23Molecular residual disease (MRD) guided adjuvant ThErapy in renal cell carcinoma (RCC) -MRD GATE RCC

Background Ultrasensitive ctDNA assays are emerging as a prognostic marker in various tumor types including in renal cell carcinoma (RCC). Pembrolizumab is currently approved for intermediate and high-risk, surgically resected RCC patients based on a survival benefit of approximately 5% at 48 months. There are no currently established biomarkers for treatment selection. We examine a tumor informed MRD-guided approach to the assignment of adjuvant immunotherapy in an ambispective cohort. Methods The study was conducted with Institutional Review Board (IRB) approval and obtained informed consent from all prospective participants. Key inclusion criteria included age ≥18 years, clear cell RCC of intermediate to high-risk of recurrence, no prior systemic therapy, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, and availability of tumor sample for development of a tumor informed ctDNA MRD probe. M1 NED(No Evidence of Disease) was an exclusion criteria. In the prospective cohort, patients were assigned to receive pembrolizumab (400 mg q6 weeks or 200 mg q3 weeks) by intravenous infusion only if found to be ctDNA positive within a MRD surveillance window (<120 days from surgery). A minimum of one MRD test was required but more were allowed. In the retrospective cohort, only patients meeting prospective inclusion criteria and treated concordant to MRD with pembrolizumab were included. Data was analyzed for a period of 1/12/2023 - 2/23/2025. The primary and secondary endpoints were 1-year DFS and OS with an MRD guided approach respectively. Results 35 patients have been accrued (7 prospective, 28 retrospective), with a median follow up of 11 months. All patients were evaluable for radiologic progression. A median of 3 MRD tests were performed within the 12-week post-surgical eligibility window (range 1–4). 5 patients were MRD positive (14.28%), of which 3 have had recurred at the time of data cutoff. Among 30 patients who were MRD negative 2 patients progressed at followup (NPV = 93%). MRD guided therapy was associated with a 1-year DFS rate of 85.7% (95% CI: 69.7% – 93.4%) and MRD positivity was associated strongly with relapse risk HR 9.48 95%CI (1.58-57.00), P = .014 [Fig 1]. The median disease free survival in patients who tested positive for MRD was 5.6 months (95% CI 4.5–9.7 months). Median DFS was not reached in MRD negative patients. OS follow-up was not mature as no deaths were recorded in the study period. Conclusions This analysis of an intermediate-high risk RCC population treated based on serial postoperative MRD monitoring suggests that intensive MRD monitoring may be a valuable approach to better tailor adjuvant therapy for intermediate to high-risk RCC patients