Mahmood rasheed Hematology/oncology fellow VCU Massey cancer center Results from the CARMENA Trial: Sunitinib Alone versus Sunitinib with Nephrectomy in Metastatic Renal Cell Carcinoma Mahmood rasheed Hematology/oncology fellow VCU Massey cancer center

Background: Renal Cell Carcinoma 4% of all adult malignancies in US, 63,000 new cases 2017, prevalence ~730,000. Metastatic disease at presentation in ~35%, treated with systemic therapy. Available systemic therapies have radically changed over time. Rationale for and role of cytoreductive nephrectomy in this setting has evolved over time.

Evolution of Systemic RCC Treatment 1980’s-1990s: Cytokine Immunotherapy 1980’s: High dose IL-2, IFN-alpha 1992: FDA approval for HDIL-2 ~5-7% durable CR Use limited by frequent and severe toxicities

Evolution of Systemic RCC Treatment 1990s-2000s: Targeted Therapies Less toxic than HDIL-2 or IFNa, easier to administer. Compared with cytokine therapy, these improved PFS, ORR, and quality of life. Negligible CR rates. No OS benefit except for temsirolimus (select poor- prognosis patients). 2005 2006

Evolution of Systemic RCC Treatment 2010s: Modern Immunotherapy

Cytoreductive Nephrectomy before Targeted Therapies Pre-systemic therapy era: Palliation of symptoms Rare spontaneous regression of metastatic disease observed after nephrectomy (<1% of cases). Cytokine therapy era: Less response in primary tumor than metastases Possibility of survival benefit through potentiating response to cytokine therapy, debulking overall tumor mass, and eliminating source of new metastases. Two RCT’s evaluating OS benefit: EORTC 30947: Nephrectomy + IFN versus IFN alone (n=85). Median OS 18mo vs 7mo. SWOG 8949: Same design, n=246. Median OS 11mo vs 8.1mo. Modest survival benefits, small n size, long time to accrue. Published in 2001, first targeted therapy approved shortly after publication - unclear applicability of findings

Retrospective Support for Cytoreductive Nephrectomy Targeted Therapy Era Numerous retrospective studies suggesting OS benefit with nephrectomy + targeted therapy versus targeted therapy alone Petreli et al (2016) Meta-analysis of 12 studies, 39,953 patients Demonstrated survival benefit with nephrectomy - HR for death 0.46 favoring nephrectomy

Retrospective Support for Cytoreductive Nephrectomy MDACC Database Retrospective (Culp et al 2007) Retrospective study of 566 patients (456 with nephrectomy and 110 without) who received systemic therapy at MDACC. 7 independent preoperative predictors of inferior OS after nephrectomy: elevated LDH, low albumin, symptomatic metastases, liver metastases, retroperitoneal adenopathy, clinical tumor stage T3-T4. Higher risk of death correlated positively with number of risk factors; surgical patients with ≥4 risk factors did not benefit from nephrectomy.

Retrospective Support for Cytoreductive Nephrectomy Heng et al IMDC database analysis 1658 patients (982 with nephrectomy, 676 without) treated with any targeted therapy (72% sunitinib) Median OS 20.6mo with nephrectomy vs 9.6mo without. Those with ≥4 IMDC risk factors did not benefit from surgery, and those with life expectancy <12mo had only marginal benefit from nephrectomy. EORTC 30073 (SURTIME): Multinational prospective study, patients randomized to sunitinib and immediate vs deferred nephrectomy 99 patients (of planned 380) accrued over 6 years period at 19 institutions. ESMO 2017: PFS unaffected, median OS 32.4mo vs 15.1mo favoring deferred nephrectomy, but severely underpowered to draw definitive conclusions.

CARMENA Study Design Multicenter open-label trial designed to demonstrate the non-inferiority of sunitinib alone versus nephrectomy followed by sunitinib in patients with metastatic RCC. Inclusion criteria: Biopsy-proven metastatic clear cell RCC Resectable primary tumor ECOG PS 0-1 No brain metastases Adequate organ function Exclusion criteria: Prior systemic therapy Medically unfit for nephrectomy

Study Design Stratified by risk according to MSKCC prognostic model: Randomized 1:1 to undergo nephrectomy followed by sunitinib treatment or to receive sunitinib alone Sunitinib 50mg daily for weeks 1-4 of 6 week cycle, dose reductions/interruptions permitted as needed. Patients started sunitinib within 3-6 weeks post- nephrectomy, sunitinib group started treatment within 21 days of randomization.

