Cabozantinib Plus Atezolizumab Reduces Risk of Disease Progression or Death in Advanced HCC

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) demonstrated improvement in both progression-free (PFS) and overall survival (OS) compared with sorafenib (Nexavar), in patients with untreated advanced hepatocellular carcinoma (HCC), meeting 1 of the primary end points of the phase 3 pivotal COSMIC-312 clinical trial (NCT03755791).

Although the combination trended towards a favorable OS result, it was not found to be statistically significant, and according to a press release from Exelixis, Inc, there is a low probability of cabozantinib/atezolizumab reaching statistical significance in terms of OS. The final OS analysis is ongoing, and results are expected to be reported in early 2022. The company also plans to discuss the trial results with the FDA.

“While we are encouraged by the data supporting the potential for the combination of cabozantinib and atezolizumab to reduce the risk of disease progression or death, we are disappointed by the interim result of lack of significant improvement on overall survival versus the comparator arm,” said Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, in a statement.

COSMIC-312 is a randomized, controlled study aiming to determine the efficacy and safety of cabozantinib in combination with atezolizumab in patients with untreated advanced HCC, as well as the single-agent activity of cabozantinib compared with sorafenib. Approximately 740 patients in the study will be randomized 2:1:1 to receive with cabozantinib 40 mg orally daily combined with atezolizumab 1200 mg intravenously once every 3 weeks versus sorafenib 400 mg orally twice daily or cabozantinib 50 mg orally once daily versus sorafenib 400 mg orally twice daily. The secondary end point of the study is the duration of PFS for the single-agent arm compared with the sorafenib arm.

Cabozantinib plus atezolizumab specifically reduced the risk of disease progression by 37% compared with sorafenib in the intent-to-treat population of COSMIC-312 (HR, 0.63; 99% CI, 0.44-0.91; P =.0012, according to the primary end point analysis. Further, the experimental combination appeared to have a safety profile consistent with the profiles of either drug alone. No new safety signals were observed in the study.

Recruitment for COSMIC-312 is ongoing. In order to be included in the study, patients are required to have a histological or cytological diagnosis of HCC or a clinical diagnosis of HCC in cirrhotic patients by CT scan or MRI. Patients must have also had a disease that is not amenable to a curative treatment approach like transplant, or surgery, have Barcelona Clinic Liver Cancer stage category B or C disease, a Child-Pugh Score of A, and an ECOG performance status of 0 or 1.

The study excludes patients who have known fibrolamellar carcinoma, sarcomatoid HCC, or mixed hepatocellular cholangiocarcinoma, certain prior therapies, known brain metastases or cranial epidural disease, and concomitant anticoagulation with oral anticoagulant

“As these data continue to mature, we are working to understand the potential impact of various contributing factors on the results, including patient demographics, subsequent anti-cancer therapy, and the impact of COVID-19 on the trial. We anticipate presenting the results at a future medical conference,” said Morrissey, in the press release.

_Reference:

_{Exelixis and Ipsen announce cabozantinib in combination with an immune checkpoint inhibitor significantly improved progression-free survival in phase 3 COSMIC-312 pivotal trial in patients with previously untreated advanced liver cancer. News release. Exelixis, Inc. June 28, 2021. Accessed June 28, 2021. https://bit.ly/35ZoMbT}