ctDNA-guided atezolizumab boosts survival in muscle-invasive bladder cancer

Treatment of muscle-invasive bladder cancer (MIBC) with atezolizumab (Tecentriq), when guided by circulating tumor DNA (ctDNA), yields statistically significant benefits in disease-free survival (DFS) and overall survival (OS), according to data from the phase 3 IMvigor011 trial (NCT04660344).^1,2

Thomas B. Powles, MBBS, MRCP, MD, a professor of genitourinary oncology and director of the Barts Cancer Centre at St. Bartholomew's Hospital in London, the United Kingdom, presented the research during a presidential symposium session at the 2025 European Society for Medical Oncology Congress in Berlin, Germany. The data were also published in the New England Journal of Medicine.

“Essentially, what we hypothesize is ctDNA can identify MRD—molecular residual disease. Those tiny cancer cells left behind will grow, and as they grow, eventually, they become detectable disease. As they become detectable disease in urothelial cancer, that's often too late for many patients, so a key question is, can we use this ctDNA test to differentiate those 2 groups of patients? The negative patients can then avoid unnecessary and toxic treatment,” Powles explained.

Powles then touched on the phase 3 IMvigor010 (NCT02450331) trial, which found that adjuvant atezolizumab did not confer a significant DFS or OS benefit to unselected patients with MIBC.³

Following this result, Powles explained, “We retrospectively went back, and we performed circulating tumor DNA on these patients. We identified that 40% of the patients were ctDNA positive. We used the Signatera assay, which is an informed approach, and intriguingly, in this exploratory analysis, we identified those positive patients who received atezolizumab had a hazard ratio of [0.59] for OS compared to placebo, and we also identified the negative patients who had about a 30% chance of relapse as opposed to a 90% chance of relapse. Those negative patients didn't benefit, with a hazard ratio of 1.38.^4,5 After that work, we thought, let's move forward and do a prospective, randomized phase 3 study to explore this further.”

IMvigor011 included patients with MIBC who were within 6 to 24 weeks of radical cystectomy, had histologically confirmed (y)pT2-T4aN0M0 or (y)pT0-T4aN+M0 urothelial cancer, no evidence of radiographic disease, and ECOG performance status 0-2. Prior neoadjuvant chemotherapy was permitted by the study protocol. The investigators conducted surveillance ctDNA monitoring until 1 year post-cystectomy. If patients were ctDNA positive at any time and were confirmed to have no evidence of radiographic disease, they were randomly assigned 2:1 to either treatment with atezolizumab 1680 mg intravenously (IV) every 4 weeks for up to 1 year, or IV placebo every 4 weeks for up to 1 year. If patients were ctDNA negative after the monitoring period, they received no treatment and underwent surveillance. The primary end point was investigator-assessed DFS, and the secondary end point was OS.

A total of 379 patients were ctDNA positive at any time during the monitoring period, and 377 patients were persistently ctDNA negative. Of the patients who were ctDNA positive, 129 were excluded to due radiographic recurrence or other factors, 250 were randomly assigned and efficacy evaluable, and ultimately 248 were safety evaluable. Of the 167 patients assigned to the atezolizumab arm, all but 2 received treatment. Eighty-three patients were assigned to placebo. Of the 377 patients who were persistently ctDNA negative, 20 were excluded, leaving 357 who were efficacy evaluable.

At a median follow-up of 16.1 months, in patients who were ctDNA positive, median DFS was 9.9 months (95% CI: 7.2-12.7) in the atezolizumab group vs 4.8 months (95% CI: 4.1-8.3) in the placebo group (stratified HR, 0.64, 95% CI: 0.47-0.87, stratified P = .0047).

The median OS for patients who were ctDNA positive was 32.8 months (95% CI: 27.7-NE) in the atezolizumab group vs 21.1 months (95% CI: 14.7-NE) for the placebo group (stratified HR, 0.59, 95% CI: 0.39-0.90, stratified P = .0131).

