Cabozantinib (Cabometyx, Exelixis, Inc.) provided “a statistically significant and clinically meaningful improvement” in median overall survival (OS) compared with placebo among patients with advanced hepatocellular carcinoma (HCC) in the global phase 3 CELESTIAL trial, Exelixis announced.
The CELESTIAL trial met its primary endpoint of OS, and the independent data monitoring committee for the study recommended that the trial should be stopped for efficacy following review of the second planned interim analysis. Exelixis will discuss the trial results with regulatory authorities and determine next steps for the trial, including offering patients currently receiving placebo the opportunity to cross over to cabozantinib.
CELESTIAL is testing cabozantinib versus placebo in patients with advanced HCC who have been previously treated with sorafenib (Nexavar, Bayer Healthcare). The safety data in the study were consistent with the established profile of cabozantinib.
Based on the results, Exelixis plans to submit a supplemental new drug application to the FDA in the first quarter of 2018. Detailed results from CELESTIAL will be submitted for presentation at a future medical conference.
“This is an important milestone for the cabozantinib development program,” said Gisela Schwab, MD, President of Product Development and Medical Affairs and Chief Medical Officer of Exelixis. The company is studying cabozantinib in a range of tumor types.
In March 2017, the FDA granted orphan drug designation to cabozantinib for the treatment of advanced HCC.
CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B, or other), geographic region (Asia versus other regions), and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms.
The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and progression-free survival. Exploratory endpoints include patient-reported outcomes, biomarkers, and safety.
Liver cancer is the third-leading cause of death worldwide, and HCC is the most common form, making up about three-fourths of the nearly 41,000 cases that will be diagnosed in 2017 in the U.S. Without treatment, patients with advanced disease usually survive less than six months, and it is estimated that 29,000 people will die due to liver cancer in the U.S. annually.
Cabozantinib’s targets include MET, AXL, and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis, and drug resistance.
The FDA has approved Cabometyx tablets for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy. Exelixis has announced licensing agreements with Ipsen and Takeda Pharmaceutical Company Ltd. that cover commercialization and further development of cabozantinib indications outside of the United States.
Source: Exelixis Inc.; October 16, 2017.