Real-world analysis of renal cell carcinoma with sarcomatoid differentiation treated with first-line immunotherapy combinations: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

448 Background: Sarcomatoid renal cell carcinoma (sRCC) is aggressive with poor outcomes. Dual checkpoint blockade (nivolumab–ipilimumab; NIVO-IPI) and immune–VEGF combinations (IO-VEGF) are standard therapies, but real-world data are limited. Methods: We retrospectively analyzed IMDC sRCC treated first-line with NIVO-IPI or IO-VEGF between 2000–2025. Favorable-risk patients were excluded to focus on a clinically homogeneous intermediate/poor-risk cohort. Objective response rate (ORR; proportion achieving complete or partial response) was assessed per investigator evaluation. Additional outcomes included treatment duration (time from therapy start to discontinuation for any reason including toxicity or response), time to next treatment (TTNT), and overall survival (OS). Kaplan–Meier estimates and log-rank tests compared survival distributions, while multivariable Cox regression adjusted for key prognostic variables and metastatic sites. Results: A total of 337 intermediate/poor-risk patients were included, of whom 87 received IO-VEGF and 250 received NIVO-IPI. Baseline characteristics (Table 1) showed no significant between-group differences. The ORR was nearly identical between regimens at 49.3% with IO-VEGF and 49.1% with NIVO-IPI (p = 0.95). Among evaluable patients (IO-VEGF n=73; NIVO-IPI n=226), complete response rate was 5.5% vs 11.5% (p=0.136) and primary progressive disease rate was 26.0% vs 25.7% (p=0.951) for IO-VEGF and NIVO-IPI respectively. Median treatment duration was longer with IO-VEGF (12.6 vs 5.0 months; log-rank p = 0.026). Median time to next treatment (TTNT) was 32.2 months for IO-VEGF and 27.6 months for NIVO-IPI (unadjusted log-rank p = 0.28; adjusted HR 1.24, 95% CI 0.81–1.96, p = 0.35). Bone metastases independently predicted shorter TTNT (HR 2.05, p < 0.001). Median overall survival (OS) was 24.0 months with IO-VEGF and 30.2 months with NIVO-IPI (unadjusted log-rank p = 0.65; adjusted HR 0.85, 95% CI 0.58–1.25, p = 0.40). Worse OS was associated with Karnofsky Performance Status < 80% (HR 1.70, p = 0.02) and the presence of bone metastases (HR 2.03, p < 0.001). Conclusions: In IMDC intermediate/poor-risk sRCC, NIVO-IPI and IO-VEGF regimens did not demonstrate statistically significant differences in ORR, TTNT, or OS. Bone metastases and reduced performance status consistently predicted poorer outcomes, highlighting the importance of accounting for disease burden and functional status when selecting first-line therapy and designing future studies. Baseline characteristics. Characteristic IO-VEGFN = 87 NIVO-IPIN = 250 p-value Intermediate risk, N (%) 55 (63.2%) 142 (56.8%) 0.36 Poor risk, N (%) 32 (36.8%) 108 (43.2%) Median Age 62.5 62.1 0.82 Bone Metastases, N (%) 28 (32.6%) 81 (32.5%) 0.99