Circulating tumor DNA response adapted treatment de-escalation in metastatic urothelial carcinoma (CT-READ).

Abstract

TPS907 Background: Metastatic urothelial carcinoma (mUC) remains a lethal disease remains an aggressive malignancy with a 5-year survival rate below 10% despite recent therapeutic advances. The phase III EV-302 trials established the combination of pembrolizumab (P) and enfortumab vedotin (EV) as the first-line (1L) standard of care, demonstrating a median overall survival (OS) of 31.5 months and progression-free survival (PFS) of 12.5 months. However, ≥Grade 3 treatment-related adverse events (TRAEs) occur in more than half of treated patients, frequently necessitating dose interruptions or discontinuations. Notably, sustained clinical benefit is often observed following EV discontinuation, suggesting that some patients may achieve durable disease control with reduced treatment intensity. Circulating tumor DNA (ctDNA) represents a dynamic, minimally invasive biomarker of tumor burden and treatment response. Retrospective longitudinal analyses in patients with mUC treated with P+EV have demonstrated the prognostic and predictive value of ctDNA dynamics. (6) Specifically, ≥50% reductions in ctDNA levels have been independently associated with improved PFS and OS, supporting ctDNA as a robust, real-time biomarker to inform response-adapted, biomarker-driven therapeutic de-escalation strategies. Methods: This single-institution, single-arm, open-label, phase II pilot trial (NCT06313666) evaluates ctDNA-guided PEV de-escalation in patients with untreated mUC. Eligible Patients will receive standard 1L PEV for 8 cycles. Plasma ctDNA is measured every 12 weeks using a tumor-informed multiplex PCR assay. Patients achieving ≥50% ctDNA reduction at 6 months and without radiographic progression discontinue EV and continue pembrolizumab monotherapy every 6 weeks until progression or toxicity. EV rechallenge is permitted at progression. Primary endpoints are 3- and 6-month PFS post-de-escalation. A Simon two-stage minimax design (n = 30; 21 expected to de-escalate) will be used; the study will be considered positive if ≥7 patients remain progression-free at 3 months. Secondary and correlative endpoints include correlation of ctDNA dynamics with imaging-based response and clinical outcomes, ctDNA clearance kinetics, and neuropathy evaluation. Clinical trial information: NCT06313666 .