Circulating kidney injury marker-1 (KIM-1) in metastatic renal cell carcinoma with divergent histologies (RCCdh): Biomarker analysis of the CAN-I trial.

538 Background: The CAN-I trial was a multi-center single arm phase II trial that evaluated cabozantinib, nivolumab and ipilimumab for treatment of metastatic RCCdh (NCT04413123). Previous studies have shown that circulating KIM-1 is associated with prognosis in clear cell RCC and that changes in KIM-1 are associated with treatment response. Preclinical data has shown that KIM-1 is overexpressed in most RCCdh except those that have a non-proximal tubular cell of origin, such as chromophobe RCC. We evaluated whether KIM-1 is associated with histology and outcomes in RCCdh. Methods: Patients with RCCdh were treated with cabozantinib, nivolumab and ipilimumab as previously described. Plasma KIM-1 was evaluated at baseline and cycle 3 day 1 (C3D1) using an established enzyme based electrochemiluminescence assay. Cox proportional hazards models were used to evaluate the associations between KIM-1 levels and outcomes. Results: Of 59 patients enrolled, 43 had plasma available for analysis. Median baseline KIM-1 was 3040 pg/mL (IQR: 842–8512) among patients with non-chromophobe RCC and 63 (IQR: 31–83) among patients with chromophobe RCC (Wilcoxon test, p < 0.0001). Higher KIM-1 at baseline was associated with worse IMDC risk score (Spearman rho = 0.37, p = 0.015). Among non-chromophobe RCC patients with paired samples (n=28), KIM-1 at C3D1 was significantly lower compared to baseline (median: 2900 vs 1232 pg/mL, Wilcoxon paired test, p = 0.002) and was strongly prognostic for PFS and OS after adjustment for IMDC risk and histology (Table). The 12-month OS rate from C3D1 was 83% among non-chromophobe patients who had decreasing KIM-1, and 37% among patients who had increasing KIM-1. Conclusions: Among patients with RCCdh, KIM-1 was overexpressed in papillary, translocation, and unclassified RCC compared to chromophobe RCC. Among non-chromophobe RCCdh patients, circulating KIM-1 is a potentially useful dynamic biomarker and should be further evaluated in trials. Circulating KIM-1 and association with outcomes. Baseline KIM-1 C3D1 KIM-1*** Hazard Ratio*(95% CI) P-value Hazard Ratio*(95% CI) P-value Unadjusted (PFS) 1.26 (0.97, 1.65) 0.088 1.53 (1.18, 1.98) 0.001 Adjusted (PFS)** 1.29 (0.94, 1.79) 0.118 1.55 (1.16, 2.07) 0.003 Unadjusted (OS) 1.23 (0.88, 1.70) 0.223 1.58 (1.20, 2.08) 0.001 Adjusted (OS)** 1.19 (0.79, 1.78) 0.413 1.66 (1.17, 2.34) 0.004 *Per unit log increase; **Adjusted for IMDC risk score and histology type (papillary vs other); ***Landmark analysis from C3D1.