Trial launches of ctDNA-based blood test in urothelial carcinoma

Natera, Inc, has announced the launch of the phase 2/3 Alliance A032103 (MODERN) trial (NCT05987241), exploring the use of Signatera, a molecular residual disease (MRD) test, to measure circulating tumor DNA (ctDNA) in the blood to help guide treatment decisions for patients with muscle-invasive urothelial carcinoma (MIUC) following radical cystectomy.¹

Patients will be divided into 2 cohorts, Signatera-positive or Signatera-negative, based on initial assessments of MRD status.

The trial is being conducted through a partnership between Natera, the developer of the test, and the Alliance for Clinical Trials in Oncology.

“The MODERN trial represents a step towards precision medicine in bladder cancer treatment. By using Signatera to measure residual cancer after surgery, the Alliance A032103 (MODERN) trial may ultimately help to tailor the use of immunotherapy after surgery and optimize the care of individual patients,” said Matthew D. Galsky, MD, in the news release.¹ Galsky is a professor of medicine (hematology and medical oncology), the director of genitourinary medical oncology, the co-director of the Center of Excellence for Bladder Cancer, and an associate director for translational research at the Tisch Cancer Institute at Mount Sinai Hospital in New York, New York.

In total, the MODERN trial plans to enroll 1000 adult patients across over 300 clinical trials sites in North America. All patients included in the study will have undergone surgical removal of their bladder.

Patients will be divided into 2 cohorts, Signatera-positive or Signatera-negative, based on initial assessments of MRD status. Those who are Signatera-positive will be randomly assigned to receive nivolumab (Opdivo) or escalation with nivolumab plus relatlimab. Patients who are Signatera-negative will be randomly assigned to receive nivolumab or de-escalation to surveillance.

The primary outcome measures are the proportion of patients who are ctDNA negative at week 12, overall survival (OS), and disease-free survival (DFS). Secondary outcome measures include ctDNA-positive conversion and adverse events.²

“MODERN, like the CIRCULATE clinical trials in colorectal cancer, is a pivotal study that examines how Signatera-guided escalation and de-escalation pathways can potentially improve patient outcomes. We are grateful to collaborate with the Alliance on this important study,” said Minetta Liu, MD, chief medical officer of oncology at Natera, in the news release.¹

Signatera is a personalized test that measures ctDNA to detect for cancer recurrence. The test is currently available for clinical and research use and covered by Medicare for patients with MIUC, as well as colorectal cancer, breast cancer, and ovarian cancer.

Completion of the MODERN study is expected for April 2026.

Additional data on Signatera

Previous data on Signatera were published in the journal Nature and showed that ctDNA may be useful as a marker for response to atezolizumab (Tecentriq) in patients with urothelial carcinoma.³ In total, the study included 581 patients with a median follow-up of 23 months.

Data from the study showed that among the patients who were ctDNA-positive at the start of therapy, patients who received atezolizumab had improved DFS (hazard ratio = 0.58; 95% CI, 0.43–0.79; P = .0024) and OS (hazard ratio = 0.59; 95% CI, 0.41–0.86) compared with those in the control arm. There was no difference in DFS or OS between treatment arms for those who were ctDNA-negative at the start of treatment.

The current MODERN study is also supported by previous data from the phase 3 CheckMate-274 (NCT02632409), which established the safety and efficacy of adjuvant nivolumab in patients with high-risk MIUC. In 2021, the FDA approved adjuvant nivolumab for patients with urothelial carcinoma who are high risk of recurrence following radical cystectomy based on data from CheckMate-274.⁴

References

1. Natera and Alliance for Clinical Trials in Oncology announce activation of Alliance A032103 (MODERN): A randomized, phase II/III adjuvant trial in urothelial cancer. News release. Natera, Inc. Published online and accessed April 1, 2024. https://www.natera.com/company/news/natera-and-alliance-for-clinical-trials-in-oncology-announce-activation-of-alliance-a032103-modern-a-randomized-phase-ii-iii-adjuvant-trial-in-urothelial-cancer/

2. Testing the role of DNA released from tumor cells into the blood in guiding the use of immunotherapy after surgical removal of the bladder for bladder cancer treatment, MODERN study. ClinicalTrials.gov. Last updated March 29, 2024. Accessed April 1, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05987241

3. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature.2021;595(7867):432-437. doi:10.1038/s41586-021-03642-9

4. U.S. Food and Drug Administration approves Opdivo (nivolumab) for the adjuvant treatment of patients with high-risk urothelial carcinoma. News release. US Food and Drug Administration. August 19, 2021. Accessed April 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-adjuvant-treatment-urothelial-carcinoma