BACKGROUND: Data in patients with malignant melanoma, who have been previously treated with pembrolizumab as adjuvant therapy, show a reduction in pembrolizumab efficacy upon rechallenge. We examined this scenario in patients with non-metastatic renal cell carcinoma (RCC) eligible for adjuvant pembrolizumab after nephrectomy. We hypothesized that a proportion of such patients will either require re-treatment with pembrolizumab upon metastatic progression prior to cancer-specific mortality (CSM) or die from other cause mortality (OCM). MATERIALS AND METHODS: We identified within the SEER database 10,635 patients, between 2004 and 2017, with a diagnosis of non-metastatic intermediate-high and high risk RCC, who had undergone nephrectomy and fulfilled criteria for enrollment in KEYNOTE-564. Kaplan-Meier analyses addressed overall survival (OS), CSM and OCM. RESULTS: 9,825 (92.4%) of the 10,635 patients had intermediate-high risk RCC and 9,456 (88.9%) underwent radical nephrectomy. Additionally, 760 (7.1%) harbored sarcomatoid features. In Kaplan-Meier analyses, median OS was 9.8 (9.1-11.4) years. At 10-years of follow-up, CSM rate was 36% and OCM rate was 22%. CONCLUSIONS: Based on CSM, our observations indicate that by 10-years of follow-up 36% of patients treated with adjuvant pembrolizumab will require a rechallenge, in a setting where a checkpoint inhibitor may have reduced efficacy. Moreover, at 10-years of follow-up, 22% of patients with RCC, previously treated with adjuvant pembrolizumab, will die of other causes. These percentages should be strongly considered prior to routine use of adjuvant pembrolizumab, especially given an OS benefit has not been proven.

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montréal Health Center Montréal Québec Canada

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montréal Health Center Montréal Québec Canada; Department of Surgical and Diagnostic Integrated Sciences University of Genova Genova Italy

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montréal Health Center Montréal Québec Canada; Department of Urology University Hospital Frankfurt Goethe University Frankfurt am Main Frankfurt am Main Germany

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montréal Health Center Montréal Québec Canada; Department of Urology University of Verona Verona Italy

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montréal Health Center Montréal Québec Canada; Division of Experimental Oncology Unit of Urology URI Urological Research Institute IRCCS San Raffaele Scientific Institute Milan Italy

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montréal Health Center Montréal Québec Canada; Martini Klinik Prostate Cancer Center University Hospital Hamburg Eppendorf Hamburg Germany

Department of Maternal Child and Urological Sciences Sapienza Rome University Policlinico Umberto 1 Hospital Rome Italy

Department of Maternal Child and Urological Sciences Sapienza Rome University Policlinico Umberto 1 Hospital Rome Italy; Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montréal Health Center Montréal Québec Canada

Department of Surgical and Diagnostic Integrated Sciences University of Genova Genova Italy

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Department of Urology University of Texas Southwestern Dallas TX; Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic; Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia; Division of Urology Department of Special Surgery Jordan University Hospital The University of Jordan Amman Jordan; Department of Urology Weill Cornell Medical College New York NY

Department of Urology University Hospital Frankfurt Goethe University Frankfurt am Main Frankfurt am Main Germany

Department of Urology University of Verona Verona Italy

Division of Experimental Oncology Unit of Urology URI Urological Research Institute IRCCS San Raffaele Scientific Institute Milan Italy

Martini Klinik Prostate Cancer Center University Hospital Hamburg Eppendorf Hamburg Germany

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