NCCN Includes PCR ctDNA-MRD Testing in MIBC Treatment Algorithm

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology for Bladder Cancer to include tumor-informed multiplex PCR circulating tumor DNA (ctDNA)–based molecular residual disease (MRD) testing in the treatment algorithm for patients with muscle-invasive bladder cancer (MIBC).¹

Version 2.2026 of the guidelines state that the Panel “currently recommends the consideration of ctDNA-MRD testing as a tool for risk stratification and to determine the use of adjuvant immunotherapy after cystectomy in patients who have not received previous immune checkpoint inhibitor treatment using an FDA-approved, personalized, tumor-informed, multiplex PCR-NGS assay for ctDNA.”² In the latest guidelines, the NCCN also listed atezolizumab (Tecentriq) as a category 1 (other recommended) agent if a patient is “ctDNA-MRD positive within 1 year post-cystectomy as determined by an FDA approved, personalized, tumor-informed multiplex PCR-NGS assay for ctDNA.”

In May 2026, the FDA approved adjuvant atezolizumab and atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza; subcutaneous atezolizumab) in adult patients with MIBC following cystectomy with ctDNA MRD, as determined by an FDA-authorized test.³ At the same time, the agency also approved Signatera CDx as a companion diagnostic device to select patients with MIBC after cystectomy who have ctDNA MRD for adjuvant treatment with the agent. The approval was supported by data from the phase 3 IMvigor011 trial (NCT04660344), which showed that patients who received adjuvant atezolizumab achieved a median disease-free survival (DFS) of 9.9 months (95% CI, 7.2-12.7) compared with 4.8 months (95% CI, 4.1-8.3) for those treated with placebo (HR, 0.64; 95% CI, 0.47-0.87; P = .0047).

“This guideline update marks an important turning point for patients with MIBC,” Matthew D. Galsky, MD, deputy director of the Mount Sinai Tisch Cancer Center, director of Genitourinary Medical Oncology, codirector of the Center of Excellence for Bladder Cancer, and a professor of medicine (Hematology and Medical Oncology) at the Mount Sinai Tisch Cancer Center in New York, New York, stated in a news release.¹ “For the first time, NCCN has incorporated ctDNA-MRD testing into clinical decision-making following cystectomy. These recommendations are supported by prospective phase 3 evidence showing that a ctDNA-guided approach, using Signatera, can help guide post-surgical treatment decisions.”

How was IMvigor011 designed?

IMvigor011 included patients with MIBC who experienced a full recovery from cystectomy and were enrolled within 24 weeks following cystectomy; a minimum of 6 weeks must have elapsed from surgery.⁴ Eligible patients were required to have histologically confirmed (y)pT2-T4aN0M0 or (y)pT0-T4aN+M0 urothelial cancer with no evidence of radiographic disease and an ECOG performance status of 0 to 2; prior neoadjuvant chemotherapy was allowed.

Eligible patients then underwent ctDNA monitoring every 6 weeks and radiographic imaging every 12 weeks for up to 1 year after cystectomy. Those who remained ctDNA negative during this period did not receive any treatment, and they were followed for surveillance.

Patients who had any positive ctDNA test within the first year of surveillance were randomly assigned in a 2:1 fashion to treatment with intravenous atezolizumab at 1680 mg or placebo once every 4 weeks for up to 1 year.

The primary end point was investigator-assessed DFS. Overall survival (OS) represented a key secondary end point.

What were the data from an exploratory analysis of ctDNA dynamics in IMvigor011?

Findings from an exploratory analysis of ctDNA dynamics in IMvigor011 presented during the 2026 Genitourinary Cancers Symposium showed that serial ctDNA testing was able to differentiate patients at high and low risk of disease recurrence, potentially allowing them to avoid unnecessary therapy. Patients who were ctDNA negative (n = 357) experienced a median DFS that was not evaluable (NE; 95% CI, NE-NE) compared with 11.1 months (95% CI, 9.2-13.5) and 6.0 months (95% CI, 5.1-6.6) among patients who were ctDNA positive at a subsequent test (n = 86) and those who were ctDNA positive at the initial test (n = 126), respectively. The median OS among these respective subgroups was NE (95% CI, NE-NE), 35.1 months (95% CI, 24.9-NE), and 21.9 months (95% CI, 15.0-NE).

Additionally, ctDNA reduction or clearance were associated with improved DFS in the atezolizumab arm and ctDNA clearance was associated with improved DFS in the placebo arm. Patients who received atezolizumab who had ctDNA clearance (n = 56) or at least a 2-fold decrease (n = 23) achieved a median DFS of NE (95% CI, 35.7-NE) and 14.5 months (95% CI, 8.3-25.1), respectively; comparatively, the median DFS among those who had no change in ctDNA and received the agent (n = 33) was 8.2 months (95% CI, 6.1-10.3). In the placebo group, patients who experienced ctDNA clearance (n = 17) had a median DFS of 27.4 months (95% CI, 13.4-NE) compared with 4.5 months (95% CI, 3.7-8.1) among those with no change in ctDNA (n = 23) and 3.9 months (95% CI, 2.2-6.2) in patients with a minimum of a 2-fold decrease (n = 29).

“These recommendations reflect years of work to generate the clinical evidence establishing MRD as a clinically actionable and predictive tool,” Kevin Masukawa, PhD, vice president, life cycle management, oncology at Natera, added in the news release.¹ “The IMvigor011 study is an important example of how Signatera-generated evidence can help change clinical practice, and we believe this guideline update is just the beginning of a broader shift toward MRD-guided cancer care.”

References

1. NCCN recommends ctDNA-MRD testing using Signatera technology in landmark bladder cancer guideline update. News release. Natera. June 23, 2026. Accessed June 23, 2026. https://www.natera.com/company/news/nccn-recommends-ctdna-mrd-testing-using-signatera-technology-in-landmark-bladder-cancer-guideline-update/
2. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 2.2026. Accessed June 23, 2026. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
3. FDA approves atezolizumab for adjuvant treatment of muscle invasive bladder cancer in patients with molecular residual disease. FDA. May 15, 2026. Accessed June 23, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-adjuvant-treatment-muscle-invasive-bladder-cancer-patients-molecular
4. Powles, Grindheim J, Yilmaz M, et al. Circulating tumor (ct)DNA-guided adjuvant atezolizumab (atezo) in muscle-invasive bladder cancer (MIBC): exploratory analysis of ctDNA dynamics in the IMvigor011 trial. J Clin Oncol. 2026;44(suppl 7):633. doi:10.1200/JCO.2026.44.7_suppl.633