Background: Advanced sRCC is an aggressive disease with limited responsiveness to chemotherapy and VEGF-targeted therapies. Subgroup analyses from randomized trials showed improved outcomes with ICI, though sample sizes were relatively small. Methods: We conducted a multi-institutional retrospective analysis of consecutive patients (pts) who had RCC with any sarcomatoid component and received systemic therapy for advanced disease. The pts were classified into ICI⁺ and ICI^- groups (gp) based on whether they had received ICI in any treatment line. Overall survival (OS) was measured from the initiation of first systemic therapy. Time to ICI failure (TIF) was defined as the interval from initiation of ICI to subsequent therapy or death. Survival distributions were estimated using the Kaplan-Meier method. Association between covariates and survival was analyzed using multivariate Cox regression. Two-tailed P< 0.05 was considered statistically significant. Results: 203 pts from 6 US academic cancer centers met the inclusion criteria – 155 in ICI⁺ gp and 48 in ICI^- gp. Overall, 137 (67%) pts were male and 181 (89%) were white; median age at mRCC diagnosis was 59.7 (IQR 52.4-67.7) years; 129 (63%) pts presented de novo with distant metastases, 154 (76%) had clear cell (CC) histology, and 182 (90%) had intermediate/poor risk by IMDC criteria. ICI⁺ had a higher proportion of purely CC tumors (81% vs 64%, P =.02); other demographic and clinical features were similar between the two gps. After a median follow-up of 48.1 (95% CI 40.7-55.5) months (mos), median OS and response rates were significantly higher in the ICI⁺ gp (Table). OS benefit, compared to ICI^-, was maintained in pts who received ICI in ≥ second line (39.6 vs 7.6 mos, HR 0.33, 95% CI 0.22-0.51, log-rank P<.001). TIF was comparable between pts treated with ICI upfront vs in ≥ second line (6.0 vs 5.3 mos, HR 1.27, 95% CI 0.87-1.85, P =.21). On multivariate analysis, ICI^- (HR 2.50, 95% CI 1.61-3.88, P<.001), non-CC histology (HR 3.14, 95% CI 1.98-5.00, P<.001) and sarcomatoid component ≥20% (HR 1.92, 95% CI 1.28-2.90, P =.002) were predictive of all-cause mortality. Among pts with non-CC or mixed histology (n=45), ICI⁺ had higher OS (18.0 vs 5.5 mos, HR 0.20, 95% CI 0.09-0.44, P<.001) and ORR (44% vs 12%, P =.03), compared to ICI^-. Conclusions: Treatment with ICI led to markedly higher survival and response rates in advanced sRCC. OS benefit was maintained with ICI in the second line and beyond. Significant benefit was also noted among pts with non-CC or mixed histology sRCC.

*Best response to ICI, ^¶best response to non-ICI in any line.