Tratamiento adyuvante y neoadyuvante del cáncer renal en Xavier Garcia del Muro Solans Institut Català d Oncologia Hospitalet.

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1 Tratamiento adyuvante y neoadyuvante del cáncer renal en 2017 Xavier Garcia del Muro Solans Institut Català d Oncologia Hospitalet. Barcelona

2 Pronóstico del CR mediante un sistema integrado en 468 pts CR localizado (N0M0): UCLA Integrated Staging System (UISS) 5-year OS: 83% 72% 44% Zisman A. JCO 2002

3 Tumor Stage, Size, Grade and Necrosis: the SSIGN score for patients with clear cell renal cell carcinoma Frank I. J Urol 2002 Leibovich BC. Cancer 2003

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5 Randomized phase III trials of adjuvant therapy after nephrectomy for high-risk RCC Treatment RT vs. observation MPA vs. observation Tm cells + BCG vs. observation INF vs. observation HD-IL 2 vs. observation INF + IL-2 + 5FU vs observation Tm cell vaccine vs. observation HSPPC-96 Vaccine vs observ. Thalidomide G250 vs observation Outcome Survival (NS) Relapse rate (NS) DFS (NS) Survival (NS) DFS (NS) OS (p=.02) 5y PFS (p=.02) RFS (NS) 3y RFS (p=.02) DFS (NS)

6 Adjuvant targeted therapy trials in RCC

7 Phase III Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN) Enrollment Criteria: Nonmetastatic RCC that meets radiologic criteria to be clinically ³ T1b N any (resectable) M0 disease N E P H R E C T O M Y Stratification UISS risk Intermediate high risk Very high risk Histologic subtype Clear cell Nonclear cell Performance status Surgery Type of approach R A N D OM I Z E N=1943 1:1:1 Arm A Sunitinib 50 mg QD 4/2 for 1 year Arm B Sorafenib 400 mg BID for 1 year Arm C Placebo Daily for 1 year Primary Endpoint Secondary Endpoints Disease-free survival (investigator assessed) Overall survival, disease-free survival for clear cell RCC, and safety Haas NB. Lancet 2016

8 Phase III trial of sunitinib versus placebo as adjuvant treatment for high-risk renal cell carcinoma after nephrectomy (S-TRAC) Patient Disposition and Treatment Dosing Information Sunitinib n=306 Placebo n=304 Treatment duration*, median (range), months ( ) ( ) Treatment completion, % Treatment discontinuation, % Reasons for discontinuation, % Adverse events Disease progression/relapse Other Dose reductions, n (%) Dose interruptions, n (%) Relative dose intensity, median (range) 88.4 ( ) 99.7 ( ) * Duration of treatment was defined as the period between first and last doses of the drug Ravaud A. NEJM 2016

9 Disease-Free Survival By Blinded Independent Central Review Proportion Disease-Free 3-year DFS rate: 64.9% 59.5% 5-year DFS rate: 59.3% 51.3% P=0.030* Disease-Free Survival (years) * Two-sided P value from log-rank test stratified by UISS high-risk group. Ravaud A. NEJM 2016

10 ASSURE and S-TRAC in perspective Variable ASSURE S-TRAC Study Conduct Central Scans Review No Yes (eligibility and efficacy) Patient Characteristics Dose administered ccrcc 79.1% 99.0% ECOG PS % 73.8% RCC Stage I-II 33.4% 0% Starting Dose levels 2 (50 mg and 37.5 mg) 1 (50 mg) 50mg 4/2 as starting dose 69.6% 100% Minimum Dose Reduction 25 mg 37.5 mg Relative Dose intensity Full Dose: 40.2% Reduced Dose 44.5% (first 3 cycles) 88.4%

11 DFS and OS for 1069 high-risk patients who had ccrcc histology and pt3, pt4, or N+ disease of ASSURE randomized trial. Outcome analyses by dose quartiles of these patients receiving sunitinib or sorafenib were also performed CONCLUSIONS: Neither prognostic category of the tumor nor dose intensity of therapy altered the lack of difference in DFS or OS in this population of patients with high-risk ccrcc

12 Randomized phase III trial of adjuvant pazopanib vs placebo after nephrectomy in patients with locally advanced RCC (PROTECT) Motzer R. ASCO 2017

13 Motzer R. ASCO 2017

14 Sternberg C. ASCO 2017

15 ONGOING ADJUVANT STUDIES IN RCC Targeted therapy trials: - SORCE: Sorafenib 1y. vs. 3y. vs. placebo. 592 pts - ATLAS: Axitinib 3 y. vs. Placebo. 142 pts - EVEREST: Everolimus vs placebo pts Immune Checkponit Inhibitors trials: - PROSPER: Perioperative Nivolumab vs. surgery alone - Immotion 10: Atezolizumab vs. placebo - KEYNOTE 564: Pembrolizumab vs. placebo

16 NEOADYUVANCIA EN CANCER DE RIÑÓN

17 OUTCOMES AND POTENTIAL BENEFITS OF NEOADJUVANT THERAPY IN RCC Tumor downsizing Aprox. 30% pts have RR % stabilization o shrinkage Reducing tumor complexity (RENAL score) 55% reduction in nephrometry score Facilitate radical to partial nephectomy Reduction of tumor volume and complexity. PN safe Regression of tumor thrombus level and facilitate surg. Aprox. 25% of reduction. Surgery safe Making unresectable tumors resectable It makes resection possible in Tm considered unrectable

18 Prospective study of preoperative Sorafenib in 30 pts candidates to nephrectomy, to assess toxicities, surgical complications and tumor responses 17 pts had localized and 13 metastatic disease 2 PR and 26 SD All pts were able to proceed with nephrectomy and no complications related to sorafenib were observed

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20 CONCLUSIONS Adjuvant therapy trials in RCC have conflicting results. However, some data suggest that appropriate selection of patients (high-risk, clear cell) and optimal doses might be relevant factors associated with benefit At present, available data do not justify the systematic use of adjuvant therapy. However, adjuvant sunitinib for one year could be an option to consider in patients with very high-risk disease Neoadjuvant therapy before surgery for localized renal cell cancer is feasible and might be especially useful in selected patients with large unresectable masses, high-level venous tumor thrombus involvement, and patients with large masses and indications for nephron sparing surgery. Nevertheless, this approach is still investigational and should be carefully used in selected patients