“This trial is telling us that ctDNA is driving who is going to benefit from receiving adjuvant immunotherapy,” Bellmunt said in an interview with OncLive® during the 2025 ESMO Congress.
In the interview, Bellmunt discussed the rationale for conducting the IMvigor011 trial of ctDNA-guided treatment with adjuvant atezolizumab vs placebo in patients with MIBC, how the trial was designed to focus on patients stratified by ctDNA status, the superior outcomes observed with atezolizumab in patients with ctDNA-positive disease, and the importance of sequential ctDNA testing in this population.
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: Despite being a negative trial for the primary end point, what did the phase 3 IMvigor010 trial (NCT02450331)show about the utility of assessing minimal residual disease (MRD) in MIBC, and how did the exploratory analysis of ctDNA-positive patients in that trial inspire IMvigor011?
Bellmunt: Three trials explored the role of immunotherapy after surgery in patients with high-risk muscle-invasive disease. These trials studied nivolumab [Opdivo], pembrolizumab [Keytruda], and atezolizumab, [respectively], after surgery. The nivolumab and pembrolizumab trials were positive for disease-free survival [DFS], and the only one that was negative was IMvigor010 exploring the role of atezolizumab given as an adjuvant treatment in patients at high risk.
However, we learn from negative experiences. We went back to all the patients who were included in IMvigor010, and we obtained ctDNA from those [who received] atezolizumab, and those who received follow-up. It was not a placebo-controlled study, it was an open study.
Patients who had ctDNA positivity who received atezolizumab had a better DFS and overall survival [OS]. This was a retrospective analysis, but the results were published in Nature. The next step was to design a prospective trial: IMvigor011.
What was the design of IMvigor011?
IMvigor011 is a trial where patients with high-risk muscle invasion after surgery who had remaining disease after having received neoadjuvant chemotherapy were screened for ctDNA status. We screened approximately [756] patients for this trial, and we saw that [379] of the patients were ctDNA positive just after surgery.1 We screened these patients for at least 6 months. This was sequential screening. [The primary end point of this trial was in] patients who were ctDNA positive. Patients with ctDNA positivity after surgery were randomly assigned to receive atezolizumab or placebo.
We ended up with 250 eligible patients with ctDNA positivity being randomly assigned 2:1 fashion to receive atezolizumab or placebo. The main end point of this trial was investigator-assessed DFS. If this end point was positive, then we would explore OS.
What were the key efficacy findings from IMvigor011?
Patients with ctDNA positivity who were randomly assigned to receive atezolizumab had superior DFS compared with patients receiving placebo. This was statistically significant. The HR was [0.64 (95% CI, 0.47-0.87; P = .0047)], and the [median] DFS was [4.8] months [(95% CI, 4.1-8.3) with placebo] vs [9.9] months [(95% CI, 7.2-127) with atezolizumab], meaning that there was a delay in disease recurrence in patients who were cDNA positive and received atezolizumab.
This [benefit also translated to] OS. We saw a HR of [0.59, (95% CI, 0.39-0.90; P = .0131), translating to a] benefit in OS [with atezolizumab]. That’s the first time we have seen an OS benefit in patients receiving adjuvant immunotherapy.
We have also been following the patients who have sequentially tested negative for ctDNA, and we have learned a lot from that. In patients who have had ctDNA checked [approximately] every 6 weeks for a year, we see that if the ctDNA test is negative at 1 year, these patients have a likelihood of being disease free [at 24 months] in [88.4%] of cases. If the patient is negative for ctDNA, maybe you can spare giving a potentially toxic and expensive treatment. That’s the main message coming from the trial.
One interesting finding from this trial is that patients who were eligible for random assignment were patients who, immediately after surgery, had ctDNA positivity. However, there were patients in whom, immediately after surgery, we didn’t see that the cDNA was positive. We followed those patients, and after several follow-ups, patients [who became ctDNA] positive later were included in the trial. The benefit [with atezolizumab] was also observed in these patients, meaning that early vs delayed adjuvant therapy, based on ctDNA status, was similarly beneficial for these patients. You can delay [treatment in patients with ctDNA-negative disease], and then the ctDNA [testing] can capture ongoing MRD. Then, these patients can still benefit in the same way as the patients who have ctDNA positivity immediately after surgery.
What were the safety findings from the IMvigor011 trial?
[Since the trial investigated] treatment vs placebo, there were adverse effects [AEs] related to the immunotherapy, but we didn’t see unexpected AEs. We know the profile of immunotherapeutic agents. [In total, 4.8%] of patients developed AEs related to immunotherapy. We didn’t see life-threatening AEs in patients receiving atezolizumab.
References
- 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.
- Powles T, Assaf ZJ, Degaonkar V, et al. 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
