FDA Approves Cabozantinib for Advanced HCC

The FDA has approved cabozantinib (Cabometyx) as a treatment for patients with hepatocellular carcinoma (HCC) who previously received sorafenib (Nexavar), according to the company developing the therapy, Exelixis.

The approval 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).

“Patients with this form of advanced liver cancer have few treatment options, particularly once their disease progresses following treatment with sorafenib,” CELESTIAL trial lead investigator Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, said in a statement.

“Physicians are eager for new options for these patients, and the results of the CELESTIAL trial demonstrate that Cabometyx has the efficacy and safety profile to become an important new therapy in our efforts to slow disease progression and improve treatment outcomes.”

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 the P value 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.

“This new indication for Cabometyx is an important treatment advance for patients with this aggressive form of liver cancer, a community in need of new therapeutic options,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, said in a statement. “This approval is an important milestone as we continue to explore how Cabometyx may benefit people with difficult-to-treat-cancers beyond renal cell carcinoma. We would like to thank the patients and clinicians who participated in CELESTIAL and to acknowledge the team at the FDA for their continued collaboration during the review of our application.”

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).