Cabozantinib Plus Atezolizumab Shows No Overall Survival Benefit in HCC

Cabozantinib (Cabometyx) in combination with atezolizumab (Tecentriq) shows neither improvement nor detriment in overall survival (OS) compared to sorafenib (Nexavar) in patients with previously untreated advanced hepatocellular carcinoma (HCC), according to Exelixis, Inc.¹

These results come from the final analysis of the second primary endpoint of OS from the phase 3 COSMIC-312 trial (NCT03755791).² Based on this outcome and rapidly evolving treatment landscape for this patient population, Exelixis does not intend to submit a supplemental New Drug Application to the FDA.

“Exelixis has a longstanding commitment to patients with liver cancer, exemplified by the 2019 approval of Cabometyx for previously treated advanced liver cancer, and we remain steadfast in our journey to further therapies for this and other difficult-to-treat cancers,” said Vicki L. Goodman, MD, executive vice president, product development and medical affairs, and chief medical officer, Exelixis, in a press release. “We are grateful to the investigators and patients who participated in the COSMIC-312 trial and contributed greatly to this research.”

COSMIC-312 is a global, multicenter, randomized, controlled phase 3 trial with the goal of determining 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.²

The study enrolled 837 patients across 281 study worldwide who had a histological or cytological diagnosis of HCC or a clinical diagnosis of HCC in cirrhotic patients by CT scan or MRI. Eligibility in the study was open to patients with disease not amenable to a curative treatment approach including transplant, or surgery, had 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.

Patients were randomized 2:1:1 to receive either cabozantinib at 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.

Based on data from the analysis of the primary endpoint of progression-free survival (PFS) presented during the European Society for Medical Oncology Asia Virtual Oncology Week 2021, at a median follow-up of 15.8 months, a median PFS of 6.8 months with the combination (n=250) compared to 4.2 months with sorafenib (n=122) was demonstrated in the PFS intention-to-treat (ITT) population.³ This ultimately met the co-primary end point of the study (HR, 0.63; 99% CI, 0.44-0.91; P=.0012).

Additionally, In the PFS ITT population, the combination of cabozantinib and atezolizumab significantly reduced the risk of disease progression or death by 37% compared with sorafenib (hazard ratio [HR]: 0.63; 99% confidence interval [CI]: 0.44-0.91; P =.0012; pre-specified critical p-value of 0.01).

At a median follow-up of 13.6 months, the median OS was 15.4 months with the combination of cabozantinib and atezolizumab (n=432) versus 15.5 months with sorafenib (n = 217) in the ITT population. This reflected a numerical but not statistically significant improvement with the combination (HR, 0.90; 96% CI, 0.69-1.18; P = .438).

In the subgroup analyses performed by disease etiology, median PFS in patients with hepatitis B (n = 109) was 6.7 months with the combination versus 2.7 months with sorafenib (HR, 0.46; 95% CI, 0.29-0.73), and the median OS in patients with hepatitis B (n = 191) was 18.2 months versus 14.9 months, respectively (HR, 0.53; 95% CI, 0.33-0.87).

For patients with hepatitis C (n = 105) the median PFS was 7.9 months with the combination versus 5.6 months with sorafenib (HR, 0.64; 95% CI, 0.38-1.09). The median OS in these patients (n=203) was 13.6 months compared to 14.0 months (HR, 1.10; 95% CI, 0.72-1.68).

The median PFS in non-viral patients (n=158) with the combination was 5.8 months and 7.0 months with sorafenib (HR, 0.92; 95% CI, 0.60-1.41). The median OS in non-viral patients (n=255) was 15.2 months and had not been reached by this point (HR, 1.18; 95% CI, 0.78-1.79).

When assessed by blinded independent central review (BICR), the median PFS with cabozantinib alone was 5.8 months (n=188) compared to 4.3 months with sorafenib (n = 217) in the ITT population. This showed a 29% reduction in the risk of disease progression or death (HR, 0.71; 99% CI, 0.51-1.01; P = .0107).

Objective response rate determined by BICR in the ITT population was 11% with the combination, 3.7% with sorafenib and 6.4% with cabozantinib alone. The disease control rates were 78%, 65%, and 84%, respectively.

In regard to safety, grade 3 or higher adverse effects (AEs) were seen in each arm and included palmar-plantar erythrodysesthesia (7.9%, 8.2%, and 8.5%), hypertension (7.0%, 6.3%, and 11.0%), aspartate aminotransferase increase (6.5%, 2.4%, and 5.3%) and alanine aminotransferase increase (6.3%, 1.9%, and 5.9%).

Grade 3/4 treatment-related AEs (TRAEs) occurred in 51% of patients in the combination arm, 30% of patients in the sorafenib arm, and 52% of patients in the single-agent cabozantinib arm. Grade 5 TRAEs occurred in 1.9%, 0.5%, and 0.5% of patients, respectively.

Treatment discontinuations due to TRAEs occurred in 6.1% of patients in the combination arm, 7.7% of patients in the sorafenib arm, 8.5% of patients in the cabozantinib monotherapy arm, and 14.0% of patients with cabozantinib and/or atezolizumab.

References:

1. Exelixis Announces Final Overall Survival Results from Phase 3 COSMIC-312 Trial of Cabozantinib in Combination with an Immune Checkpoint Inhibitor in Patients with Previously Untreated Advanced Liver Cancer. News Release. Exelixis, Inc. March 14, 2022. Accessed March 15, 2022. https://bwnews.pr/34IrBkD

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. Accessed March 15, 2022. https://clinicaltrials.gov/ct2/show/NCT03755791

3. Exelixis Announces Detailed Results from Phase 3 COSMIC-312 Pivotal Trial of Cabozantinib in Combination with an Immune Checkpoint Inhibitor in Patients with Previously Untreated Advanced Liver Cancer at ESMO Asia Virtual Oncology Week 2021. News release. Exelixis, Inc. November 20, 2021. Accessed March 15, 2022. https://yhoo.it/3FFlkDc