4 Baseline and Early On-Treatment Plasma Kidney Injury Molecule-1 (KIM-1) Levels are Associated with Outcomes in Advanced Renal Cell Carcinoma (aRCC)

Vollständiger Abstract

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Abstract Background KIM‑1 is a circulating biomarker expressed by injured renal tubular epithelium and renal tumor cells. Prior studies suggest prognostic relevance in aRCC; however, validation in large prospective trials and contemporary immunotherapy‑based regimens is limited. We evaluated baseline and early on-treatment plasma KIM‑1 levels and their associations with baseline characteristics and clinical outcomes in COSMIC‑313 (NCT03937219), a randomized phase III trial comparing cabozantinib plus nivolumab and ipilimumab (C+N+I) versus nivolumab plus ipilimumab (N+I) as first‑line therapy in aRCC (N = 855). Methods Plasma KIM‑1 was measured using an enzyme‑based electrochemiluminescence assay. Associations between baseline KIM‑1 and clinicopathologic features and radiographic tumor burden were assessed. Associations between baseline and early on-treatment changes in KIM-1 and progression‑free survival (PFS) and overall survival (OS) were assessed in the intention‑to‑treat population and by treatment arm using Cox proportional hazards models. Baseline KIM‑1 was analyzed as a continuous variable and by using optimal cut points for OS identified via a minimum p‑value approach. Results Baseline KIM‑1 levels were evaluated in 703 patients and balanced between treatment arms. Higher baseline KIM‑1 levels were associated with higher International Metastatic RCC Database Consortium risk category and absence of prior nephrectomy (both p < 0.001). Baseline KIM-1 levels demonstrated a strong linear correlation (Pearson R = 0.57; p < 0.001) with radiographic tumor burden, measured as the sum of target lesion diameters. In the intention‑to‑treat population, higher baseline KIM‑1 was associated with shorter PFS when analyzed continuously (p = 0.020), but not as a dichotomous variable. In contrast, baseline KIM‑1 was a strong and consistent predictor of OS. Higher baseline KIM‑1 was associated with increased risk of death in the overall population (p < 0.001) and both treatment arms. Early changes in circulating KIM‑1 provided complementary prognostic information beyond baseline risk and revealed treatment‑specific kinetics. In patients treated with N+I, a ≥ 30% reduction in KIM‑1 as early as week 3 was associated with improved objective response rate, PFS, and OS, with these associations persisting at later time points (weeks 6, 9, and 13). In contrast, early KIM‑1 dynamics were not predictive in the C+N+I arm; however, patients achieving a ≥ 30% KIM‑1 reduction at later assessments (weeks 6 and 13) demonstrated improved PFS. These findings suggest that KIM‑1 reflects distinct temporal treatment effects across regimens. Conclusions Baseline plasma KIM‑1 strongly reflected disease biology and tumor burden. In this large prospective phase III trial, baseline plasma KIM‑1 emerged as a robust prognostic biomarker for OS, reflecting underlying tumor burden and aggressive disease biology rather than treatment‑specific PFS benefit. Early on‑treatment KIM‑1 dynamics provided complementary, regimen‑dependent information associated with depth of response. Reductions in KIM-1 observed at week 3 closely recapitulated findings from CheckMate 214 (Xu J Clin Oncol 2025) and were clinically meaningful and potentially actionable. Collectively, these results position plasma KIM‑1 as a clinically useful biomarker with distinct baseline prognostic and longitudinal predictive roles across immunotherapy‑based and VEGF receptor tyrosine kinase inhibitor‑based treatment strategies in aRCC.