METHODS: In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation.
FINDINGS: Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p<0·0001) and objective response (17% [13–22] with cabozantinib vs 3% [2–6] with everolimus; p<0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration).
INTERPRETATION: Treatment with cabozantinib increased overall survival delayed disease progression and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications.
FUNDING: Exelixis Inc.
This trial is registered with ClinicalTrials.gov, number NCT01865747.
Lancet. 2016, June 05 [Epub ahead of print]
Toni K Choueiri, MD,1 Bernard Escudier, MD,2 Thomas Powles,MD,3 Nizar M Tannir, MD,4 Paul N Mainwaring, MD,5 Brian I Rini, MD,6 Hans J Hammers, MD,7 Frede Donskov, MD,8 Bruce J Roth, MD,9 Katriina Peltola, MD,10 Jae Lyun Lee, MD,11 Daniel Y C Heng, MD,12 Manuela Schmidinger, MD,13 Neeraj Agarwal, MD,14 Cora N Sternberg, MD,15 David F McDermott, MD,16 Dana T Aftab, PhD,17 Colin Hessel, MS,17 Christian Scheffold, MD,17 Gisela Schwab, MD,17 Thomas E Hutson, DO,18 Sumanta Pal, MD,19 Robert J Motzer, MD20 for the METEOR investigators
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. 19. University of Texas M.D. Anderson Cancer Center, Houston, Texas
5. Icon Cancer Care, South Brisbane, QLD, Australia
6. Cleveland Clinic, Cleveland, Ohio
7. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
8. Aarhus University Hospital, Aarhus, Denmark
9. Washington University in St. Louis, St. Louis, Missouri
10. Helsinki University Central Hospital Cancer Center, Helsinki, Finland
11. Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
12. Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada
13. Medical University of Vienna, Vienna, Austria
14. Huntsman Cancer Institute at The University of Utah, Salt Lake City, Utah
15. San Camillo and Forlanini Hospitals, Rome, Italy
16. Beth Israel Deaconess Medical Center, Boston, Massachusetts
17. Exelixis, South San Francisco, California
The 18. Texas Oncology–Baylor Sammons Cancer Center, Dallas, Texas
19. City of Hope National Medical Center, Duarte, California
20. Memorial Sloan Kettering Cancer Center, New York, New York
The Lancet, DOI:https://doi.org/10.1016/S1470-2045(16)30107-3