Impact of Cytoreductive Nephrectomy on Immune Checkpoint Inhibitor Therapy: Treatment Outcomes of Immune Inhibitors Combination Therapies for Metastatic Renal Cell Carcinoma With Primary Kidney Tumors

OBJECTIVE: Treatment outcomes for metastatic renal cell carcinoma (mRCC) have significantly improved with immune checkpoint inhibitors (ICIs); however, optimal treatment strategies remain incompletely defined. This study evaluated treatment outcomes in mRCC patients with intact primary renal tumors, focusing on the survival impact of cytoreductive nephrectomy (CN). METHODS: We retrospectively analyzed 104 consecutive mRCC patients (2019-2024) treated with immuno-oncology combinations (IO+IO) or IO plus tyrosine kinase inhibitors (IO+TKI). Surgical timing was classified as upfront CN, deferred CN, or non-CN. Landmark analyses at 6 and 12 months minimized immortal time bias. Multivariable analyses identified survival predictors. RESULTS: IO+IO patients were younger (63 vs. 68 years; p = 0.033) with higher progressive disease rates (31% vs. 2%), but similar objective response rates (50% vs. 47%) compared to IO+TKI. Of 104 patients, 25 underwent upfront CN, 25 deferred CN, and 54 non-CN. Deferred CN independently predicted improved survival versus non-CN in multivariable analysis (HR 0.17; 95% CI 0.05-0.57) and 6-month landmark analysis (HR 0.22; 95% CI 0.06-0.83), but not at the 12-month landmark, suggesting time-varying effects. CONCLUSIONS: IO+IO and IO+TKI demonstrated comparable efficacy with distinct profiles. Deferred CN may improve survival when performed within an optimal therapeutic window in selected patients, emphasizing the importance of treatment timing and response-adapted selection in the ICI era.