Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373: DOI: /NEJMoa

2 SUPPLEMENTARY APPENDIX Choueiri, T. K., Escudier, B., Powles, T., et al. Cabozantinib versus everolimus in advanced renal cell carcinoma. Table of Contents Study Investigators Pg. 2 Others Involved in METEOR Study Conduct Pg. 3 Figure S1 - Patients, Randomization, and Treatment (Overall Survival Population) Pg. 4 Figure S2 - Patients, Randomization, and Treatment (Progression-free Survival Population) Pg. 5 Figure S3 - Kaplan-Meier Estimates of Investigator-assessed Progression-free Survival Pg. 6 Figure S4 - Progression-free Survival in Subgroups (Independent Radiology Review Committee) Pg. 7 Table S1 - Memorial Sloan-Kettering Cancer Center (MSKCC) Prognostic Criteria for Previously Treated Patients with Renal Cell Carcinoma Pg. 8 Table S2 - Tumor Response by Independent Review Committee (PFS Population) Pg. 9 Table S3 - Subsequent Anticancer Therapy (Overall Survival Population) Pg. 10 Table S4 - Summary of Dose Reduction and Discontinuation (Safety Population) Pg. 11 References Cited in the Supplemental Appendix Pg P a g e

3 Study Investigators The following investigators enrolled patients in METEOR: Australia H. Tan, E. Hovey, P. Mainwaring, C. Steer, G. Marx, P. desouza, I. Davis, S. Begbie, L. Nott, D. Pook, K. Cuff, R. Epstein, H. Gurney; Austria M. Schmidinger, W. Loidl, M. De Santis; Belgium T. Gil, W. Wynendaele, W. Demey, P. Schöffski; Canada J. Knox, D. Soulieres, P. Czaykowski, N. Basappa, C. Kollmannsberger, G. Bjarnason, L. Wood, P. Zalewski, S. Hotte, D. Heng, E. Winquist; Chile P. Salman, O. Aren Frontera; Czech Republic J. Katolicka, B. Melichar; Denmark N. Jensen, P. Geertsen, F. Donskov; Finland K. Peltola; France B. Escudier, G. Gravis, F. Joly, C. Chevreau, S. Oudard, B. Laguerre, F. Rolland, E. Voog, S. Negrier, T. Maurina, M. Gross Goupil; Germany M. Staehler, D. Pfister, M. Rink, V. Gruenwald, M. Retz, M. Wirth, W. Schultze-Seemann, R. Depenbusch, T. Schnöller, L. Bergmann, C. Gruellich; Hungary T. Csoszi, L. Geczi; Ireland J. McCaffrey, R. McDermott; Italy C. Sternberg, P. Passalacqua, U. De Giorgi, R. Sabbatini, F. Boccardo, F. Carrozza, F. Roila, D. Santini, S. Bracarda; Netherlands J. van Thienen, M. Aarts, S. Osanto; Poland P. Tomczak, J. Pikiel, M. Wojtukiewicz, C. Szczylik; Portugal N. Sousa, J. Passos Coelho, L. Costa; Russia S. Cheporov, E. Kopyltsov, D. Nosov; Slovakia I. Mincik, J. Mikulas; South Korea S. Rha, B. Keam, J. Lee, S. Park; Spain E. Grande, I. Chirivella, X. Garcia del Muro Solans, C. Suarez, I. Duran, D. Castellano, J. Garcia Donas, J. Perez Gracia, A. Martinez, M. Saez Medina, P. Maroto, E. Esteban Gonzalez; Sweden U. Harmenberg, M. Thomasson, R. Blom; Taiwan C. Lin, Y. Chang, Y. Ou; Turkey A. Sevinc, F. Dane, E. Gokmen, R. Yildiz; United Kingdom R. Hawkins, S. Hussain, J. Larkin, P. Nathan, E. Porfiri, J. Malik, A. MacDonald, T. Powles, S. Chowdhury, H. Glen; United States R. Motzer, T. Choueiri, D. Geynisman, H. Kluger, L. Appleman, D. 2 P a g e

4 Shaffer, M. Fishman, J. Hainsworth, G. Sonpavde, H. Drabkin, H. Hammers, D. George, J. Merchan, A. Hussain, A. Koletsky, W. Hanna, M. Troner, U. Vaishampayan, B. Costello, T. Olencki, D. Vaena, B. Redman, B. Rini, W. Stadler, B. Roth, N. Tannir, T. Kuzel, J. Wright, T. Hutson, P. Van Veldhuizen, S. Richey, G. Doshi, J. Sarantopoulos, C. Ryan, W. Samlowski, S. Tykodi, S. Pal, N. Agarwal, F. Kabbinavar, R. Figlin, T. Ho, B. Wong, P. Singh, T. Kolevska, J. Randall. Others Involved in METEOR Study Conduct Members of the METEOR Steering Committee: Toni K. Choueiri, M.D., Bernard Escudier, M.D., Thomas Powles, M.D., and Robert J. Motzer, M.D. Members of the METEOR Independent Data Monitoring Committee: Ronald Bukowski, M.D., Primo N. Lara, Jr., M.D., Ronald de Wit, M.D., Ph.D., and Daniel Sargent, Ph.D. Staff of the sponsor involved in data collection and analyses: Jason Adriani, Alan Arroyo, Mark Dean, Isagani Cornelio, Paul Foster, Alfonso Kondo, James Lenihan, Milan Mangeshkar, Steve Milwee, Mahesh Patel, Margaret Parker, and Jill Youkstetter. 3 P a g e

