Ghassan Abou-Alfa, MD
Treatment with cabozantinib (Cabometyx) improved median overall survival (OS) by 2.2 months compared with placebo for patients with previously treated advanced hepatocellular carcinoma (HCC), according to findings from the phase III CELESTIAL trial released ahead of the 2018 Gastrointestinal Cancers Symposium.
In the double-blind trial, median OS with cabozantinib was 10.2 months compared with 8.0 months with placebo, representing a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.63-0.92; P
= .0049). The median progression-free survival (PFS) with cabozantinib 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
Based on findings from the CELESTIAL trial, Exelixis, the company developing the multikinase inhibitor, plans to submit a supplemental new drug application to the FDA before the end of the first quarter. The agent is already approved as a treatment for patients with renal cell carcinoma and medullary thyroid cancer.
“Patients with advanced hepatocellular carcinoma often have a poor prognosis and limited treatment options following prior systemic therapy,” lead investigator Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, said in a statement. “The clinically significant benefits in both overall survival and progression-free survival shown in the CELESTIAL trial suggest that, if approved, cabozantinib could become an important addition to the treatment landscape for these patients.”
In the CELESTIAL trial, 707 patients were randomized in a 2:1 ratio 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). Patients were stratified based on etiology of disease, geographic region, and the presence of extrahepatic spread (EHS) and/or macrovascular invasion (MVI).
Baseline characteristics were balanced between the arms. Overall, 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 EHS (78%) and 30% had MVI, with 27% of patients having both. A quarter of patients were enrolled in Asia (25%) and 27% had received 2 prior systemic therapies.
By RECIST 1.1 criteria, 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 AEs with cabozantinib (16%) versus placebo (3%). The most common grade 3/4 adverse events (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.
“We are excited by the potential benefit cabozantinib may offer to patients with previously treated advanced hepatocellular carcinoma,” Gisela Schwab, MD, president, Product Development and Medical Affairs and chief medical officer, Exelixis, said in a statement. “Given the worldwide prevalence of advanced hepatocellular carcinoma, there is a continued urgency to bring new treatment options to this patient population. We look forward to submitting our supplemental new drug application to the FDA for cabozantinib in the first quarter of 2018, and to further advancing our mission to help cancer patients recover stronger and live longer.”
In October 2017, Exelixis announced that an independent monitoring committee had recommended stopping the study for efficacy following review of the second planned interim analysis. A stoppage was planned if the P
value for OS reached ≤.021. Prior to this event, cabozantinib had received an orphan drug designation for advanced HCC, which is granted by the FDA for treatments intended for disease with fewer than 200,000 annual diagnoses.
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).
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