Background For the past twenty years, cytoreductive nephrectomy has - PowerPoint PPT Presentation

CARMENA : Cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma (mRCC) - Results of a phase III non-inferiority trial. (NCT00930033) Arnaud Méjean, Alain Ravaud, Simon Thezenas, Sandra Colas, Jean-Baptiste Beauval, Karim Bensalah, Lionnel Geoffrois, Antoine Thiery-Vuillemin, Luc Cormier, Hervé Lang, Laurent Guy, Gwenaelle Gravis, Frederic Rolland, Claude Linassier, Eric Lechevallier, Christian Beisland, Michael Aitchison, Stephane Oudard, Jean-Jacques Patard, Christine Theodore, Christine Chevreau, Brigitte Laguerre, Jacques Hubert, Marine Gross-Goupil, Jean-Christophe Bernhard, Laurence Albiges, Marc-Olivier Timsit, Thierry Lebret, Bernard Escudier On Behalf of Carmena investigators 1 Arnaud Méjean

Background • For the past twenty years, cytoreductive nephrectomy has been the standard of care in mRCC • Randomized studies have demonstrated a benefit vs cytokine therapy alone 1,2 • Many targeted therapies have demonstrated efficacy in treating mRCC, 3 but there is no direct comparison with nephrectomy • Retrospective studies and meta-analyses have suggested a benefit for nephrectomy 4,5 mRCC, metastatic renal cell carcinoma 1. Flanigan R, et al. N Engl J Med 2001;345:1655. 2. Mickish G, et al. Lancet 2001;358:966. 3. Bamias A, et al. Oncologist 2017;22:667. 4. Garcia-Perdomo H, et al. Investig Clin Urol 2018;59:2. 5. Bhindi B, et al. J Urol 2018; doi: 10.1016/j.juro.2018.03.077. 2 Arnaud Méjean

(IMDC) retrospective database study found better survival in patients given nephrectomy… 3245 mRCC patients 2569 (79%) patients with nephrectomy EXCLUDED 1587 (49%) with nephrectomy prior to metastases 676/1658 (41%) 982/1658 (59%) No nephrectomy Nephrectomy FINAL NUMBERS IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; mRCC, metastatic renal cell carcinoma Heng D, et al, Eur Urol 2014;66:704. 3 Arnaud Méjean

(IMDC) retrospective database study found better survival in patients given nephrectomy… 3245 mRCC patients Nephrectomy No Nephrectomy 2569 (79%) Overall Survival patients with But only for patients with nephrectomy 1, 2 or 3 IMDC risk factors EXCLUDED 1587 (49%) with nephrectomy prior to metastases 676/1658 (41%) 982/1658 (59%) No nephrectomy Nephrectomy FINAL NUMBERS Months Since Initiation of Targeted Therapy IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; mRCC, metastatic renal cell carcinoma Heng D, et al, Eur Urol 2014;66:704. 4 Arnaud Méjean

Case 1: RCC PS 0 Small metastatic tumor burden Nephrectomy makes sense RCC, Renal cell carcinoma PS, performance status 5 Arnaud Méjean

Case 2: RCC PS 2 High metastatic tumor burden Nephrectomy does not make sense RCC, Renal cell carcinoma PS, performance status 6 Arnaud Méjean

Case 3: RCC PS 0 - 1 Limited metastatic tumor burden Who knows if nephrectomy is useful ? RCC, Renal cell carcinoma PS, performance status 7 Arnaud Méjean

In the era of targeted therapy, is cytoreductive nephrectomy still necessary ? 8 Arnaud Méjean

CARMENA: Prospective, multicenter, open-label, randomized, phase 3 non-inferiority study Arm A • Confirmed metastatic 3 – 6 Sunitinib clear cell RCC / Biopsy nephrectomy weeks 50 mg QD 4 wks on / 2 wks off ECOG-PS 0-1 • • Amenable to nephrectomy R • Eligible for sunitinib 1:1 Brain metastases • Arm B absent/controlled by Stratification treatment Sunitinib • MSKCC risk group No prior systemic therapy • • Center location 50 mg QD 4 wks on / 2 wks off for RCC Primary endpoint: Secondary endpoints: Overall survival Progression-free survival, objective response rate, clinical benefit, safety LPI, last patient included; MSKCC, Memorial Sloan Kettering Cancer Center; QD, once daily; R, randomization; RCC, renal cell carcinoma 9 Arnaud Méjean

Statistical hypothesis : non inferiority design • The study was designed to have 80% power at a 1-sided significance level of 5% (risk alpha) • Non-inferiority margin of HR: upper 95 % CI ≤ 1.20 for sunitinib alone • Enrolment of 576 patients needed to observe 456 events for demonstration of non-inferiority • Two interim analyses were planned (after 152 and 302 events) • Monitored by independent DSMB CI, confidence interval; HR, hazard ratio 1 Arnaud Méjean 0

Study conduct • From Sept. 2009 to Sept. 2017, 450 patients were enrolled • Second interim analysis, cutoff Sept. 9, 2017: 326 events had occurred • Median follow-up 50.9 months • Based on overall survival results, the Steering Committee decided to stop the trial and considered this interim analysis as final 1 Arnaud Méjean 1

