SAN FRANCISCO—Two significant announcements came recently from Exelixis Inc., both concerning Cabometyx, the tablet form of cabozantinib. Its targets include MET, AXL and VEGFR-1, -2 and -3, and 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 first announcement concerned the company’s global Phase 3 CELESTIAL study, which met its primary endpoint of overall survival, with Cabometyx providing a statistically significant and clinically meaningful improvement in median overall survival compared to placebo in patients with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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 and, based on these results, Exelixis plans to submit a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2018.
In March 2017, the FDA granted Orphan Drug designation to cabozantinib for the treatment of advanced HCC. Liver cancer is the third-leading cause of death worldwide, with HCC being the most common form.
Cabozantinib has demonstrated clinical activity in multiple solid tumor types, including a cohort of 41 patients with advanced HCC who were treated in a Phase 2 randomized discontinuation study. In this trial, cabozantinib showed encouraging clinical activity in this patient population. Sorafenib is the only therapy approved by the FDA for the first-line treatment of advanced HCC. Regorafenib and nivolumab are currently the only treatments approved by the FDA for patients with advanced HCC who have been previously treated with sorafenib, underscoring the need for more options.
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. Enrollment of the trial was completed in September 2017. 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) with no crossover allowed between the study arms. Secondary endpoints include objective response rate and progression-free survival, and exploratory endpoints include patient-reported outcomes, biomarkers and safety.
“We are excited that these positive results from the Phase 3 CELESTIAL trial bring us one step closer to the potential of offering previously treated patients with this aggressive form of advanced liver cancer a much-needed new treatment option,” remarked Dr. Gisela Schwab, president of product development and medical affairs and chief medical officer for Exelixis. “This is an important milestone for the cabozantinib development program; we are committed to studying cabozantinib in a range of tumor types as part of our mission to deliver medicines that improve treatment outcomes and give patients hope for the future.”
Results of the CELESTIAL trial were accepted in late November as a late-breaking abstract to be presented as an oral presentation at the 2018 Gastrointestinal Cancers Symposium in January 2018 in San Francisco.
Additionally, Exelixis is studying cabozantinib in combination with immunotherapies for patients with HCC. The company has entered into a clinical development collaboration with Bristol-Myers Squibb to evaluate cabozantinib with Opdivo (nivolumab), either alone or in combination with Yervoy (ipilimumab), and under an amendment to the CheckMate040 combination trial, Bristol-Myers Squibb has initiated a study to evaluate the tolerability, safety and preliminary efficacy of cabozantinib in combination with Opdivo with or without Yervoy in patients with advanced HCC.
The second major Cabometyx-related announcement focused on the FDA, which has determined the company’s sNDA for Cabometyx for patients with previously untreated advanced renal cell carcinoma (RCC) to be sufficiently complete to permit a substantive review. The FDA has granted Priority Review of the filing and assigned a Prescription Drug User Fee Act action date of Feb. 15, 2018. This sNDA is based on data from CABOSUN, a randomized Phase 2 trial conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program.
“The acceptance of the sNDA filing with a Priority Review is an important regulatory milestone for Cabometyx and for our mission to improve treatment outcomes for patients with cancer,” said Schwab. “We look forward to working with the FDA as they review the application in our effort to offer Cabometyx to patients with previously untreated metastatic RCC who are in need of new treatment options.”