Patients with muscle-invasive bladder cancer have varied outcomes after cystectomy. Circulating tumor DNA (ctDNA)-based detection of molecular residual disease may identify patients at high risk for recurrence after cystectomy who can benefit from adjuvant immunotherapy, thus sparing patients at lower risk from unnecessary treatment burden.
In a phase 3, double-blind, randomized trial, we used serial ctDNA testing to monitor (for up to 1 year) patients with muscle-invasive bladder cancer and no radiographic evidence of disease after surgery. Eligible patients who tested ctDNA-positive during surveillance were randomly assigned in a 2:1 ratio to receive intravenous atezolizumab or placebo every 4 weeks for up to 1 year. The primary end point was investigator-assessed disease-free survival. Overall survival was a secondary end point that was assessed in a hierarchical fashion to control for alpha. Patients who persistently tested ctDNA-negative did not receive atezolizumab or placebo.
A total of 761 patients were enrolled; 250 eligible patients who tested ctDNA-positive underwent randomization (167 to the atezolizumab group and 83 to the placebo group). The median disease-free survival was 9.9 months with atezolizumab, as compared with 4.8 months with placebo (hazard ratio for first event of disease recurrence or death, 0.64; 95% confidence interval [CI], 0.47 to 0.87; P = 0.005). The median overall survival was 32.8 months with atezolizumab, as compared with 21.1 months with placebo (hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P = 0.01). A total of 28% of the patients who received atezolizumab and 22% of those who received placebo had adverse events of grade 3 or 4 (related to atezolizumab or placebo in 7% vs. 4%); 3% and 2% of the patients, respectively, had fatal adverse events (related to atezolizumab or placebo in 2% vs. none). Among 357 patients with persistent ctDNA-negative status, disease-free survival was 95% at the end of the 1-year monitoring period and 88% at 2 years.
Among patients with muscle-invasive bladder cancer, ctDNA-guided adjuvant therapy with atezolizumab led to significantly longer disease-free survival and overall survival than placebo. (Funded by F. Hoffmann-La Roche; IMvigor011 ClinicalTrials.gov number, NCT04660344.).
The New England journal of medicine. 2025 Oct 20 [Epub ahead of print]
Thomas Powles, Ariel G Kann, Daniel Castellano, Marine Gross-Goupil, Hiroyuki Nishiyama, Sergio Bracarda, Jørgen Bjerggaard Jensen, Lydia Makaroff, Shusuan Jiang, Ja Hyeon Ku, Se Hoon Park, Oscar Reig Torras, Dingwei Ye, Marco Maruzzo, Andrea Necchi, Rafael Morales-Barrera, Emilio Francesco Giunta, Jae Lyun Lee, Giampaolo Tortora, Yüksel Ürün, Lukasz Dolowy, Dilek Erdem, Alvaro Pinto, Fabricio Grando, Wei Zou, Zoe June Assaf, Jacqueline Vuky, Viraj Degaonkar, Elizabeth E Steinberg, Joaquim Bellmunt, Jürgen E Gschwend, IMvigor011 Investigators
Barts Cancer Institute, National Institute for Health Research Biomedical Research Centre, Queen Mary University of London, London., Hospital Alemão Oswaldo Cruz, São Paulo., Hospital Universitario 12 de Octubre, Madrid., University Hospital of Bordeaux, Bordeaux, France., University of Tsukuba, Tsukuba, Japan., Azienda Ospedaliera Santa Maria, Terni, Italy., Aarhus University, Aarhus, Denmark., Fight Bladder Cancer, Chinnor, United Kingdom., Hunan Cancer Hospital, Changsha, China., Seoul National University Hospital, Seoul, South Korea., Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea., Department of Medical Oncology, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Hospital Clinic, Barcelona., Fudan University Shanghai Cancer Center, Shanghai., Istituto Oncologico Veneto, IRCCS, Padua, Italy., Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan., Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona., Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori," IRCCS, Meldola, Italy., Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea., Medical Oncology Unit, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome., Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey., University Clinical Hospital, Warsaw, Poland., Istinye University Medical Faculty, Istanbul, Turkey., University Hospital La Paz, Madrid., Centro de Pesquisas Oncológicas, Florianópolis, Brazil., Genentech, South San Francisco, CA., Dana-Farber Cancer Institute and Harvard University, Boston., Technical University Munich, Munich, Germany.