CONSOLIDATE: A phase I/II study of radiotherapy combined with enfortumab vedotin (EV) for locally advanced bladder cancer with paired translational ctDNA and utDNA.

TPS912 Background: Locally advanced muscle invasive bladder cancer (LA-MIBC) is currently treated with sequential lines of systemic therapy, with local therapies rarely pursued. Trimodal therapy (TMT) with concurrent chemotherapy and radiotherapy (RT) is a curative local therapy; however, poorly tolerated with suboptimal outcomes in this patient population. Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has demonstrated promising activity in LA-MIBC, and pre-clinical models have shown synergy between ADCs and RT. This phase I/II study is being conducted to determine the safety and efficacy of the combination of EV with RT and to analyze translational biomarkers, including circulating tumor DNA (ctDNA) and urine tumor DNA (utDNA), with treatment response and outcomes. Methods: CONSOLIDATE is enrolling T4N0 or T1-4N2-3 LA-MIBC patients. Key exclusion criteria include prior pelvic RT and metastases beyond regional lymph nodes. Prior to study enrollment, patients must receive at least 2 cycles of EV with pembrolizumab. Patients must have no evidence of progression from EV with pembrolizumab prior to study enrollment. The phase I component of the study was conducted to determine the safe EV dose to be combined with RT with the starting dose of 1 mg/kg day 1 and 8 every 28 days during days of RT. RT schedule is 55 Gy in 20 fractions delivered over 4-5 weeks. Post study maintenance EV is optional per medical oncologist discretion. Primary endpoint of the phase I lead-in is safety of this combination therapy, with progression free survival as the primary endpoint of the phase II component. Key translational endpoints include ctDNA and utDNA collected prior to EV+RT and at 3 month follow up using an ultra-sensitive, tumor- informed minimal residual disease (MRD) assay. The planned enrollment is 41 patients, with 6 patients in the Phase I component. Patient characteristics from Phase I are summarized in Table 1. All patients receive intensity modulated RT with pelvic lymph nodes and selective lymph node boosting included. We will continue to enroll patients in the Phase II component with paired, bespoke ctDNA and utDNA assays for post-hoc minimal residual disease detection and prognostication. Clinical trial information: NCT06434350 .