Study Design Endpoints: Primary: overall survival Secondary: PFS ORR (CR + PR rates by RECIST criteria) Post-operative morbidity/mortality Adverse events on treatment by CTCAE "Clinical benefit" - percentage of patients with CR, PR, or SD for more than 12 weeks Statistics: Non-inferiority trial designed to show non-inferiority for death at a HR of ≤1.20 with 95% confidence interval. Planned to enroll 576 patients for 456 observed deaths, to accrue over 4 year period (10 patients per month across 92 centers) Over an 8 year period, 450 patients were enrolled (average 0.6 patients per center per year). At a planned interim analysis (326 deaths) trial was closed due to poor accrual, trial committee deemed results from interim analysis adequate to meet trial objectives.

Results: Patients 17%! Significant issues with patient crossover 7.1%

Results: Patients No favorable-risk patients – MSKCC intermediate-poor only. 44.5% (nephrectomy) and 41.5% (sunitinib) with poor risk disease. Higher T-stage (70% vs 50%) in the nephrectomy-sunitinib group Average number, size, distribution of metastatic disease balanced, but extent of metastatic burden fairly high – 40% of disease volume from metastases versus primary tumor. High proportion of patients with bone metastases (35.9% and 37.1%)

Subgroup Median OS (SUN vs CN-SUN) HR for Death [95% CI] All Patients 18.4 vs 13.9 months 0.89 [0.71 to 1.10] MSKCC Intermediate-risk 23.4 vs. 19.0 months 0.92 [0.68-1.24] MSKCC Poor-risk 13.3 vs. 10.2 months 0.86 [0.68-1.17]

Oncologic Outcomes in Sunitinib Arm of Recent RCC Trials Enrolled Patient Population Median OS in Sunitinib arm PFS ORR Checkmate 214 (2018) IMDC int-poor risk 26mo 8.4mo 27% CABOSUN (2017) 21.8mo 8.2mo 12% COMPARZ (2013) Any risk 29.3mo 9.5mo 25% CARMENA (2018) – Nephrectomy Arm Any risk (but only MSKCC int-poor enrolled) 18.4mo 7.2mo 27.4% CARMENA (2018) – Sunitinib only Arm 23.4mo 8.3mo 29.1% Median OS in MSKCC intermediate risk – 33.6mo, MSKCC poor risk – 15.2mo (Tamada et al, Oncotarget 2018)

G3-4 adverse events in sunitinib group in CheckMATE 214 (63%), CABOSUN (68%)

Postoperative death in the month after nephrectomy in 4/210 patients in the nephrectomy–sunitinib group. Not reported in the “sunitinib only” group. 82/210 (40%) patients with post-operative complications, 13/82 (16%) requiring procedural intervention or resulting in critical illness, organ dysfunction, or death. Rates of complications fairly similar between upfront nephrectomy group and in the “sunitinib only” group.

The Good Prospectively confirm prior retrospective observations that high-risk patients likely do not benefit from cytoreductive nephrectomy. The Bad Very poor accrual led to premature closure and underpowered study Clear lack of clinical equipoise leading to patients most likely to benefit from surgery not being enrolled: Disproportionately higher risk disease in enrolled patients (MSKCC risk features, bone metastases, higher metastatic burden) Imbalance between arms (T3-4 in 70% in nephrectomy arm versus 50% of sunitinib only arm) also skews results to favor sunitinib only. Significant crossover between groups (17.0% of the no-surgery group got surgery, 7% of the surgery group didn’t get surgery). Sunitinib no longer ideal comparator given superior efficacy of newer treatments (better PFS with cabozatinib, OS with ipi/nivo, likely superior outcomes with combinatorial regimens) Discussion

Common approach to metastatic RCC While this study attempts to provide valuable prospective data on the merits of CN, I do not see it as practice changing overall.

Thank You