A supplemental new drug application seeking the approval of cabozantinib for the treatment of patients with previously-treated advanced hepatocellular carcinoma has been accepted by the FDA, according to a statement from Exelixis, the company developing the agent.
Gisela Schwab, MD
A supplemental new drug application (sNDA) seeking the approval of cabozantinib for the treatment of patients with previously-treated advanced hepatocellular carcinoma (HCC) has been accepted by the FDA, according to a statement from Exelixis, the company developing the agent.
The application was based on findings from the phase III CELESTIAL trial, in which overall survival (OS) was improved by 2.2 months with cabozantinib versus placebo. Median OS with cabozantinib was 10.2 versus 8.0 months for placebo, representing a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.63-0.92;P= .0049). Under the Prescription Drug User Fee Act, the FDA will render a decision by January 14, 2019.
“Patients with this aggressive form of advanced liver cancer urgently need new treatment options after they progress on first-line therapy,” Gisela Schwab, MD, president, Product Development and Medical Affairs and chief medical officer, Exelixis, said in a statement. “The acceptance of our sNDA filing for Cabometyx is a critical step forward as we work to help address this unmet need, and we intend to work closely with the FDA as they review the application.”
Results from the CELESTIAL trial were first presented at the 2018 Gastrointestinal Cancers Symposium. The study was stopped in October 2017, following a positive interim analysis that showed a significant improvement in OS for cabozantinib. The stoppage was preplanned if thePvalue for OS reached ≤.021.
In the trial, 707 patients were randomized to receive cabozantinib at 60 mg daily (n = 470) or placebo (n = 237). All patients had an ECOG performance status of 0 or 1, a Child-Pugh score of A, and had progressed on at least 1 prior systemic therapy for advanced HCC, with 70% having received only prior sorafenib (Nexavar).
Baseline characteristics were balanced between the arms. The median age was 64 years and 82% were male. The baseline etiologies included hepatitis B virus infection (38%) and hepatitis C virus infection (24%). Over three-fourths of patients had extrahepatic spread (78%) and 30% had macrovascular invasion, with 27% of patients having both. A quarter of patients were enrolled in Asia (25%) and 27% had received 2 prior systemic therapies.
The median progression-free survival (PFS) was 5.2 months compared with 1.9 months for placebo, which was a 56% reduction in the risk of progression or death with the targeted therapy (HR, 0.44, 95% CI, 0.36-0.52;P<.0001). The objective response rate (ORR) was 4% with cabozantinib compared with 0.4% with placebo (P= .0086). When including those with stable disease, the disease control rate with the multikinase inhibitor was 64% compared with 33% for placebo.
In a subgroup analysis of those who received only prior sorafenib for advanced HCC, the median OS was 11.3 months with cabozantinib compared with 7.2 months for placebo (HR, 0.70; 95% CI, 0.55-0.88). The median PFS in this group was 5.5 months with cabozantinib versus 1.9 months with placebo (HR, 0.40; 95% CI, 0.32-0.50).
More patients discontinued therapy due to treatment-related adverse events (AEs) with cabozantinib (16%) versus placebo (3%). The most common grade 3/4 AEs with cabozantinib versus placebo were palmar-plantar erythrodysesthesia (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%).
There was a higher incidence of grade 5 AEs in the cabozantinib arm compared with placebo. Overall, 6 patients had a grade 5 AE in the cabozantinib arm, which included hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism, and hepatorenal syndrome. One patient in the placebo group died of hepatic failure.
“The clinically significant benefits in both overall survival and progression-free survival shown in the CELESTIAL trial suggest that, if approved, cabozantinib could become an important addition to the treatment landscape for these patients,” CELESTIAL trial lead investigator Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, said in a statement when the results were presented.
Cabozantinib was initially approved by the FDA as a treatment for patients with medullary thyroid cancer in 2012. In April 2016, the agent received a new indication as a treatment for patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. This approval was further expanded in December 2017 to include the treatment of patients with advanced RCC in the first-line setting. Numerous other trials exploring the agent remain ongoing.
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).