2 Relationships Between Plasma KIM-1 Levels, Peripheral Immune Profiles and Disease-Free Survival Outcomes in the TransRAMPART Study

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Abstract Background Despite optimal surgery, approximately 1 in 3 patients with renal cell carcinoma (RCC) will develop relapse. Adjuvant pembrolizumab has demonstrated a disease-free survival (DFS) and overall survival (OS) benefit in RCC, and recent data have also shown a DFS benefit with the addition of belzutifan to pembrolizumab. RAMPART (NCT03288532) is an investigator-led, international randomized phase III study, that enrolled patients with RCC at intermediate and high risk of relapse. Patients were randomized to observation (Arm A), durvalumab (Arm B), or durvalumab plus tremelimumab (Arm C). A significant DFS benefit was observed for Arm C compared to Arm A (DFS HR = 0.65, 95% CI 0.45 to 0.93, 1p = 0.009), but not for Arm B compared to Arm A (DFS HR = 0.74, 95% CI 0.53 to 1.04, 1p = 0.041). Given the toxicities associated with immunotherapy, biomarkers are needed to stratify patient risk and improve assignment to treatment. Kidney Injury Molecule-1 (KIM-1) has been identified as a prognostic marker post nephrectomy, though the mechanisms linking KIM-1 levels to risk are not fully established. Methods TransRAMPART prospectively collected longitudinal blood, tissue and urine samples alongside the main study, with the aim of identifying prognostic or predictive markers for adjuvant treatment. A total of 187 patients were recruited. Samples were collected at baseline, 16 weeks, 32 weeks, and at later timepoints up to 5 years. Plasma samples were profiled by MSD cytokine array including KIM-1, and peripheral blood mononuclear cells (PBMCs) were profiled by high resolution flow cytometry by IMU Biosciences. A baseline KIM-1 high threshold of ≥ 86pg/mL was applied, as used in the IMmotion010 study (Rini et al 2025). Survival analyses were performed using the Kaplan–Meier method, with log-rank p-values reported. Here we report the results for these exploratory blood-based analyses of Arms A, B and C. Results In the observation Arm A, patients with high baseline KIM-1 had significantly worse DFS compared to patients with low KIM-1 (HR 8.3, 95% CI 1.8 to 38, p = 0.0012, n = 45). This was not seen in either the durvalumab monotherapy group (HR 0.51, 95% CI 0.1 to 2.5, p = 0.41, n = 42) or in the combination group (HR 1.3, 95% CI 0.32 to 5.1, p = 0.72, n = 32). Within the KIM-1 high subgroup, durvalumab monotherapy was associated with significantly improved DFS compared to observation (HR 0.19, 95% CI 0.041–0.86, p = 0.016, n = 37), however no significant benefit was observed with combination therapy versus observation (HR 0.51, 95% CI 0.16–1.6, p = 0.25, n = 34). Among patients with low KIM-1, no significant differences in DFS were observed between durvalumab and observation (n = 49), nor between combination therapy and observation (n = 43). Patients with high KIM-1 had higher levels of baseline plasma CCL3 (p = 0.00248) and IL-12 (p = 0.0138). We were unable to detect any significant differences in PBMC profiles between patients with high and low KIM-1 levels. Conclusions As previously shown, elevated postoperative KIM-1 levels are prognostic in untreated patients. Although this exploratory analysis only assessed a subgroup of patients recruited to RAMPART, adjuvant therapy appears to attenuate the adverse prognostic effect of high KIM-1. High KIM-1 was predictive of benefit from durvalumab monotherapy. In contrast, no clear benefit from adjuvant therapy was observed in patients with low KIM-1. These findings support the hypothesis that KIM-1 may have predictive value for selecting patients for adjuvant therapy. Plasma cytokine profiles suggest increased baseline immune activity in patients with high KIM-1. Further work is needed to establish the relationship between KIM-1 status, immune activation states, and benefit from adjuvant immunotherapy.

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