Timing of Second-Line Nivolumab and Survival in Metastatic Renal Cell Carcinoma.

INTRODUCTION: Circadian rhythms modulate immune function and drug response, prompting interest in chronotherapy for immune checkpoint inhibitors (ICIs). This study aimed to evaluate the prognostic impact of ICI infusion timing in metastatic renal cell carcinoma (mRCC), particularly in the second-line setting after tyrosine kinase inhibitor (TKI) therapy. PATIENTS: This retrospective cohort study included adult patients with histologically confirmed mRCC who progressed on first-line TKI therapy and received second-line nivolumab. METHODS: Patients were classified as early (Group A; ≥ 20% of infusions before noon) or late (Group B; < 20%). Progression-free survival (PFS) and overall survival (OS) were calculated from the date of nivolumab initiation. Survival was analyzed using Kaplan-Meier and log-rank tests, and prognostic factors were assessed using Cox regression. RESULTS: A total of 115 patients were included (median age 65 years; 70% male). Baseline clinical characteristics were well balanced between the two groups. Patients in the early infusion group experienced significantly longer PFS (log-rank χ² = 28.619, P < .001) and OS (log-rank χ² = 20.851, P < .001) compared with the late infusion group. In multivariate Cox regression, the late infusion timing group (Group B) was independently associated with worse PFS (HR 3.67, 95% CI, 2.17-6.20; P < .001) and OS (HR 3.06, 95% CI, 1.83-5.13; P < .001), while absence of prior nephrectomy remained an independent predictor of poorer outcomes for both PFS (HR 2.04, 95% CI, 1.23-3.41; P = .006) and OS (HR 1.87, 95% CI, 1.10-3.19; P = .021). CONCLUSION: In mRCC patients receiving second-line nivolumab, earlier infusion timing was independently associated with improved PFS and OS.