Circulating KIM-1 and ctDNA as prognostic markers in oligometastatic clear cell renal cell carcinoma (ccRCC): The K-COMPASS model.

537 Background: Biomarkers do not yet exist to triage patients with oligometastatic ccRCC for de-escalation strategies. Two promising biomarkers are kidney injury molecule-1 (KIM-1) and circulating tumor DNA (ctDNA). Methods: Patients with ccRCC and ≤5 metastases were enrolled on a single-arm phase 2 trial of metastasis-directed therapy (MDT) without systemic therapy (NCT03575611), powered for the primary endpoint of systemic therapy–free survival (STFS). Plasma samples for ctDNA and KIM-1 measurement were collected at baseline and 3-month follow-up. Personalized ctDNA detection panels (≤2000 somatic variants) were constructed from tumor whole-genome sequencing (Myriad Genetics). To create the Kidney Cancer OligoMetastasis Prognostic Assessment Systemic Score (K-COMPASS), we screened 24 candidate variables by elastic net-penalized Cox regression with 5-fold cross-validation repeated 100 times, with performance assessed by C-index. Predictors with nonzero coefficients were refit with Weibull regression for STFS. Results: Among 112 patients with KIM-1 measurements available, median baseline KIM-1 level was 127.0 pg/mL (IQR 71.5–228.0). KIM-1 and ctDNA were associated with STFS at baseline and 3 months in univariable and multivariable analyses (table). Progression-free survival (PFS) and overall survival (OS) were also associated with KIM-1 at baseline (PFS: HR=2.2, 95% CI 1.5–3.3; OS: HR=5.1, 95% CI 2.5–10.2, P <0.001) and at 3 months (PFS: HR=3.5, 95% CI 2.2–5.5; OS: HR=5.0, 95% CI 2.3–10.9) (all P <0.001). K-COMPASS construction selected baseline KIM-1, baseline ctDNA MRD, and 4 clinical variables (prior systemic therapy lines, ECOG performance status, number of metastatic lesions, time from diagnosis to metastasis). The complete model showed strong discrimination (C-index=0.76) and excellent calibration (slope=1). A user-facing K-COMPASS tool is available online (www.trialdesign.org). Conclusions: To our knowledge, this is the first evaluation of KIM-1 in oligometastatic ccRCC and the first to analyze KIM-1 and ctDNA in tandem for RCC. Both biomarkers were strongly and independently associated with outcomes in patients receiving MDT without systemic therapy. Integrating KIM-1 and ctDNA with clinical factors (K-COMPASS) yielded a well-calibrated model with high discrimination to support risk-adapted decision-making. External validation is planned. Univariable and multivariable association of baseline KIM-1 and ctDNA MRD status with systemic therapy free survival. HR (95% CI) Baseline 3-Month Follow-Up Univariable Multivariable Univariable Multivariable KIM-1(per log10[pg/mL]) 2.5 (1.5–4.1) P <0.001 1.9 (1.0–3.6) P =0.041 3.2 (1.9–5.4) P< 0.001 2.2 (1.1–4.5) P =0.028 ctDNA (MRD+ vs MRD–) 2.8 (1.3–5.9) P =0.0089 2.5 (1.1–5.6) P =0.032 4.4 (2.1–9.5) P< 0.001 2.7 (1.1–6.7) P =0.032