Cabozantinib Improves Survival in Advanced Hepatocellular Carcinoma


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Patients with previously treated advanced hepatocellular carcinoma derived a survival benefit from cabozantinib (Cabometyx), in the phase III CELESTIAL trial.1

“Cabozantinib represents a new treatment option for patients with advanced hepatocellular carcinoma after prior systemic anticancer therapy,” Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center, reported at the 2018 Gastrointestinal Cancers Symposium. “Cabozantinib showed a clear evidence of an improvement in survival in the second-line setting, and even beyond the second line in certain patients with exposure to more than sorafenib.”

Cabozantinib is an oral small-molecule inhibitor that targets several tyrosine kinases associated with poor prognosis and the development of resistance to antiangiogenic agents. The drug is currently approved for the treatment of advanced renal cell carcinoma.

CELESTIAL Details

The global, randomized, double-blind, phase III CELESTIAL trial evaluated the benefit of cabozantinib in patients with hepatocellular carcinoma whose disease progressed on prior sorafenib (Nexavar)—the standard of care for advanced disease—or other systemic therapies. Patients were randomly assigned 2:1 ratio to receive 60 mg of cabozantinib orally once daily or placebo. The eligibility criteria restricted entry to patients with a Child-Pugh A score and good performance status. Patients could have received up to two lines of prior systemic therapy, one of which had to be sorafenib.

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The second interim analysis was based on 707 patients; the median age was 64 years, 81% were male, 38% had hepatitis B virus, 22% had hepatitis C virus, 25% were enrolled in Asia, 79% had extrahepatic disease spread, 27% had macrovascular invasion, and 27% had received two prior systemic anticancer regimens.

The CELESTIAL trial met the primary study endpoint, showing an improvement in overall survival with cabozantinib. Median overall survival reached 10.2 months with cabozantinib, compared with 8.0 months with placebo, resulting in a

CABOZANTINIB IN LIVER CANCER

  • The phase III CELESTIAL trial examined the benefit of cabozantinib in patients with advanced hepatocellular carcinoma whose disease had progressed on sorafenib.
  • Cabozantinib improved survival, compared with placebo, with median survival reaching 10.2 months vs 8.0 months
    (HR = 0.76; P = .0049).
  • Median progression-free survival was 5.2 months with cabozantinib vs 1.9 months with placebo
    (HR = 0.44; P < .0001).
  • Among patients who received sorafenib alone and no further treatment (ie, cabozantinib as second-line treatment), median survival was 11.3 vs 7.2 months, respectively (HR = 0.70).

24% reduction in the risk of death (hazard ratio [HR] = 0.76, P = .0049). Cabozantinib also improved progression-free survival, with the median being 5.2 months vs 1.9 months (HR = 0.44, P < .0001). Although objective response rates were “relatively limited,” noted Dr. Abou-Alfa, they were nevertheless improved with cabozantinib (4.0% vs 0.4% [P = .0086]), and stable disease rates were doubled (60% vs 33%), he said.

“An overall survival benefit was evident in most of the subgroups, as was a progression-free survival benefit,” he commented.

When investigators restricted the analysis to patients who had received sorafenib alone and no further treatment, the benefit with cabozantinib was even greater: Median overall survival was extended to 11.3 months, vs 7.2 months with placebo (HR = 0.70, 95% confidence interval [CI] = 0.55–0.88). Median progression-free survival was 5.5 months vs 1.9 months, respectively (HR = 0.40, 95% CI = 0.32–0.50).

Safety Profile

The most common grade 3/4 adverse events seen more frequently in the cabozantinib group included hand-foot syndrome (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase levels (12% vs 7%), fatigue (10% vs 4%), diarrhea (10% vs 2%), asthenia (7% vs 2%), and decreased appetite (6% vs < 1%). Dose reductions

were necessary in 62% of cabozantinib-treated patients, and 16% of that arm discontinued treatment due to an adverse event.

“The safety profile is acceptable [with cabozantinib], with a low rate of discontinuation due to treatment-related adverse events,” stated Dr. Abou-Alfa. ■

DISCLOSURE: Dr. Abou-Alfa reported no conflicts of interest.

REFERENCE

1. Abou-Alfa GK, Meyer T, Cheng A-L, et al: Cabozantinib versus placebo in patients with advanced hepatocellular carcinoma who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. 2018 Gastrointestinal Cancers Symposium. Abstract 207. Presented January 19, 2018.


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