Comparative survival outcomes of non-clear cell and clear cell renal cell carcinomas with indications for adjuvant pembrolizumab.

515 Background: While immunotherapy has become first-line treatment for metastatic renal cell carcinoma in both clear cell (ccRCC) and non-clear cell (nccRCC) histologies, there has been limited investigation into adjuvant therapies for nccRCC in the context of high-risk localized RCC. As adjuvant Pembrolizumab is being more commonly employed for high-risk non-metastatic ccRCC, its application in nccRCC remains less understood. This study aims to compare survival outcomes between patients with high-risk localized ccRCC and nccRCC, focusing on cancer-specific survival (CSS) and overall survival (OS). Methods: Prospectively collected data from a multicenter database, including University of California San Diego Health (USA), IRCCS San Raffaele Hospital (Italy), Emory University Hospital (USA) and Tokyo Medical and Dental University (Japan), were retrospectively analyzed. Non-metastatic patients treated with surgery were included. The cohort was divided between nccRCC and ccRCC groups for descriptive and survival analyses, with the aim of comparing survival of the two groups according to subgrouping factors, specifically high-grade disease (G3-G4 or sarcomatoid features) at final pathology (HG) and locally advanced disease (pathological stage T3). Kaplan-Meier analyses (KMA) and Cox regression multivariable analyses (COX) were conducted to evaluate for cancer-specific survival (CSS) and overall survival (OS) and predictors of cancer-specific (CSM) and all-cause mortality (ACM). Results: With median follow-up of 58 months, a total of 5968 patients were analyzed. 4724 (79%) patients had a ccRCC while 1244 (21%) had a nccRCC. The nccRCC cohort comprised 923 (74%) papillary, 240 (19%) chromophobe and 81 (7%) variant histology patients. KMA comparing nccRCC high-grade (G3-G4; HG) tumors and ccRCC high-grade (HG) tumors showed no difference in 5-year CSS rates (nccRCC-HG 91% vs ccRCC-HG 88%, p=0.08) and 5-year OS (nccRCC-HG 79% vs ccRCC-HG, p=0.1). Comparing T3 stage tumors between nccRCC and ccRCC, KMA also showed similar 5-year CSS (nccRCC-T3 83% vs. ccRCC-T3 84%, p=0.05) and 5-year OS (nccRCC-T3 73% vs ccRCC-T3 73%, p=0.2). Cox regression for predictors of mortality showed that histology was not an independent predictor of CSM (p=0.17) and ACM (p=0.11). Conclusions: Although focus of most RCC adjuvant therapy clinical trials has been on ccRCC, aggressive features in nccRCC patients yield similar 5-year cancer-specific and overall survival rates. This study highlights the need for further clinical trials to evaluate efficacy of adjuvant systemic therapy in the setting of unfavorable groups of non-clear cell RCC.