Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma
By G. Abou-Alfa, T. Meyer, A. Cheng, A. El-Khoueiry, L. Rimassa, B. Ryoo, I. Çiçin, P. Merle, Yen-Chang Chen, Joong-Won Park and 12 more. New England Journal of Medicine, 2018
1,996 citations recorded by the source corpus.
BACKGROUND Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double‐blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. METHODS A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression‐free survival and the objective response rate. RESULTS At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression‐free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high‐grade events were palmar–plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). CONCLUSIONS 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. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426.)
Subfields: Hepatology, Immunology
View Paper: https://www.semanticscholar.org/paper/b1a98011f64b9be677181d98e284a377062d0e94
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In Hepatology
Citations in the corpus
- Angiogenic signaling pathways and anti-angiogenic therapy for cancer (2023, background): “Up to now, cabozantinib has been ratified for several most common angiogenic carcinomas (NCT01908426, NCT01865747).(431,432) A randomized and open-label phase III clinical trial has shown that combination of immune checkpoint inhibitors with cabozantinib significantly improved the OS and PFS rates o”
- Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy (2023, background): “In patients with disease progression on sorafenib, the multikinase inhibitors regorafenib 180 and cabozantinib 181 , as well as the anti-VEGFR2 monoclonal antibody ramucirumab have each been demonstrated to improve OS relative to placebo in phase III trials, although the benefit of ramucirumab was…”
- Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. (2019, background): “All of these are antiangiogenic agents, including tyrosine kinase inhibitors lenvatinib in the first-line setting and regorafenib, cabozantinib, and the monoclonal antibody ramucirumab in the second-line setting after prior sorafenib therapy.(3-6)”
- AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma (2023, neutral): “[314] OS was significantly improved versus placebo (10.2 vs. 8.0 mo), as were PFS and ORR.”