MRD Negativity Status Following Surgery Confers Survival in MIBC

Investigators of the double-blind IMvigor011 trial intended to assess an estimated population of 520 patients with MIBC and ctDNA positivity who are at a high risk of recurrence after cystectomy.

Surveillance following cystectomy for patients with muscle-invasive bladder cancer (MIBC) who tested serially negative for molecular residual disease (MRD) with the SignateraTM companion diagnostic experienced positive survival outcomes, according to a press release on findings from the phase 3 IMvigor011 trial (NCT04660344).¹

Investigators presented these findings at the European Association of Urology Congress 2024 in Paris, France.

Among 171 patients with high-risk MIBC who entered screening for the IMvigor011 trial and consistently tested negative for MRD during a surveillance window, the overall survival (OS) rate was 100% at 12 months and 98% at 18 months. Additionally, the 12-month and 18-month disease-free survival (DFS) rates were 92% and 88%, respectively. Based on results from this analysis, investigators concluded that those who retain MRD negativity via serial testing with Signatera may be eligible to avoid adjuvant treatment.

“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 [MIBC],” John Simmons, vice president of BioPharma at Natera, said in the press release.¹ “We believe the results of this trial will further demonstrate how Signatera can help personalize treatment decisions and improve outcomes for [patients with] bladder cancer….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.”

Findings from this analysis follow previously published data from the phase 3 IMvigor010 trial (NCT02450331). According to findings published in Nature, those with MIBC who tested positive for circulating tumor DNA (ctDNA) appeared to benefit from adjuvant atezolizumab (Tecentriq) compared with those assigned to observation with respect to DFS (HR, 0.58; 95% CI, 0.43-0.79; P = .0024) as well as OS (HR, 0.59; 95% CI, 0.41-0.86).²

Investigators of the double-blind IMvigor011 trial intended to assess an estimated population of 520 patients with MIBC and ctDNA positivity who are at a high risk of recurrence after cystectomy.³ Patients were randomly assigned to receive atezolizumab at 1680 mg on day 1 of each 28-day cycle for 12 cycles or a maximum of 1 year or matched placebo. Study treatment continued until disease recurrence, unacceptable toxicity, withdrawal of consent, or study termination.

The trial’s primary end point was investigator-assessed DFS in those who tested positive for ctDNA within 24 weeks following cystectomy. Secondary end points included OS, disease-specific survival, distant metastasis-free survival, ctDNA clearance, adverse effects, and health-related quality of life.

Patients 18 years and older with histologically confirmed MIBC who received prior platinum-containing neoadjuvant chemotherapy were eligible for enrollment on the trial. Additional eligibility criteria included having evaluable PD-L1 expression, an absence of residual disease and metastasis as confirmed by CT or MRI, and full recovery from cystectomy within 24 weeks following the procedure. Having an ECOG performance status of 0 to 2, a minimum life expectancy of 12 weeks, and adequate hematologic and organ function were additional requirements for enrollment on the treatment phase of the study.

Developers previously submitted the first module of a premarket approval application to the FDA for Signatera as a companion diagnostic for those with MIBC in October 2023.⁴

“This milestone reflects the significant efforts of our team in developing an FDA-grade quality and manufacturing system, a strong foundation designed to support future regulatory submissions across disease indications for Signatera and across product lines,” Steve Chapman, chief executive officer at Natera, said in a press release at the time of this submission.⁴

References

1. Natera announces positive surveillance analysis from the randomized phase III IMvigor011 trial in muscle-invasive bladder cancer. News release. Natera, Inc. April 5, 2024. Accessed April 8, 2024. https://tinyurl.com/3t5td7vf
2. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021;595:432-437. doi:10.1038/s41586-021-03642-9
3. A study of atezolizumab versus placebo as adjuvant therapy in patients with high-risk muscle-invasive bladder cancer who are ctDNA positive following cystectomy (IMvigor011). ClinicalTrials.gov. Accessed April 8, 2024. https://tinyurl.com/3r77ebjp
4. Natera submits first PMA module to the FDA for Signatera. News release. Natera, Inc. October 2, 2023. Accessed April 8, 2024. https://tinyurl.com/mr29uu8e