Urinary Tumor DNA MRD Analysis to Identify Responders to Neoadjuvant Immunotherapy in Muscle-invasive Bladder Cancer
Ruiyun Zhang, Jingyu Zang, Di Jin, Feng Xie, Akezhouli Shahatiaili, Guangyu Wu, Lu Zhang, Lu Wang, Yue Zhang, Zhixin Zhao, Pan Du, Shidong Jia, Jinhai Fan, Guanglei Zhuang, Haige Chen
Abstract
PURPOSE: Bladder preservation is a viable option for some patients with muscle-invasive bladder cancer (MIBC), 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. PATIENTS AND METHODS: 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). RESULTS: We showed that neoadjuvant toripalimab therapy was feasible, safe, and induced a 40% rate (8/20) of pathologic 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 response and 4 harboring FGFR3 mutants, all of whom (60%, 12/20) could have postponed or avoided RC. CONCLUSIONS: 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 patients with MIBC.