Phase 1/2 REINFORCE tests enfortumab vedotin Nectin-4 ADC + pembrolizumab PD-1 blockade with consolidation

University of Washington’s Phase 1/2 REINFORCE pilot asks whether patients with unresectable locally advanced, node-positive, or oligometastatic muscle-invasive bladder cancer who achieve a favorable response (CR/PR) after enfortumab vedotin + pembrolizumab can benefit from aggressive local “clean-up” of residual disease. The systemic backbone is enfortumab vedotin (Astellas + Pfizer), a Nectin-4–targeted antibody–drug conjugate delivering the microtubule toxin MMAE, combined with pembrolizumab (Merck), a PD-1 immune checkpoint inhibitor. After re-TURBT, participants with residual bladder disease proceed via shared decision-making to bladder-directed consolidation with either chemoradiation (IMRT/VMAT; 55 Gy/20 fractions with radiosensitizing cisplatin or alternatives such as gemcitabine, 5-FU, or mitomycin) or radical cystectomy with lymphadenectomy; metastasis-directed therapy (preferably SBRT) can treat limited metastatic sites. A key differentiator is biomarker-guided monitoring using circulating tumor DNA (ctDNA) and urine tumor DNA (utDNA) to help risk-stratify and inform stopping vs continuing systemic therapy (observation vs pembrolizumab maintenance). Today’s care for metastatic/locally advanced urothelial cancer is systemic therapy (now often EV+pembrolizumab up front), while local bladder control is typically palliative or for select responders—this trial tests a curative-intent, de-escalation-enabled multimodality strategy.