Urinary tumor DNA MRD analysis to identify responders to neoadjuvant immunotherapy in muscle-invasive bladder cancer.

Abstract

Bladder preservation is a viable option for some muscle-invasive bladder cancer (MIBC) patients, but an effective noninvasive biomarker test to accurately identify promising candidates is lacking. Here we present the clinical application of a novel tissue-agnostic, urine-based minimal residual disease (MRD) assay in the neoadjuvant setting for personalized disease surveillance and actionable target identification to facilitate bladder-sparing treatment approaches. The urinary tumor DNA (utDNA) analysis was evaluated in an investigator-initiated phase I trial RJBLC-I2N003 in which 20 patients diagnosed with resectable MIBC were treated presurgically with the PD-1 inhibitor toripalimab followed by radical cystectomy (RC). We showed that neoadjuvant toripalimab therapy was feasible, safe, and induced a 40% rate (8/20) of pathological complete response. Longitudinal utDNA profiling outperformed radiographic assessment and conventional biomarkers to predict the pathologic outcome of immune checkpoint blockade. In addition to detecting 3 exceptional responders with molecular MRD-negative status, we identified 7 other individuals characterized for utDNA clearance and 4 harboring FGFR3 mutants, all of whom (60%, 12/20) could have postponed or avoided RC. These findings demonstrate the safety and efficacy of neoadjuvant toripalimab, and suggest the immense potential of noninvasive utDNA MRD testing to guide tailored decision-making with regard to bladder preservation and change the current treatment paradigm for MIBC patients.