Pivotal Phase III Trial Initiated to Investigate Role of Cabozantinib in Advanced HCC

Saturday, December 29, 2018
A large pivotal phase III trial has been initiated to evaluate the potential for the first-line combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) in comparison with standard-of-care sorafenib (Nexavar) for patients with advanced hepatocellular carcinoma (HCC). Exelixis and Ipsen, the companies developing cabozantinib, announced the COSMIC-312 trial.

“With more than 800,000 new diagnoses of liver cancer worldwide each year and a poor prognosis for patients with advanced disease, there is an urgent need to identify new treatment options,” said lead study investigator R. Kate Kelley, MD, associate professor of clinical medicine, division of hematology/oncology, University of California, San Francisco, in a statement. “We look forward to learning whether the combination of cabozantinib and atezolizumab may improve outcomes for previously untreated patients.”

COSMIC-312 (NCT03755791) is a multicenter, randomized, open-label, controlled phase III trial for patients with advanced HCC who have not yet received systemic therapy for their disease that expects to enroll about 640 patients. Patients with an ECOG performance status of 0 or 1 and Barcelona Clinic Liver Cancer stage B or C and Child-Pugh score A disease that is not amenable to a curative treatment approach are eligible for the trial. Fibrolamellar carcinoma, sarcomatoid HCC, and mixed hepatocellular cholangiocarcinoma are all excluded from the trial, as well as those with known brain metastases.

Enrolled patients will be randomized in 6:3:1 ratio to either the experimental arm with cabozantinib plus atezolizumab, the control arm of sorafenib, or the exploratory arm of single-agent cabozantinib. In the experimental arm, oral cabozantinib will be administered at 40 mg daily plus intravenous infusion of 1200 mg atezolizumab once every 3 weeks. Cabozantinib monotherapy will be administered at 60 mg once daily.

The primary endpoints for the study are the duration of progression-free survival (PFS) and overall survival (OS), and the secondary endpoint is objective response rate per RECIST 1.1 criteria by blinded independent central review.

The combination is also being studied in an ongoing phase Ib study, COSMIC-021 (NCT03170960), which is investigating the multikinase inhibitor in combination with the anti–PD-L1 therapy for patients with locally advanced or metastatic solid tumors. The HCC cohort was one of 10 new expansion cohorts recently added. Promising findings from a renal cell carcinoma cohort were just presented at the 2018 ESMO Annual Congress.

“Based on past evidence of potential synergistic effects with cabozantinib and immune checkpoint inhibitors, the combination offers promise for patients with advanced liver cancer who have not received prior treatment,” said Gisela Schwab, MD, president of product development and medical affairs and chief medical officer, Exelixis, in a statement.

Earlier this year, Exelixis announced that the FDA had accepted a supplemental new drug application for the approval of cabozantinib monotherapy for the treatment of patients with previously treated advanced HCC. The application was based on findings from the phase III CELESTIAL trial that demonstrated an OS benefit for cabozantinib versus placebo in this setting (10.2 vs 8.0 months; HR, 0.76; 95% CI, 0.63-0.92; = .0049). The median PFS was 5.2 months with cabozantinib versus 1.9 months with placebo (HR, 0.44; 95% CI, 0.36-0.52; <.0001). The FDA is scheduled to decide on the application by January 14, 2019.

Cabozantinib had already previously received an orphan drug designation from the FDA for the treatment of patients with advanced HCC.


Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. J Clin Oncol. 2018;36 (suppl 4S; abstr 208).

This article originally appeared on Targeted Oncology® as “Pivotal Phase III Trial Initiated to Investigate Role of Cabozantinib in Advanced HCC.”

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