Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma

BACKGROUND: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. 

METHODS: We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary endpoint was progression-free survival. Secondary efficacy endpoints were overall survival and objective response rate.

RESULTS: Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus.

CONCLUSIONS: Progression-free survival was longer with cabozantinib than with everolimus among patients with renal cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.)

N Engl J Med. 2015, September 25 [Epub ahead of print]

Toni K. Choueiri, MD,1 Bernard Escudier, MD,2 Thomas Powles, MD,3 Paul N. Mainwaring, MD,4 Brian I. Rini, MD,5 Frede Donskov, MD, PhD,6 Hans Hammers, MD, PhD,7 Thomas E. Hutson, DO, PharmD,8 Jae-Lyun Lee, MD, PhD,9 Katriina Peltola, MD, PhD,11 Bruce J. Roth, MD,12 Georg A. Bjarnason, MD,13 Lajos Géczi, MD, PhD,15 Bhumsuk Keam, MD, PhD,10 Pablo Maroto, MD,16 Daniel Y.C. Heng, MD, MPH,14 Manuela Schmidinger, MD,17 Philip W. Kantoff, MD,1 Anne Borgman-Hagey, MD,18 Colin Hessel, MS,18 Christian Scheffold, MD, PhD,18 Gisela M. Schwab, MD,18 Nizar M. Tannir, MD,19 and Robert J. Motzer, MD20

1. Dana–Farber Cancer Institute, Boston, Massachusetts
2. Institut Gustave Roussy, Villejuif, France
3. Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London, United Kingdom
4. Icon Cancer Care, South Brisbane, QLD, Australia
5. Cleveland Clinic, Cleveland, Ohio
6. Aarhus University Hospital, Aarhus, Denmark
7. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
8. Texas Oncology–Charles A. Sammons Cancer Center, Baylor University, Dallas, Texas
9. University of Ulsan College of Medicine, Seoul, South Korea
10. Seoul National University Hospital, Seoul, South Korea
11. Helsinki University Central Hospital Cancer Center, Helsinki, Finland
12. Washington University in St. Louis, St. Louis, Missouri
13. Sunnybrook Odette Cancer Centre, Toronto, Canada
14. Tom Baker Cancer Centre, Calgary, Alberta, Canada
15. National Institute of Oncology, Budapest, Hungary
16. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
17. Medical University of Vienna, Vienna, Austria
18. Exelixis, South San Francisco, California
19. University of Texas M.D. Anderson Cancer Center, Houston, Texas
20. Memorial Sloan Kettering Cancer Center, New York, New York

N Engl J Med 2015; 373:1814-1823 DOI: 10.1056/NEJMoa1510016
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