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 (log2Mo1/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.
Fiala et al. (Sun,) studied this question.