Toni K Choueiri1, Bernard Escudier, Thomas Powles, Paul N Mainwaring, Brian I Rini, Frede Donskov, Hans Hammers, Thomas E Hutson, Jae-Lyun Lee, Katriina Peltola, Bruce J Roth, Georg A Bjarnason, Lajos Géczi, Bhumsuk Keam, Pablo Maroto, Daniel Y C Heng, Manuela Schmidinger, Philip W Kantoff, Anne Borgman-Hagey, Colin Hessel, Christian Scheffold, Gisela M Schwab, Nizar M Tannir, Robert J Motzer. 1. From the Dana-Farber Cancer Institute, Boston (T.K.C., P.W.K.); Institut Gustave Roussy, Villejuif, France (B.E.); Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London (T.P.); Icon Cancer Care, South Brisbane, QLD, Australia (P.N.M.); Cleveland Clinic, Cleveland (B.I.R.); Aarhus University Hospital, Aarhus, Denmark (F.D.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (H.H.); Texas Oncology-Charles A. Sammons Cancer Center, Baylor University, Dallas (T.E.H.); University of Ulsan College of Medicine (J.-L.L.) and Seoul National University Hospital (B.K.) - both in Seoul, South Korea; Helsinki University Central Hospital Cancer Center, Helsinki (K.P.); Washington University in St. Louis, St. Louis (B.J.R.); Sunnybrook Odette Cancer Centre, Toronto (G.A.B.), and Tom Baker Cancer Centre, Calgary, AB (D.Y.C.H.) - both in Canada; National Institute of Oncology, Budapest, Hungary (L.G.); Hospital de la Santa Creu i Sant Pau, Barcelona (P.M.); Medical University of Vienna, Vienna (M.S.); Exelixis, South San Francisco, CA (A.B-H., C.H., C.S., G.M.S.); University of Texas M.D. Anderson Cancer Center, Houston (N.M.T.); and the Memorial Sloan Kettering Cancer Center, New York (R.J.M.).
Abstract
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 end point was progression-free survival. Secondary efficacy end points 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.).
RCT Entities:
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 end point was progression-free survival. Secondary efficacy end points 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.).
Authors: Robert J Motzer; Thomas E Hutson; Piotr Tomczak; M Dror Michaelson; Ronald M Bukowski; Olivier Rixe; Stéphane Oudard; Sylvie Negrier; Cezary Szczylik; Sindy T Kim; Isan Chen; Paul W Bycott; Charles M Baum; Robert A Figlin Journal: N Engl J Med Date: 2007-01-11 Impact factor: 91.245
Authors: F Michael Yakes; Jason Chen; Jenny Tan; Kyoko Yamaguchi; Yongchang Shi; Peiwen Yu; Fawn Qian; Felix Chu; Frauke Bentzien; Belinda Cancilla; Jessica Orf; Andrew You; A Douglas Laird; Stefan Engst; Lillian Lee; Justin Lesch; Yu-Chien Chou; Alison H Joly Journal: Mol Cancer Ther Date: 2011-09-16 Impact factor: 6.261
Authors: Robert J Motzer; Bernard Escudier; Stephane Oudard; Thomas E Hutson; Camillo Porta; Sergio Bracarda; Viktor Grünwald; John A Thompson; Robert A Figlin; Norbert Hollaender; Andrea Kay; Alain Ravaud Journal: Cancer Date: 2010-09-15 Impact factor: 6.860
Authors: Erinn B Rankin; Katherine C Fuh; Laura Castellini; Kartik Viswanathan; Elizabeth C Finger; Anh N Diep; Edward L LaGory; Mihalis S Kariolis; Andy Chan; David Lindgren; Håkan Axelson; Yu R Miao; Adam J Krieg; Amato J Giaccia Journal: Proc Natl Acad Sci U S A Date: 2014-09-03 Impact factor: 11.205
Authors: Thomas E Hutson; Bernard Escudier; Emilio Esteban; Georg A Bjarnason; Ho Yeong Lim; Kenneth B Pittman; Peggy Senico; Andreas Niethammer; Dongrui Ray Lu; Subramanian Hariharan; Robert J Motzer Journal: J Clin Oncol Date: 2013-12-02 Impact factor: 44.544
Authors: Robert J Motzer; Jennifer Bacik; Lawrence H Schwartz; Victor Reuter; Paul Russo; Stephanie Marion; Madhu Mazumdar Journal: J Clin Oncol Date: 2004-02-01 Impact factor: 44.544
Authors: Barbara Sennino; Toshina Ishiguro-Oonuma; Ying Wei; Ryan M Naylor; Casey W Williamson; Vikash Bhagwandin; Sebastien P Tabruyn; Weon-Kyoo You; Harold A Chapman; James G Christensen; Dana T Aftab; Donald M McDonald Journal: Cancer Discov Date: 2012-02-24 Impact factor: 39.397
Authors: Don S Dizon; Lada Krilov; Ezra Cohen; Tara Gangadhar; Patricia A Ganz; Thomas A Hensing; Stephen Hunger; Smitha S Krishnamurthi; Andrew B Lassman; Merry Jennifer Markham; Erica Mayer; Michael Neuss; Sumanta Kumar Pal; Lisa C Richardson; Richard Schilsky; Gary K Schwartz; David R Spriggs; Miguel Angel Villalona-Calero; Gina Villani; Gregory Masters Journal: J Clin Oncol Date: 2016-02-04 Impact factor: 44.544
Authors: Xin Gao; Opeyemi Jegede; Connor Gray; Paul J Catalano; Jesse Novak; David J Kwiatkowski; Rana R McKay; Daniel J George; Toni K Choueiri; David F McDermott; Sabina Signoretti; Rupal S Bhatt Journal: Clin Genitourin Cancer Date: 2018-04-25 Impact factor: 2.872
Authors: Luciana de M Leite; Paulo G Bergerot; Aldo L A Dettino; José Augusto R; Stenio de C Zequi; Maria Nirvana da C Formiga Journal: Int Braz J Urol Date: 2021 May-Jun Impact factor: 1.541
Authors: Toni K Choueiri; Sabina Signoretti; Abdallah Flaifel; Wanling Xie; David A Braun; Miriam Ficial; Ziad Bakouny; Amin H Nassar; Rebecca B Jennings; Bernard Escudier; Daniel J George; Robert J Motzer; Michael J Morris; Thomas Powles; Evelyn Wang; Ying Huang; Gordon J Freeman Journal: Clin Cancer Res Date: 2019-08-01 Impact factor: 12.531