Serial ctDNA Testing Could Improve Risk Stratification in High-Risk MIBC

Serial testing of circulating tumor DNA (ctDNA) could have greater clinical utility as a risk stratification tool vs landmark ctDNA testing in patients with high-risk muscle-invasive bladder cancer (MIBC) following cystectomy, according to results from an analysis of outcomes for patients with persistent ctDNA negativity enrolled in the surveillance cohort of the phase 3 IMvigor011 trial (NCT04660344).¹

Findings presented at the 2024 European Association of Urology Annual Meeting showed that at a median follow-up of 16.3 months (IQR, 11.6-19.3), 9.9% of patients in the ctDNA-negative population (n = 17/171) experienced a disease-free survival (DFS) event. The 12- and 18-month DFS rates were 92% and 88%, respectively. Furthermore, 2 patients in this cohort died during follow-up, and the 12- and 18-month overall survival (OS) rates were 100% and 98%, respectively. Presenting study author Thomas Powles, MBBS, MRCP, MD, noted that 1 of the 2 deaths was not related to MIBC.

“These data lead us to have increased confidence around these high-risk patients with serial ctDNA testing. Those patients who are negative [post cystectomy] and remain negative only have about a 10% chance of relapse over this period and very small chance of death,” Powles said.

Powles is a professor of Genitourinary Oncology, lead for Solid Tumor Research, and director of Barts Cancer Centre at St. Bartholomew’s Hospital in London, United Kingdom.

Previously reported data from the phase 3 IMvigor010 trial (NCT02450331) suggested that ctDNA could help identify patients at risk of relapse following cystectomy. The study, which evaluated adjuvant atezolizumab (Tecentriq) vs observation in patients with high-risk MIBC, did not meet its primary DFS end point.² However, survival outcomes were worse for patients who were ctDNA positive, and this subgroup of patients experienced a survival benefit with atezolizumab vs observation.³

“IMvigor010 was a study in which we did an exploratory analysis, and in that, we identified that ctDNA with 1 test post-surgery could potentially select patients at a low risk and at a high risk of relapse. [Patients who were] ctDNA negative had about [a] 20% to 30% chance of relapse [in IMvigor010]. This was hypothesis-generating work, so we’ve gone on to [launch] a study called IMvigor011,” Powles explained.¹

The ongoing, double-blind, randomized IMvigor011 trial is evaluating atezolizumab vs placebo in patients with high-risk MIBC who are ctDNA positive following cystectomy. Patients are required to have (y)pT2-T4a N0 M0 or (y)pT0-T4a N+ M0 disease at the time of surgery. Notably, prior neoadjuvant chemotherapy is allowed but not required, and patients do not need to be eligible for adjuvant chemotherapy. Cystectomy must be performed 6 to 24 weeks prior to enrollment, and no evidence of residual disease is allowed. A tumor sample must be available to determine PD-L1 status.

Serial plasma is being collected once every 6 weeks for 6 months following cystectomy, then once every 12 weeks thereafter through month 12. Patients are also undergoing radiographic imaging once every 12 weeks for up to 12 months following surgery.

Patients who are ctDNA positive at any point are being randomly assigned in a 2:1 fashion to receive 1 year of atezolizumab or placebo, and this population is comprising the primary analysis population.

However, those who are ctDNA negative are being included in the surveillance group, where they will undergo radiographic imaging once every 6 months for 2 years, followed by survival follow-up once every 6 months for 2 years. Specifically, ctDNA negativity is defined as being disease-free at baseline; having at least 1 negative ctDNA result and no positive results; having at least 1 post-baseline disease assessment; and completing at least 12 months of surveillance post-cystectomy or discontinuing surveillance less than 12 months after surgery with no positive ctDNA test.

Investigator-assessed DFS is the study’s primary end point, and OS is a key secondary end point.

As of this analysis, 286 patients were ctDNA negative; follow-up was ongoing for 115 patients, and 171 met the criteria to be included in the analysis. Of those 171, 144 completed ctDNA surveillance and were continuing radiographic evaluation; 27 discontinued surveillance prior to completion; 15 experienced an investigator-assessed recurrence; 1 patient died due to recurrence; 1 patient died due to a cause unrelated to MIBC; and 10 patients were listed as other.

In the evaluable ctDNA-negative population, the median age was 69 years (range, 40-90). Most patients were White (56.1%), male (78.9%), and had an ECOG performance status of 0 (67.3%). Patients had either urothelial carcinoma (83.0%) or urothelial carcinoma with mixed histology (17.0%). Tumor stage included less than T2 (10.7%), T2 (34.9%), T3 (43.8%), and T4 (10.7%). Most patients had nodal stage N0 disease (78.9%), a PD-L1 immune cell (IC) score 0/1 (57.6%), at least 10 lymph nodes removed (77.8%), and a lymph node density of less than 20 (97.0%). Slightly more than half of patients (51.5%) did not undergo neoadjuvant chemotherapy.

Additional data showed that among patients with a PD-L1 IC of 0/1 (n = 98) and those with a PD-L1 IC of 2/3 (n = 72), the median DFS was not evaluable in both groups.

In the 15 patients who experienced disease recurrence, tumor stage included less than T2 (13.3%), T2 (40.0%), T3 (40.0%), and T4 (6.7%). Most patients in this group had a nodal stage of N0 (73.3%), a PD-L1 IC score of 0/1 (73.3%), at least 10 lymph nodes removed (80.0%), a lymph node density of less than 20 (100%), distant recurrence (73.3%), and no prior neoadjuvant chemotherapy (53.3%).

Active enrollment is ongoing in IMvigor011.

“A key question for us as a group: can we spare these patients [with high-risk MIBC] adjuvant treatment? We know immune checkpoint inhibition is associated with [approximately] a 10% chance of life-changing toxicity. Treating patients with such a small chance of relapse and death is a question that we will need to address,” Powles concluded.

Disclosures: Dr Powles reported receiving payment or honoraria from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Seagen, and Roche; receiving research funding from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Seagen, and Roche; and receiving travel accommodations from AstraZeneca, Ipsen, Merck Sharp & Dohme, Pfizer, and Roche.

References

1. Powles T, Bellmunt J, Jensen JB, et al. Clinical outcomes in patients with high-risk, post-cystectomy MIBC with persistent circulating tumour DNA-negative status on serial testing: surveillance analysis from the IMvigor011 study. Presented at: 2024 European Association of Urology Annual Meeting; April 5-8, 2024; Paris, France.
2. 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
3. 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