Results from the phase 3 IMvigor011 trial (NCT04660344) evaluating adjuvant atezolizumab (Tecentriq) showed that circulating tumor DNA (ctDNA) testing could refine muscle-invasive bladder cancer (MIBC) management by guiding adjuvant immunotherapy decisions, although further research is needed to enhance treatment precision across disease stages and regimens, according to Joaquim Bellmunt, MD, PhD.
In an interview with OncLive®, Bellmunt highlighted ways that ctDNA testing could augment bladder cancer treatment standards, the need for data from ongoing trials to determine the optimal use of ctDNA test results in various clinical scenarios, and the promise of ctDNA results for identifying patients likely to benefit from immunotherapy. He discussed the IMvigor011 trial results in more detail in another portion of the interview.
Bellmunt is director of the Bladder Cancer Center and a senior physician at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.
OncLive: What do the IMvigor011 data indicate about the potential role for ctDNA in bladder cancer detection and management? What additional data are needed to help determine how to incorporate this information into clinical decision-making strategies?
Bellmunt: [ctDNA analyses are] happening in [many] diseases. Sometimes we are lagging behind in how the [urothelial cancer treatment paradigm] is evolving. Nowadays, for example, since [IMvigor11] was designed in [2020], we have had several positive trials. We have had the phase 3 NIAGARA trial [NCT03732677], where patients [with MIBC] received neoadjuvant chemoimmunotherapy followed by surgery, and then adjuvant durvalumab [Imfinzi] for 8 cycles, independent of their pathological response after neoadjuvant chemoimmunotherapy.
At the 2025 ESMO Congress, we also heard the outstanding results on the use [of pembrolizumab (Keytruda) plus enfortumab vedotin-ejfv (Padcev)] in patients [with MIBC] who are unfit for platinum[-based chemotherapy]; [this regimen is] 3 cycles [of the combination] before surgery, and then after surgery, patients receive 6 additional cycles [of the combination] and then maintenance immunotherapy [with pembrolizumab alone]. This phase 3 KEYNOTE-905/EV-303 [trial (NCT03924895) regimen] is likely a new standard of care because for the first time, we have seen a survival benefit in patients receiving neoadjuvant enfortumab vedotin/pembrolizumab, followed by adjuvant [treatment with the combination, followed by pembrolizumab alone]. We have seen a [57.1% (95% CI, 49.3%-64.6%)] pathologic complete response [(pCR) rate with this regimen].1 Those are outstandingly good results never seen before.
IMvigor011 Trial: Key Takeaways
- Adjuvant atezolizumab significantly improved disease-free survival (DFS; HR, 0.64; 95% CI, 0.47-0.87; P = .0047) and overall survival (OS; HR, 0.59; 95% CI, 0.39-0.90; P = .0131) compared with placebo in patients with ctDNA-positive MIBC.
- Patients who persistently tested ctDNA negative had a low risk of recurrence and death, with only 10.9% of patients experiencing a DFS event and 3.9% of patients experiencing an OS event in the no-treatment population after a median follow-up of 21.8 months from cystectomy.
- Subgroup analysis for DFS revealed a particularly strong benefit with atezolizumab in patients with high PD-L1 status (HR, 0.33; 95% CI, 0.19-0.58) and those who tested ctDNA positive earlier following cystectomy (HR, 0.52; 95% CI, 0.36-0.74).
The question is: How are we going to use ctDNA in other trials? The results of IMvigor011 [were] based on the decision to give adjuvant treatment in patients who were ctDNA positive. Is [ctDNA] going to be used in other settings? Those are questions that unless we get results from these ongoing or completed trials, we cannot start extrapolating.
What [should we] do in patients who have a pCR? Do we need to give, for example, 8 cycles of adjuvant immunotherapy? Data from the breast cancer [field are] telling that, yes, despite the pCRs, still there is benefit [with additional immunotherapy]. However, if the patient’s getting a CR after neoadjuvant chemoimmunotherapy, maybe they will not be willing to receive adjuvant treatment.
These are good questions. The paradigm is evolving, so [there will be] new treatment options for patients. We’ll see how [these new data are] going to [affect it] in the end.
What are the next steps for the IMvigor011 investigation?
[We presented] the initial results [at ESMO 2025].2 We are analyzing the cohort of patients with more granularity. For example, [we are investigating] how the ctDNA affects or correlates with staging before receiving neoadjuvant therapy or at the time of surgery; this might give us [more] prognostic data.
We know that ctDNA is prognostic. Patients who have high ctDNA levels do worse than patients who are ctDNA negative. [However, there may be] correlations made in this trial, [such as] correlations between staging, response to prior treatment, and patient outcomes.
How do the IMvigor011 results open the door for a new treatment paradigm for patients with bladder cancer who are positive for recurrence on a molecular level without evidence of disease progression or recurrence on imaging?
[IMvigor011] formed the basis for other trials that are already ongoing. For example, we have the phase 2/3 MODERN trial [NCT05987241], where patients with [urothelial cancer with] ctDNA positivity are assigned to receive immunotherapy. That trial is asking an additional question: Can we optimize adjuvant therapy? For example, in the MODERN trial, patients who are ctDNA positive are randomly assigned to receive nivolumab [Opdivo] or nivolumab plus a LAG-3 inhibitor—another immunotherapy compound. This could potentially end up [showing that patients] can obtain further benefit if they are adding immunotherapy compounds to an immunotherapy [backbone] in patients who are ctDNA positive.
[ctDNA analysis] is a dynamic test. In [the phase 3] IMvigor010 [trial (NCT02450331)], we only had baseline [testing for] determination of ctDNA [status]. [In IMvigor011], we had sequential checking of ctDNA for up to 1 year. In patients who are [ctDNA] negative after 1 year, the likelihood of recurrence was only [11.6% at 24 months without adjuvant treatment].
References
- Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: phase 3 KEYNOTE-905 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA2.
- Powles T, Kann AG, Castellano D, et al. IMvigor011: a phase 3 trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA8.