Patient disposition 450 patients randomized Arm A: Nephrectomy + sunitinib Arm B: Sunitinib alone (n=226) (n=224) 6 inclusion criteria deviation 8 inclusion criteria deviation 40 did not receive sunitinib 11 did not receive sunitinib Safety population Safety population Arm B: Sunitinib alone (213) Arm A: Nephrectomy + sunitinib (186) 38 received secondary 3 withdrawal of consent nephrectomy , including 3 not 16 not operated treated with sunitinib 165 deaths 161 deaths 2 lost to follow up 2 lost to follow up Data cutoff : September 9, 2017 ITT, intention to treat 1 Arnaud Méjean 2

Patient population 450 patients ITT population randomized Arm A: (n=226) Arm B: (n=224) Nephrectomy (n=205) Sunitinib (n=206) Nephrectomy + sunitinib (n=176) Data cutoff : September 9, 2017 ITT, intention to treat 1 Arnaud Méjean 3

Patient population 450 patients PP1 population randomized Arm A: (n=226) Arm B: (n=224) Nephrectomy (n=205) Sunitinib (n=206) Nephrectomy + sunitinib (n=176) Data cutoff : September 9, 2017 PP1, per protocol 1 Arnaud Méjean 4

Patient population 450 patients PP2 population randomized Arm A: (n=226) Arm B: (n=224) Nephrectomy (n=205) Sunitinib (n=206) Nephrectomy + sunitinib (n=176) Data cutoff : September 9, 2017 PP2 : per protocol 1 Arnaud Méjean 5

Patient characteristics (1) Arm A: Arm B: Characteristic Nephrectomy + sunitinib Sunitinib alone (N = 226) (N = 224) Median age (range), years 63 (33 – 84) 62 (30 – 87) Male sex, n (%) 169 (75) 167 (75) MSKCC score, n (%) Intermediate 125 (56) 131 (59) Poor 100 (44) 93 (41) Missing 1 0 ECOG PS, n (%) 0 130 (57) 122 (54) 1 96 (42) 102 (45) CN, cytoreductive nephrectomy; ECOG PS, Eastern Cooperative Oncology Group performance status; MSKCC, Memorial Sloan Kettering Cancer Center 1 Arnaud Méjean 6

Patient characteristics (2) Arm A: Arm B: Characteristic Nephrectomy + sunitinib Sunitinib alone (N = 226) (N = 224) Median size of primary tumor, mm 88 (6 – 200) 86 (12 – 190) (range) Median number of metastatic sites, n 2 (1 – 5) 2 (1 – 5) (range) Tumor burden* by RECIST v1.1, mm 140 (23 – 399) 144 (39 – 313) (range) Location of metastases, n (%) Lung 172 (79) 161 (73) Bone 78 (36) 82 (37) Lymph nodes 76 (35) 86 (39) Other 78 (36) 90 (40) *Assessed as a combination of primary renal tumour and metastases. RECIST, Response Evaluation Criteria In Solid Tumors 1 Arnaud Méjean 7

Overall Nephrectomy + sunitinib survival (ITT) Sunitinib alone HR 95%CI = 0.89 (0.71 – 1.10) Non inferiority study ≤ 1.20 Median follow-up was 50.9 months (range 0.0 – 86.6) 1 Arnaud Méjean 8

Overall survival (ITT) Median OS, months Arm A: Arm B: HR (95% CI) Nephrectomy + Sunitinib Sunitinib alone (n = 226) (n = 224) (95% CI) Overall 13.9 18.4 0.89 (11.8 – 18.3) (14.7 – 23.0) (0.71 – 1.10) MSKCC intermediate risk 19.0 23.4 0.92 (12.0 – 28.0) (17.0 – 32.0) (0.6 – 1.24) MSKCC poor risk 10.2 13.3 0.86 (9.0 – 14.0) (9.0 – 17.0) (0.62 – 1.17) Non inferiority study ≤ 1.20 1 Arnaud Méjean 9

Overall survival by patient population Arm A Arm B Population HR (95% CI), (Nephrectomy + sunitinib) (Sunitinib) stratified by Median Median MSKCC risk n Events, n (%) (95% CI), n Events, n (%) (95% CI), group months months 13.9 18.4 0.89 ITT 226 165 (73) 224 161 (72) (11.8 – 18.3) (14.7 – 23.0) (0.71 – 1.10) 14.5 20.5 0.87 PP1* 205 149 (73) 206 143 (69) (11.9 – 20.2) (15.6 – 25.2) (0.69 – 1.1) 18.3 20.5 0.98 PP2 # 176 122 (64) 206 143 (69) (13.7 – 23.2) (15.6 – 25.2) (0.77 – 1.25) *The PP1 analysis included only patients who had nephrectomy in Arm A, and patients who receive sunitinib in Arm B. #The PP2 analysis included only patients who had nephrectomy and receive sunitinib after nephrectomy in Arm A, and patients who receive sunitinib in Arm B. CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; MSKCC, Memorial Sloan Kettering Cancer Center; PP, per-protocol. 2 Arnaud Méjean 0

Progression free survival (ITT) Median PFS, HR (95% CI) Nephrectomy + sunitinib months (95% CI) Sunitinib alone Arm A: 7.2 Nephrectomy + Sunitinib (6.5 – 8.5) (n = 226) 0.82 (0.67 – 1.00) Arm B: 8.3 Sunitinib alone (6.2 – 9.9) (n = 224) CN + sunitinib Sunitinib alone CN, cytoreductive nephrectomy; PFS, progression-free survival 2 Arnaud Méjean 1