5 Figure S1. Patients, Randomization, and Treatment (Overall Survival Population) 922 Patients screened 658 Patients randomized 264 Failed screening, primarily for: Brain metastases requiring treatment Inadequate organ or marrow function Uncontrolled or significant illness 330 Allocated to cabozantinib 331 Received cabozantinib 328 Allocated to everolimus 322 Received everolimus 5 Did not receive study drug 1 Received incorrect study drug 198 Discontinued cabozantinib 121 Disease progression per RECIST Adverse event 31 Clinical deterioration 6 Withdrew consent 9 Other 255 Discontinued everolimus 158 Disease progression per RECIST Adverse event 49 Clinical deterioration 11 Withdrew consent 6 Other 133 Continued cabozantinib 67 Continued everolimus 330 analyzed for interim overall survival 331 analyzed for safety 328 analyzed for interim overall survival 322 analyzed for safety 4 P a g e

6 Figure S2. Patients, Randomization, and Treatment (Progression-free Survival Population) First 375 patients randomized 187 Allocated to cabozantinib 188 Allocated to everolimus 187 Received cabozantinib 185 Received everolimus 131 Discontinued cabozantinib 81 Disease progression per RECIST Adverse event 19 Clinical deterioration 3 Withdrew consent 7 Other 152 Discontinued everolimus 92 Disease progression per RECIST Adverse event 29 Clinical deterioration 7 Withdrew consent 4 Other 56 Continued cabozantinib 33 Continued everolimus 187 Analyzed for progression-free survival and response rate 188 Analyzed for progression-free survival and response rate 5 P a g e

7 In v e s tig a to r-a s s e s s e d P r o g re s s io n -fr e e S u r v iv a l (% ) Figure S3. Kaplan-Meier Estimates of Investigator-assessed Progression-free Survival No. of Patients Median Progression-free Survival mo (95% CI) No. of Events Cabozantinib ( ) 133 Everolimus ( ) 142 Hazard ratio for progression or death, 0.61 (95% CI ) P< C a b o z a n tin ib 1 0 E v e ro lim u s M o n th s No. at Risk Cabozantinib Everolimus P a g e

8 Figure S4. Progression-free Survival in Subgroups (Independent Radiology Review Committee) Subgroup Cabozantinib Everolimus Hazard Ratio (95% CI) no. of patients (events) All patients 187 (121) 188 (126) 0.58 (0.45, 0.75) Prior VEGFR TKIs (87) 136 (95) 0.56 (0.42, 0.75) >2 50 (34) 52 (31) 0.67 (0.41, 1.10) MSKCC risk group Favorable 80 (51) 83 (56) 0.54 (0.37, 0.79) Intermediate 80 (49) 75 (47) 0.56 (0.37, 0.84) Poor 27 (21) 30 (23) 0.84 (0.46, 1.53) C a b o z a n t in ib B e t t e r E v e r o lim u s B e t t e r 7 P a g e

9 Table S1. Memorial Sloan-Kettering Cancer Center (MSKCC) Prognostic Criteria for Previously Treated Patients with Renal Cell Carcinoma 1 No. of Risk Factors* Expected Outcome 0 Favorable 1 Intermediate 2 or 3 Poor *The three risk factors are: Karnofsky performance status score < 80% Hemoglobin < 13 g/dl for males or < 11.5 g/dl for females Corrected calcium > upper limit of normal 8 P a g e

10 Table S2. Tumor Response by Independent Radiology Review Committee (PFS Population) Variable Cabozantinib (N = 187) Everolimus (N = 188) n (%) Objective response rate a 40 (21) ***,b 9 (5) c Complete response 0 0 Partial response 40 (21) 9 (5) Stable disease 116 (62) 116 (62) Progressive disease 26 (14) 51 (27) Not evaluable or missing 5 (3) 12 (6) a Confirmed complete and partial responses b 95% CI, 16% to 28% c 95% CI, 2% to 9% *** P < compared to everolimus (Cochran-Mantel-Haenszel test) 9 P a g e

11 Table S3. Subsequent Anticancer Therapy (Overall Survival Population) Subsequent Treatment Cabozantinib (N = 330) Everolimus (N = 328) n (%) Systemic therapy 126 (38) 155 (47) Tyrosine kinase inhibitors 52 (16) 131 (40) Axitinib 36 (11) 74 (23) Pazopanib 3 (1) 17 (5) Sorafenib 5 (2) 23 (7) Sunitinib 10 (3) 23 (7) Cabozantinib 0 5 (2) Everolimus 75 (23) 13 (4) Temsirolimus 5 (2) 4 (1) Bevacizumab 5 (2) 8 (2) Chemotherapy 9 (3) 5 (2) Interferon/Interleukin 3 (1) 9 (3) PD-1/PD-L1 Inhibitor 1 (<1) 2 (<1) Other 7 (2) 8 (2) External beam radiotherapy 41 (12) 69 (21) Surgery (tumor lesions) 12 (4) 8 (2) 10 P a g e

12 Table S4. Summary of Dose Reduction and Discontinuation (Safety Population) Dose Reduction or Discontinuation of Study Treatment Cabozantinib (N = 331) n (%) Everolimus (N = 322) Experienced 1 dose reduction 197 (60) 79 (25) Experienced first-level dose reduction 193 (58) 77 (24) Experienced second-level dose reduction 65 (20) 5 (2) Discontinued due to adverse event 31 (9) 31 (10) 11 P a g e

13 References Cited in the Supplemental Appendix 1) Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22: P a g e