Frontline Cabozantinib Plus Atezolizumab Significantly Improves PFS in Advanced HCC

Michael M. Morrissey, PhD

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) was found to significantly improve progression-free survival (PFS) compared with sorafenib (Nexavar) when used in the first-line treatment of patients with advanced hepatocellular carcinoma (HCC), meeting a primary end point of the phase 3 COSMIC-312 trial (NCT03755791).¹

In the planned primary analysis for PFS in the intent-to-treat patient population, cabozantinib plus atezolizumab resulted in a significant 37% reduction in the risk of disease progression or death vs sorafenib (HR, 0.63; 95% CI, 0.44-0.91; P = .0012).

Additional data from a prespecified interim analysis for the second primary end point of overall survival (OS), which was done at the same time as the primary analysis for PFS, demonstrated a trend toward the doublet over sorafenib but was not found to reach statistical significance.

Based on the preliminary findings for OS, Exelixis Inc., shared that the probability of reaching statistical significance at the time of the final analysis is low. However, the trial will continue as planned to the final analysis of OS, and data are anticipated in early 2022.

The safety of the doublet appears to be consistent with the known profiles of both agents. No new safety signals were observed with the combination in this trial.

“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 OS vs the comparator arm,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, Inc. stated in a press release. “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 anticancer therapy and the impact of COVID-19 on the trial. We anticipate presenting the results at a future medical conference.”

In the global, multicenter, randomized, phase 3 trial, investigators set out to examine the safety and efficacy of cabozantinib plus atezolizumab vs standard-of-care sorafenib in adult patients with advanced HCC who have not previously received systemic anticancer therapy.²

The trial is aimed to enroll approximately 840 patients. To be eligible for enrollment, patients needed to have histological or cytological diagnosis of HCC, disease that is not amenable to a curative approach, measurable disease per RECIST v1.1 criteria, Barcelona Clinic Liver Cancer stage category B or C disease, and an ECOG performance status of 0 to 1.

If patients had fibrolamellar carcinoma, sarcomatoid HCC or mixed hepatocellular cholangiocarcinoma, received previous systemic anticancer therapy for advanced disease, or underwent radiation therapy for bone metastasis within 2 weeks of treatment or any other radiation therapy within 8 weeks before randomization, they were excluded. Moreover, if patients had known brain metastases or cranial epidural disease and if they were receiving concomitant anticoagulation with oral anticoagulants, they were not included on the study.

Study participants was randomized 2:1:1 into 1 of 3 arms: cabozantinib at a daily dose of 40 mg plus atezolizumab at 1200 mg every 3 weeks; sorafenib alone at a twice-daily dose of 400 mg; or cabozantinib monotherapy at a daily dose of 60 mg.

The co-primary end points of the trial were PFS and OS in the experimental arm vs the control arm. The secondary end point focused on PFS in the single-agent arm vs the control arm.

Exelixis, Inc. plan to discuss the data from COSMIC-312 and next steps for potential regulatory filing with the FDA.

References

1. Exelixis and Ipsen announce cabozantinib in combination with an immune checkpoint inhibitor significantly improved progression-free survival in phase 3 COSMIC-312 pivotal trail in patients with previously untreated advanced liver cancer. News release. Exelixis, Inc. June 28, 2021. Accessed June 28, 2021. https://bit.ly/3A5dcKc
2. Study of cabozantinib in combination with atezolizumab versus sorafenib in subjects with advanced HCC who have not received previous anticancer therapy (COSMIC-312). ClinicalTrials.gov. Updated June 4, 2021. Accessed June 28, 2021. https://clinicaltrials.gov/ct2/show/NCT03755791