ECOG ACRIN EA8192 cohort C: A phase II trial of neoadjuvant gemcitabine/durvalumab in patients (pts) with high grade (HG) upper tract urothelial carcinoma (UTUC) ineligible for cisplatin-based chemotherapy.

749 Background: There is mounting data for neoadjuvant chemotherapy use in HG UTUC, but the role of neoadjuvant chemoimmunotherapy remains less clear, including in cisplatin-ineligible pts, representing an unmet need in this population. Our multicenter trial evaluated the efficacy and safety of neoadjuvant gemcitabine/durvalumab (GD) in pts with HG UTUC. Methods: Cisplatin-ineligible pts with localized cN0 HG UTUC planned for radical nephroureterectomy (NU) were assigned to 4 GD cycles. Primary endpoint was pCR (ypT0N0/x); accrual goal was 29 pts; 18% pCR was considered worthy of further study, while 4% pCR would not justify further pursuit. Simon’s two stage design was used and if ≥1 out of the first 14 pts (13 evaluable) had pCR in stage I, another 15 pts (14 evaluable) would be accrued. With 27 evaluable (eligible and treated) pts, success was defined as ≥3 pCRs. Secondary endpoints included safety/tolerability, event-free survival (EFS) and overall survival (OS) both measured from registration and disease-free survival (DFS) measured from NU. Results: From 2022–2025, 31 pts enrolled (19 men) with median age 79 (44-88), including 15 renal pelvis, 15 ureteral, and 1 multifocal tumor; 5 with sessile appearance. Thirty pts were eligible and received ≥ 1 therapy dose and 23 completed all 4 planned cycles. Three patients achieved pCR (10%; 90%CI: 3.0 - 25.2%), 10 achieved pathologic stage < ypT2N0/x (33%, 90%CI: 19.3 – 49.9%). All 30 pts experienced treatment-related adverse events (TRAEs), 13 experienced G3-4 TRAEs (most common were anemia and neutropenia: 4 pts each), with no G5 TRAE. Among pts who underwent NU, median time from last neoadjuvant dose to NU was 10 weeks (range 5-22 weeks); 6 pts did not have lymph node dissection; 5 treated pts did not undergo NU: 1 due to progression before NU, 1 due to unresectable tumor, 1 due to cancer-related death, 1 due to refusal of further intervention, 1 due to deconditioning. With median follow-up of 11 months, the estimated 1-year EFS was 77.4% (60.9 – 98.3%). Conclusions: Neoadjuvant GD was feasible and relatively well tolerated in pts with HG UTUC; associated with 10% pCR, 33% < ypT2N0/x and promising 1-year EFS. Follow-up continues to further assess EFS, DFS, OS, while biomarker analysis is planned. Lymph node dissection for pts with HG UTUC is standard of care. The addition of durvalumab to accelerated MVAC chemotherapy is being evaluated in the randomized phase 3 part of this trial for cisplatin eligible patients (cohort A vs B; NCT04628767). Clinical trial information: NCT04628767 .