countries, and the trial was open-label, randomized, and stratified by disease etiology and geographical region.
- Median PFS was 6.8 months in the combination treatment group versus 4.2 months in the sorafenib group.
- Median OS was 15.4 months in the combination treatment group versus 15.5 months in the sorafenib group.
- Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed.
In solid tumors, cabozantinib combined with checkpoint inhibitors has shown clinical activity. First-line systemic treatment for advanced hepatocellular carcinoma was compared between cabozantinib plus atezolizumab and sorafenib in the COSMIC-312 trial. Patients aged 18 and up from 178 sites in 32 countries who had never received systemic anticancer treatment for advanced hepatocellular carcinoma that had not responded to curative or locoregional therapy were enrolled in the COSMIC-312 trial. Patients with sarcomatoid hepatocellular carcinoma, fibrolamellar carcinoma, or a combination were ineligible. It was okay to have a tumor in a major vein like the portal vein. Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) disease measurement, Barcelona Clinic Liver Cancer stage B or C disease, Eastern Cooperative Oncology Group performance status 0 or 1, adequate organ and marrow function, and Child-Pugh class A were all prerequisites for inclusion.
When performed more than 28 days before randomization, prior resection, tumor ablation, radiotherapy, or arterial chemotherapy was permitted. Patients were randomly assigned to receive either cabozantinib (40 mg once daily orally plus atezolizumab (1200 mg intravenously every 3 weeks) or sorafenib (400 mg twice daily orally) or cabozantinib (60 mg once daily orally) using a web-based interactive response system. Patients were randomly assigned to treatment groups based on their location and whether or not they had the extrahepatic disease and macrovascular invasion. Primary endpoints included progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population) and overall survival in all patients randomly assigned to cabozantinib plus at (ITT population). The cumulative overall and progression-free survival data have been analyzed to this point. ClinicalTrials.gov identifies this study as NCT03755791.
First 837 patients were analyzed at data cut-off (March 8, 2021) and were assigned to receive either cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188) between December 7, 2018, and August 27, 2020. The ITT population was followed for a median of 13 months (IQR 10–16), while those who experienced progression-free survival were followed for a median of 15 months (IQR 14–17). The combination treatment group had a median progression-free survival of 6 months (99% CI 5 months to 8 months), while the sorafenib group only had a median progression-free survival of 4 months (99% CI 2 months to 7 months). The interim analysis showed that the combination treatment group had a longer median overall survival of 15.4 months (96% CI 13.7-17.7) than the sorafenib group of 15.5 months (12.2-1.not estimable; HR 0.90, 96% CI 0.69-1.18; p=0.44). Alanine aminotransferase elevation (38 [9%] of 429 patients in the combination treatment group versus six [3%] of 207 in the sorafenib group versus 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] versus 17 [8%] versus 23 [12%]), aspartate aminotransferase elevation (37 [9%] versus eight [4%] versus 18 [ Six percent of patients receiving the combination therapy experienced grade 5 treatment-related events (encephalopathy, hepatic failure, drug-induced liver injury, esophageal varices hemorrhage, multiple organ dysfunction syndrome, and tumor lysis syndrome), compared to one percent of patients receiving sorafenib (general physical health deterioration) and one percent of patients receiving single-agent cabozantinib (no treatment-related grade 5 events) (gastrointestinal hemorrhage). Patients with advanced hepatocellular carcinoma may benefit from treatment with cabozantinib plus atezolizumab; however, more research is required.
Source: https://pubmed.ncbi.nlm.nih.gov/35798016/
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03755791
Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX, Chan SL, Melkadze T, Sukeepaisarnjaroen W, Breder V, Verset G, Gane E, Borbath I, Rangel JDG, Ryoo BY, Makharadze T, Merle P, Benzaghou F, Banerjee K, Hazra S, Fawcett J, Yau T. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomized, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):995-1008. doi: 10.1016/S1470-2045(22)00326-6. Epub 2022 Jul 4. PMID: 35798016.
