Disitamab vedotin combined with toripalimab and radiotherapy for multimodal organ-sparing treatment of muscle invasive bladder cancer: a proof-of-concept study

PURPOSE: Although trimodal therapy is currently the standard organ-sparing approach for muscle-invasive bladder cancer (MIBC), its clinical benefit is limited, and noninvasive biomarkers to guide dynamic decision-making are lacking. Here, we present a proof-of-concept study evaluating disitamab vedotin (RC48, a HER2-targeted antibody-drug conjugate) combined with toripalimab (JS001, anti-PD-1) and radiotherapy for bladder preservation in localized HER2-positive MIBC. PATIENTS AND METHODS: In the first-stage of an open-label phase II clinical trial (ClinicalTrials.gov identifier: NCT05979740), six patients were enrolled and received disitamab vedotin, toripalimab, and radiotherapy. Adverse events were documented according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5.0). Tumor response was evaluated every 12 weeks by radiographic imaging, cystoscopy with biopsies, and urine cytology. In parallel, we performed longitudinal liquid biopsy analyses of circulating tumor DNA (ctDNA) and urinary tumor DNA (utDNA) using PredicineCARE assay. RESULTS: The combination was overall tolerable, with no grade 4 treatment-related adverse events or deaths. Five patients (83.3 %) achieved a complete response and remained recurrence-free. Notably, utDNA testing showed high accuracy in monitoring therapeutic effectiveness and enabled early detection of tumor relapse, whereas ctDNA was largely undetectable across blood samples. CONCLUSIONS: These findings establish the feasibility, efficacy, and potential biomarker utility of a novel bladder-preserving regimen, setting the stage for a paradigm shift in MIBC management.