LAUSR

4514 Background: S/R mRCC are poorly characterized rapidly progressing tumors associated with poor prognosis. Although conventional therapies are less effective for these tumors, emerging data suggests that ICIs may be especially effective. Our aim was to characterize the genomic alterations (GA) in S/R mRCC tumors and evaluate their response to ICIs. Methods: We retrospectively compared the activity of first-line ICIs to non-ICI-based therapies for S/R mRCC patients (pts) treated at DFCI and analyzed sequencing data from an NGS panel (275-447 genes) on a subset of these patients (matched by histology to non-S/R mRCC). For S/R mRCC pts treated with ICI vs non-ICI therapies, overall survival (OS) and time to treatment failure (TTF) were compared by Cox regression and objective response rate (ORR) by logistic regression. GA frequencies were compared by Fisher’s test and tumor mutational burden (TMB) by Mann Whitney U between S/R and non-S/R mRCC. Results were considered statistically significant if p < 0.05 or q < 0.10. Results: 125 S/R mRCC pts were included (88 S, 23 R, 14 S&R) among which 103 were clear cell and 48 had sequencing data. GA in BAP1 were significantly more frequent in S/R vs non-S/R (25% vs 4.3%; q = 0.096) while other GA had similar frequencies and TMB (median [IQR]) was similar (7.2 [5.2-8.4] vs 6.8 [5.3-9.1] mut/Mb; p = 0.98). Median follow-up was 35.4 (95% CI = 24.9 – 46.0) months (m). On multivariable analysis, S/R mRCC pts treated with ICI had significantly better clinical outcomes (Table). Conclusions: Pts with S/R mRCC have a higher frequency of BAP1 GA and better outcomes on ICIs compared to non-ICI-based therapies. Future studies should determine the molecular mechanisms underlying the improved response to ICIs in S/R mRCC. [Table: see text]