Early systemic inflammatory-metabolic trajectory phenotypes are associated with survival outcomes in metastatic renal cell carcinoma treated with nivolumab.

Prognosis in metastatic renal cell carcinoma (mRCC) treated with PD-1 blockade remains difficult to estimate early during therapy. Routine laboratory markers of systemic inflammation and metabolic stress are widely available, yet single-marker approaches may not reflect coordinated early inflammatory-metabolic dynamics. In a multicenter real-world cohort of previously treated mRCC patients receiving nivolumab monotherapy, we applied a prespecified day-28 (1-month) landmark framework. Using baseline (BL) and month-1 (Mo1) LDH and complete blood count (CBC)-derived indices (NLR, PLR, SII) as systemic inflammatory and metabolic markers, we engineered BL, Mo1, and early relative change features (log2[Mo1/BL]), standardized them within the phenotype-eligible cohort, and derived early inflammatory-metabolic trajectory phenotypes via unsupervised k-means clustering (k = 3). Phenotypes were labeled post hoc as IM-Quiescent (P1), IM-Quiescent-to-Inflamed (P2), and IM-Inflamed-Persistent (P3). OS and PFS were analyzed from the landmark using Kaplan-Meier and multivariable Cox models. Durable benefit was assessed as 24-month OS (OS24) using multivariable logistic regression. The overall cohort included 498 patients; 329 were phenotype-eligible (P1 n = 142; P2 n = 69; P3 n = 118). Survival differed across phenotypes (log-rank OS p = 0.002; PFS p = 0.001). In multivariable Cox models (reference P1), P3 was associated with worse outcomes (OS HR 1.63, 95% CI 1.09-2.45; p = 0.019; PFS HR 1.92, 95% CI 1.36-2.73; p < 0.001), whereas P2 was not statistically supported versus P1 (OS HR 1.30, 95% CI 0.82-2.07; p = 0.262; PFS HR 1.21, 95% CI 0.82-1.79; p = 0.336). OS24 rates differed across phenotypes and phenotype remained associated with OS24 after covariate adjustment. Early inflammatory-metabolic trajectory phenotypes derived from routine systemic inflammatory and metabolic markers within a day-28 landmark framework were clinically interpretable and associated with OS, PFS, and durable benefit in nivolumab-treated mRCC. External validation and prospective evaluation in contemporary ICI-based regimens are warranted.