Primary resistant disease is clinically heterogeneous in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

The study aimed to characterize clinical heterogeneity among patients with primary resistant disease (PRD) after first-line nivolumab plus ipilimumab (NIVO+IPI) for metastatic renal cell carcinoma (mRCC) and to explore clinical factors associated with death within 1 year among patients with PRD. We retrospectively analyzed 151 patients with mRCC who received first-line NIVO+IPI at four institutions in Japan between May 2018 and January 2025. PRD was defined as disease progression occurring within 3 months after treatment initiation, based on radiographic and clinical assessment, or death from any cause within the same period. For exploratory analyses, primary resistant disease with early mortality (PRD-EM) was defined as death within 1 year among patients with PRD. Survival was estimated by the Kaplan-Meier method. Because the PRD subgroup was small and several variables had sparse cell counts, associations with PRD-EM were assessed using Firth penalized logistic regression. PRD occurred in 31 of 151 patients (20.5%). Median overall survival was 3.9 months [95% confidence interval (CI) = 1.8-13.6] in patients with PRD and 46.7 months (95% CI = 38.8-62.8) in those without PRD (log-rank P < 0.001). Among patients with PRD, 20 of 31 (64.5%) met the exploratory PRD-EM definition. In the parsimonious two-variable Firth model, baseline C-reactive protein (CRP) ≥2 mg/dL [adjusted odds ratio (OR) = 7.95; 95% CI = 1.32-68.18; P = 0.023] and lymph node involvement (adjusted OR = 11.65; 95% CI = 1.78-142.82; P = 0.009) were associated with PRD-EM. PRD after first-line NIVO+IPI was associated with heterogeneous clinical outcomes. Elevated baseline CRP and lymph node involvement were associated with PRD-EM in an exploratory analysis. The PRD-EM classification and these associations require validation in larger independent cohorts before they can be used for clinical decision-making.