Cabozantinib vs Placebo in Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib
As reported in The New England Journal of Medicine by Abou-Alfa and colleagues, the second interim analysis of the phase III CELESTIAL trial has shown a significant improvement in overall and progression-free survival with cabozantinib (Cabometyx) vs placebo in patients with sorafenib (Nexavar)-treated advanced hepatocellular carcinoma. Cabozantinib is an inhibitor of VEGFR-1, - 2, and -3, MET, and AXL kinases, which are associated with progressive disease and sorafenib resistance.
In the double-blind trial, 773 patients from 95 sites in 19 countries were randomized 2:1 between September 2013 and September 2017 to receive cabozantinib at 60 mg once daily or placebo. The primary endpoint was overall survival in the intent-to-treat population. At data cutoff for the second interim analysis of overall survival in June 2017, a total of 707 patients had been randomized to cabozantinib (n = 470) or placebo (n = 237).
Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and could have received up to two previous systemic regimens for advanced disease. Patients had to have Child–Pugh class A liver function. Randomization was stratified by etiologic factor (hepatitis B virus [HBV] with or without hepatitis C virus [HCV], HCV without HBV, or other); geographic region (Asia or other); and evidence of extrahepatic spread of disease, macrovascular invasion, or both (yes or no).
Survival Outcomes
The second interim analysis occurred after 484 deaths (78% of the 621 deaths planned for the prespecified final analysis). As of data cutoff for the interim analysis, 26% of patients in the cabozantinib group and 33% in the placebo group had received subsequent systemic or local anticancer therapy excluding radiotherapy. A total of 16% of the cabozantinib group and 11% of the placebo group were still receiving study treatment.
Median overall survival was 10.2 months (95% confidence interval [CI] = 9.1–12.0 months) in the cabozantinib group vs 8.0 months (95% CI = 6.8–9.4 months) in the placebo group (stratified hazard ratio [HR] = 0.76, P = .005). Kaplan-Meier estimates of overall survival were 72% vs 61% at 6 months, 46% vs 34% at 12 months, 32% vs 18% at 18 months, and 18% vs 13% at 24 months.
In subgroup analysis, median overall survival was 11.3 vs 7.2 months among patients whose only prior systemic therapy was sorafenib (HR = 0.70, 95% CI = 0.55–0.88), 8.6 vs 8.6 months among patients receiving 2 prior systemic therapies (HR = 0.90, 95% CI = 0.63–1.29), 10.9 vs 10.2 months for patients from Asia (HR = 1.01, 95% CI = 0.68–1.48), and 10.2 vs 7.8 months for patients from other regions (HR = 0.71, 95% CI = 0.57–0.88).
Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (HR = 0.44, P < .001), including 5.5 vs 1.9 months among patients who had received only sorafenib (HR = 0.40, 95% CI = 0.32–0.50) and 3.7 vs 1.9 months among those receiving 2 prior therapies (HR = 0.58, 95% CI =0.41–0.83). Objective response rates were 4% vs < 1% (P = .009).
Adverse Events
Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group vs 36% in the placebo group, with the most common being palmar–plantar erythrodysesthesia (17% vs 0%), hypertension (16% vs 2%), increased aspartate transaminase (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%). Serious adverse events were reported in 50% of the cabozantinib group vs 37% of the placebo group. Adverse events leading to death that were considered related to study treatment occurred in 6 patients in the cabozantinib group (1 event each of hepatic failure, bronchoesophageal fistula, portal-vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism, and hepatorenal syndrome) and in 1 patient in the placebo group (hepatic failure).
The investigators concluded, “Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group.”
The study was funded by Exelixis.
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