IMvigor011: ctDNA-Guided Adjuvant Atezolizumab Improves Survival in Muscle-Invasive Bladder Cancer
This phase 3 trial used serial ctDNA monitoring after cystectomy to selectively treat only ctDNA-positive bladder cancer patients with adjuvant atezolizumab. ctDNA-guided therapy significantly improved both disease-free survival (9.9 vs 4.8 months) and overall survival (32.8 vs 21.1 months) versus placebo, while ctDNA-negative patients had 95% one-year disease-free survival without treatment. This is the first phase 3 trial to demonstrate that ctDNA-guided adjuvant therapy can improve overall survival.
The original study
ctDNA-Guided Adjuvant Atezolizumab in Muscle-Invasive Bladder Cancer.
- Authors
- Powles T, Kann AG, Castellano D, Gross-Goupil M, Nishiyama H, Bracarda S, et al.
- Journal
- The New England journal of medicine
- Type
- Journal Article, Randomized Controlled Trial, Clinical Trial, Phase III, Multicenter Study
- PMID
- 41124204
Original abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).