ctDNA status selects for favorable prognosis in MIBC

Findings from the phase 3 IMvigor011 trial (NCT02450331) suggest that patients with muscle-invasive bladder cancer (MIBC) who have persistent circulating tumor DNA (ctDNA)-negative status on serial monitoring with the molecular residual disease (MRD) test Signatera may forego adjuvant treatment following cystectomy.

"These data lend increasing confidence that patients with high-risk MIBC who have persistent ctDNA− status after cystectomy may be spared from adjuvant treatment," concluded the investigators.

Data from the trial were presented by Thomas B. Powles, MBBS, MRCP, MD, at the 39th Annual European Association of Urology (EAU) Congress in Paris, France.¹

John Simmons, vice president of BioPharma at Natera, commented in a news release on the findings,² “IMvigor011 is an important randomized study that is designed to address a critical unmet need for the more than 35,000 patients a year diagnosed with muscle-invasive bladder cancer. We believe the results of this trial will further demonstrate how Signatera can help personalize treatment decisions and improve outcomes for bladder cancer patients. Together with Professor Powles and our collaborators at Genentech, we look forward to the full trial read-out which could serve as the basis of Natera’s first FDA companion diagnostic submission for Signatera.”

The global phase 3 IMvigor011 trial stratified patients based on ctDNA status. Patients who were ctDNA-positive at any point during the surveillance window were randomly assigned to receive the anti-PD-L1 atezolizumab (Tecentriq) or to placebo. Patients who were ctDNA-negative continued to undergo radiographic imaging every 6 months for up to 2 years.

Previous data from the IMvigor011 trial showed that around 30% of patients who tested ctDNA-negative on landmark testing experienced a disease-free survival (DFS) event. The current findings presented at the EAU Congress included assessments of 171 patients with high-risk MIBC who remained ctDNA-negative on serial ctDNA monitoring during the surveillance window.

Data showed a 12-month DFS rate of 92% and an 18-month DFS or 88% among patients who remained serially ctDNA-negative throughout the study. The total number of DFS events was 17.

Further, overall survival (OS) was 100% at 12 months and 98% at 18 months in this patient population. OS events occurred in 2 patients.

In total, the study included 171 patients with high-risk MIBC, of which 144 completed ctDNA surveillance and continuing radiographic evaluation. Of the 27 patients who discontinued surveillance prior to study completion, 15 were due to INV-assessed recurrence, 1 death due to recurrence, 1 death due to other, and 10 other.

The median follow-up for all patients was 16.3 months (IQR, 11.6-19.3). The median age of patients was 69. The primary end point was investigator-assessed DFS, and a key secondary end point was OS.

In the trial, ctDNA-negative was defined as having a disease-free status at baseline, at least 1 ctDNA-negative result and no ctDNA-positive result, at least 1 disease assessment after baseline assessment, and completion of at least 12 months of surveillance after surgery or discontinued surveillance after less than 12 months with no ctDNA-positive result.

In October 2023, Natera submitted the first module of its premarket approval application to the FDA for Signatera as a companion diagnostic assay for patients with MIBC.³ The remaining modules are expected to be submitted through 2025 following completion of the registrational trial.

Enrollment for IMvigor011 remains ongoing.

Overall, the investigators concluded in the presentation at EAU,¹ “This analysis suggests that serial ctDNA testing may have greater clinical utility than landmark ctDNA testing as a risk stratification tool. These data lend increasing confidence that patients with high-risk MIBC who have persistent ctDNA− status after cystectomy may be spared from adjuvant treatment.”

References

1. Powles T, Bellmunt J, Jensen JB, et al. Clinical outcomes in patients with high-risk, post-cystectomy muscle-invasive bladder cancer (MIBC) with persistent circulating tumour DNA-negative (ctDNA-) status on serial testing: surveillance analysis from the IMvigor011 study. Presented at: European Association of Urology Congress 2024. Paris, France. April 5-8, 2024.

2. Natera announces positive surveillance analysis from the randomized phase III IMvigor011 trial in muscle-invasive bladder cancer. News release. Natera, Inc. Published online April 5, 2024. Accessed April 8, 2024. https://www.natera.com/company/news/natera-announces-positive-surveillance-analysis-from-the-randomized-phase-iii-imvigor011-trial-in-muscle-invasive-bladder-cancer/

3. Natera submits first PMA module to the FDA for Signatera. News release. Natera, Inc. October 2, 2023. Accessed April 9, 2024. https://www.natera.com/company/news/natera-submits-first-pma-module-to-the-fda-for-signatera/