The European Commission (EC) has approved cabozantinib (Cabometyx) for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (Nexavar), according to Ipsen, which develops the multikinase inhibitor with Exelixis.1
The approval is based on findings from the international, placebo-controlled, phase III CELESTIAL trial, in which cabozantinib led to a statistically significant improvement in overall survival (OS) versus placebo in patients with advanced HCC who were previously treated with sorafenib. Results showed that the median OS with cabozantinib was 10.2 months versus 8.0 months for placebo, demonstrating a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.63-0.92; P
“Patients with HCC in Europe can now benefit from a treatment that has, through the CELESTIAL trial, proven effective in prolonging life and delaying disease progression,” Philippe Merle, MD, PhD, hepatology and gastroenterology specialist at La Croix-Rousse Hospital, Lyon, said in a news release. “This is a very encouraging development for liver cancer patients, and provides physicians with a new therapeutic option for this complex disease.”
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.
Additionally, baseline characteristics were balanced between the 2 arms. The median age was 64 years and 82% of patients were male. The baseline etiologies included hepatitis B virus infection (38%) and hepatitis C virus infection (24%). Moreover, three-fourths of patients had extrahepatic spread (78%) and 30% had macrovascular invasion, with 27% of patients having both. One-quarter of patients were enrolled in Asia (25%) and 27% had received 2 prior systemic therapies. The primary endpoint was OS; secondary endpoints were progression-free survival (PFS) and objective response rate (ORR).
Updated results of the CELESTIAL trial were published in the New England Journal of Medicine in July 2018.2
At a second planned interim analysis, the median PFS was 5.2 months with cabozantinib versus 1.9 months with placebo (HR, 0.44; 95% CI, 0.36-0.52; P <.001). The objective response rates were 4% and less than 1%, respectively (P
= .009), and the disease control rate was 64% with cabozantinib and 33% with placebo.
A subgroup analysis of patients who received only prior sorafenib for advanced HCC, the median OS was 11.3 months with cabozantinib versus 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).
Regarding safety, grade 3/4 adverse events were reported in 68% of patients on the cabozantinib arm compared with 36% of those who received placebo. The most common high-grade events were palmar-plantar erythrodysesthesia (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase level (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%), with cabozantinib and placebo, respectively.
In May 2018, the FDA accepted a supplemental new drug application for cabozantinib as a treatment for patients with previously treated advanced HCC. Under the Prescription Drug User Fee Act, the FDA will decide on the application by January 14, 2019.
“Today’s EC approval for the use of Cabometyx provides a much needed new option for HCC patients. Until now, physicians in Europe had only one approved therapy for the second-line treatment of this aggressive and difficult-to-treat cancer. We are proud to offer Cabometyx as an innovative treatment that has been shown to extend survival in previously treated patients with HCC,”Harout Semerjian, chief commercial officer of Ipsen, said in a statement. “This new indication reinforces Ipsen’s commitment to improve patients’ lives through the expansion of the clinical benefit of Cabometyx in the treatment of solid tumors.”
Cabozantinib was initially approved by the FDA as a treatment for patients with medullary thyroid cancer in 2012. In April 2016, the multikinase inhibitor was granted an indication as a treatment for patients with advanced renal cell carcinoma (RCC) following one prior antiangiogenic therapy; it received this indication in the European Union in September 2016. This approval was further expanded in December 2017 to include the treatment of patients with advanced RCC in the frontline setting, followed by the EC to grant the same approval in May 2018.
- European Commission approves Ipsen’s Cabometyx® (cabozantinib) for the treatment of hepatocellular carcinoma in adults previously treated with sorafenib. Ipsen. Published November 15, 2018.Accessed November 15, 2018. https://bit.ly/2PtjvDH.
- Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Eng J Med. 2018;379:54-63. doi: 10.1056/NEJMoa1717002.