Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial.
BACKGROUND
Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis.


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. This trial is registered with ClinicalTrials.gov, number NCT01865747.


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
Exelixis Inc.
Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: toni_choueiri@dfci.harvard.edu.
Toni K
TK
Choueiri
Institut Gustave Roussy, Villejuif, France.
Bernard
B
Escudier
Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London, UK.
Thomas
T
Powles
University of Texas, MD Anderson Cancer Center Hospital, Houston, TX, USA.
Nizar M
NM
Tannir
Icon Cancer Care, Brisbane, Queensland, Australia.
Paul N
PN
Mainwaring
Cleveland Clinic Foundation, Cleveland, OH, USA.
Brian I
BI
Rini
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
Hans J
HJ
Hammers
Aarhus University Hospital, Aarhus, Denmark.
Frede
F
Donskov
Washington University in St Louis, St Louis, MO, USA.
Bruce J
BJ
Roth
Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
Katriina
K
Peltola
Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Jae Lyun
JL
Lee
Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada.
Daniel Y C
DYC
Heng
Medical University of Vienna, Vienna, Austria.
Manuela
M
Schmidinger
Huntsman Cancer Institute at The University of Utah, Salt Lake City, Utah.
Neeraj
N
Agarwal
San Camillo and Forlanini Hospitals, Rome, Italy.
Cora N
CN
Sternberg
Beth Israel Deaconess Medical Center, Boston, MA, USA.
David F
DF
McDermott
Exelixis, South San Francisco, CA, USA.
Dana T
DT
Aftab
Exelixis, South San Francisco, CA, USA.
Colin
C
Hessel
Exelixis, South San Francisco, CA, USA.
Christian
C
Scheffold
Exelixis, South San Francisco, CA, USA.
Gisela
G
Schwab
Texas Oncology-Baylor Sammons Cancer Center, Dallas, TX, USA.
Thomas E
TE
Hutson
City of Hope National Medical Center, Duarte, CA, USA.
Sumanta
S
Pal
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Robert J
RJ
Motzer
D000368:Aged; D000813:Anilides / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000401:mortality* / Q000556:secondary; D000068338:Everolimus / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011725:Pyridines / Q000008:administration & dosage; D015996:Survival Rate
D000813:Anilides; D011725:Pyridines; C558660:cabozantinib; D000068338:Everolimus