Clinical and immunogenomic outcomes of consolidative cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with immune checkpoint blockade.
Authors: Reese Stephen W. , Jiang Hui , Kuo Fengshen , Wu Chih-Ying , Vuong Lynda , Mascareno Eduardo , Oparanozie Arnold , Motzer Robert J. , Voss Martin H , Reznik Eduard , Reuter Victor E. , Coleman Jonathan , Russo Paul , Chen Ying-Bei , Kotecha Ritesh R , Hakimi A. Ari 
Published: March 2023

720 Background: Immune checkpoint blockade (ICB) alone and in combination has dramatically improved outcomes in metastatic renal cell carcinoma (RCC). We performed in-depth clinical, histopathologic and immunogenomic analysis of a cohort of RCC patients treated with upfront ICB followed by delayed consolidative cytoreductive nephrectomy. This highly selected cohort included extreme responders defined by complete pathologic response and no evidence of disease at more than 25 months of follow-up. Methods: Clinicopathologic data was collected from 32 patients who received ICB (alone or combined with anti-VEGF therapy) and then subsequently underwent resection of primary tumor. Immunogenomic analysis was performed on select pre-treatment and nephrectomy tissue using targeted next-generation sequencing (MSK-IMPACT) and immunohistochemical (IHC) staining analyses. We further performed single-cell (sc)RNA sequencing of both peripheral blood and residual tumor tissue (where available), including 4 patients who demonstrated complete pathologic response. The Kaplan-Meier method was used to calculate survival outcomes. Results: All 32 patients underwent successful consolidative surgery and were further stratified based on evidence of radiographic progression, with 13 pts (40.6%) demonstrating no evidence of disease after surgery. The most common histopathology was clear cell RCC (n=29, 90.6%). Half the patients received dual ICB (CTLA-4/PD-1) (n=16, 50%), while the rest received an immunotherapy agent plus an anti-VEGF agent (n=13, 40.6%) or a single immunotherapy agent (n=3, 9.4%). Median follow-up for the cohort was 33.1 mo. (95%CI: 20.5-42.5) and median OS was 45.2 mo. (95%CI:23.9 – NR). Median OS for those who had progressive disease after CN was 25.5 (95%CI: 16.4- NR). At a median follow-up of 25.5 mo. in patients without evidence of disease after CN, 24-month survival rate was 100%. On pathologic evaluation, those without evidence of disease had a median of 8% (IQR: 0-35%) residual viable tumor. Mutational analysis revealed enrichment for BAP1 (n=3, 20.0% vs. n=0, 0%) and SETD2 (n=7, 46.7% vs. n=0, 0%) in progressive patients. scRNAseq and scTCRseq analysis of peripheral blood revealed distinct expansion of Natural Killer (NK), CD4 subsets and unique T cell clonal expansions amongst long term responders. Additionally, we identified an inverse relationship between NK cell populations and B cell infiltration in long term responders. Conclusions: Delayed cytoreductive nephrectomy in select patients is associated with favorable outcomes, especially in those who demonstrate complete response after surgery. Examination of this population offers opportunities for identification of unique tissue and peripheral based biomarkers for long term clinical responses in metastatic RCC.