Powles also reported DFS and OS for patients who tested ctDNA positive at baseline and those who were ctDNA positive at a subsequent test. In patients who were ctDNA positive at baseline in the atezolizumab group, median DFS was 8.3 months (95% CI: 6.2-12.6) vs 4.2 months (95% CI: 2.4-7.7) in the placebo group (unstratified HR, 0.62, 95% CI: 0.42-0.91). In patients who were ctDNA positive at a subsequent test in the atezolizumab group, median DFS was 10.5 months (95% CI: 7.1-14.6) vs 8.3 months (95% CI: 4.2-12.6) in the placebo group (unstratified HR, 0.66, 95% CI: 0.40-1.10). In patients who were ctDNA positive at baseline in the atezolizumab group, median OS was 27.7 months (95% CI: 22.0-35.9) vs 18.2 months (95% CI: 10.9-NE) in the placebo group (unstratified HR, 0.71, 95% CI: 0.43-1.17). In patients who were ctDNA positive at a subsequent test in the atezolizumab group, median OS was NE (95% CI, 34.4-NE) vs 27.4 months (95% CI: 18.1-NE) in the placebo group (unstratified HR, 0.52, 95% CI: 0.24-1.12).

Powles also reported on ctDNA clearance, which occurred in 25.1% of the atezolizumab group vs 14.5% in the placebo group.

Turning to the patients who were persistently ctDNA negative, Powles reported “great outcomes,” with a 24-month DFS rate of 88.4% and 24-month OS rate of 97.1%.

Regarding safety, Powles said, “The adverse event profile is what you would expect for atezolizumab.” Grade 3-4 treatment-related adverse events occurred in 12 (7.3%) patients in the atezolizumab group vs 3 (3.6%) patients in the placebo group.

“This is an example of one of the big negative trials that we performed in bladder cancer. The group paused, looked back. The scientists, the precision oncologists, the biomarker folks, and the clinicians went back to the study, performed exploratory analysis, launched a subsequent randomized phase 3 based off that, which was positive. We did what we said we would do. It was a huge undertaking, and it resulted in a progression-free and an overall survival advantage,” Powles said in his concluding remarks.

“Early intervention with immune therapy saves lives. I strongly believe that's the case, and this trial helps tell that story. The clinical benefit was across subgroups of patients, including those patients at lower risk. What that tells us is ctDNA trumps other forms of prognostication such as pathology stage at surgery. Similar efficacy was observed irrespective of whether you were ctDNA positive or you became positive, and indeed, those patients who were persistently negative did extremely well. Atezolizumab was well tolerated with no new findings. These findings indicate serial ctDNA monitoring identified patients with muscle-invasive bladder cancer who benefit from adjuvant atezolizumab while sparing patients who are persistently negative from unnecessary treatment,” he added.

DISCLOSURES: Powles noted disclosures from Astellas, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Exelixis, F. Hoffmann-La Roche Ltd, Foundation Medicine Inc, Genentech Inc, Gilead, GlaxoSmithKline, Ipsen, Janssen, Johnson & Johnson, Mashup, Merck-Serono, Merck Sharp & Dohme, Natera, Novartis, Pfizer, and Seagen.

REFERENCES

1. Powles T, Kann AG, Castellano D, et al. IMvigor011: A phase III trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA8

2. Powles T, Kann AG, Castellano D, et al. ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med. Published online October 20, 2025. Accessed October 20, 2025. doi:10.1056/NEJMoa2511885

3. Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(4):525-537. doi:10.1016/S1470-2045(21)00004-8

4. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021;595(7867):432-437. doi:10.1038/s41586-021-03642-9

5. Updated overall survival by circulating tumor dna status from the phase 3 IMvigor010 trial: Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma. Eur Urol. 2024;85(2):114-122. doi:10.1016/j.eururo.2023.06.007