CELESTIAL Results May Lead to Cabozantinib Approval in Second-Line HCC

CELESTIAL Results May Lead to Cabozantinib Approval in Second-Line HCC

Dr. Ghassan K. Abou-Alfa presents Abstract 207 during Oral Abstract Session B
The phase III CELESTIAL trial met its primary endpoint by demonstrating a survival advantage with cabozantinib in patients with advanced hepatocellular carcinoma (HCC) that progressed following prior systemic therapy (Abstract 207). Other outcomes included improvements in progression-free survival (PFS) and objective response rate (ORR), as well as an acceptable safety profile, thus positioning cabozantinib for potential approval in the second-line setting in HCC.

“Cabozantinib represents a new treatment option for patients with advanced HCC after prior systemic anticancer therapy,” Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center, said.

Cabozantinib is an oral small-molecule inhibitor that targets several tyrosine kinases including VEGFR, MET, and AXL, each of which has been tied to a poor HCC prognosis and the development of resistance to antiangiogenic agents. Cabozantinib is currently approved for the treatment of advanced renal cell carcinoma.

The global, randomized, double-blind, phase III CELESTIAL trial was designed to evaluate whether cabozantinib could confer benefit to patients with HCC progression following prior sorafenib—the standard of care for advanced disease—or other systemic therapies. Toward this end, previously treated patients with advanced HCC were first stratified by disease etiology (HBV, HCV, other), geographic region (Asia, other), and the presence of extrahepatic spread and/or macrovascular invasion (yes, no) before being randomly assigned in a 2:1 ratio to receive 60 mg of cabozantinib orally once daily or matched placebo. Treatment was continued until loss of clinical benefit or intolerable toxicity, and no crossover was permitted.

The eligibility criteria restricted entry to patients with a Child-Pugh A score and an Eastern Cooperative Oncology Group performance status of 0 or 1. Moreover, patients could have received up to two lines of prior systemic therapy for HCC, one of which had to be sorafenib.

Although 773 patients were enrolled in CELESTIAL from September 2013 through September 2017, the current data, based on the second interim analysis, reflect data for 707 patients who were randomly selected. These individuals had a median age of 64 years, 81% were male, 38% had HBV, 22% had HCV, 25% enrolled in Asia, 79% had extrahepatic spread, 27% had macrovascular invasion, and 27% had received two prior systemic anticancer regimens for advanced HCC.

CELESTIAL met the primary study endpoint at the second planned interim analysis. Median overall survival (OS) reached 10.2 months with cabozantinib versus 8.0 months with placebo, resulting in a 24% reduction in the risk of death (HR 0.76, 95% CI [0.63, 0.92]; p = 0.0049). Cabozantinib also excelled over placebo for PFS (median: 5.2 vs. 1.9; HR 0.44, 95% CI [0.36, 0.52]; p < 0.0001) and ORR (4.0% vs. 0.4%; p = 0.0086).

Cabozantinib benefits improved, particularly the OS benefit, when the data analyses were restricted to patients who had received sorafenib as the only prior therapy for advanced HCC. Among these individuals, median OS was pushed out another month and reached 11.3 months with cabozantinib versus 7.2 months with placebo (HR 0.70, 95% CI [0.55, 0.88]). Median PFS was 5.5 months with cabozantinib and 1.9 months with placebo (HR 0.40, 95% CI [0.32, 0.50]).

The safety profile of cabozantinib appeared to be acceptable and did not yield any unexpected signals. The most common grade 3/4 adverse events that occurred more frequently in the cabozantinib arm than the placebo arm included hand-foot skin reaction (17% vs. 0%), hypertension (16% vs. 2%), increased aspartate aminotransferase (12% vs. 7%), fatigue (10% vs. 4%), diarrhea (10% vs. 2%), asthenia (7% vs. 2%), and decreased appetite (6% vs. < 1%).

Dose reductions were common in the cabozantinib arm (occurring in 62%) in order to adjust the dose to individual patient tolerability. With this approach, 16% of patients discontinued cabozantinib because of treatment-related adverse events, as compared with 3% of patients receiving placebo.

Discussant Jordi Bruix, MD, PhD, of the University of Barcelona, in Spain, noted that the CELESTIAL results illustrate that cabozantinib provides a clinically meaningful survival benefit to patients with advanced HCC who have exhausted use of sorafenib.

However, Dr. Bruix observed that the median duration of exposure to cabozantinib was 3.8 months whereas the median PFS was 5.5 months, making him suspect that something led to treatment interruption in many individuals. “This is something that I would like to see better explored when talking about adverse events and management to understand to what extent the drug is safe and can be managed,” he said.

Dr. Bruix also remarked that nearly all of the systemic therapies that prove useful in advanced HCC—sorafenib, lenvatinib, regorafenib, and now cabozantinib—target the VEGF pathway. Patients who cannot receive anti-VEGF agents are still in need of effective treatments that have been shown to prolong survival based on data from phase III trials.

– Kara Nyberg, PhD