Natera's Moshkevich Discusses TOMR Approach and the Future of MRD-Guided Care

Even before the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting began, the molecular diagnostics company Natera had good news to share: On May 15, 2026, it received an FDA approval, the first of its kind, for a blood-based molecular residual disease (MRD) test to be used as a companion diagnostic.¹

In this case, the approval was for Natera’s Signatera CDx test, to be used with atezolizumab (Tecentriq; Genentech) in muscle-invasive bladder cancer (MIBC), following the October 2025 results from the IMvigor011 trial (NCT04660344).²

The study results represent a paradigm shift, with huge import for managed care: Investigators used circulating tumor DNA (ctDNA) testing to monitor patients for evidence of disease after surgery. And after giving immunotherapy only to those with positive test results for disease during a yearlong follow-up period, they had survival outcomes on par with giving everyone adjuvant therapy.²

The FDA approval is more than a milestone for Natera, said Solomon Moshkevich, MBA, the company’s president of clinical diagnostics.

“The significance of this goes well beyond bladder cancer,” he said in an interview with The American Journal of Managed Care. As a laboratory-developed test, Signatera has never needed FDA approval to reach patients; that is governed by CMS and the College of American Pathologists. But the MIBC indication created a new situation: A companion therapeutic was now available based on a patient's MRD status, which Moshkevich said called for regulatory authorization.¹

In the global phase 3 IMvigor011 trial, patients who remained with MRD-negative status did remarkably well with monitoring alone, achieving 100% survival at 1 year and 97% at 2 years. “That's just incredible…and that shows how strong the diagnostic stratification is with Signatera,” he said.

The Key Question: Can MRD Allow Treatment to Be Deferred?

The rise of MRD testing in clinical trials and in monitoring has raised the question: Is it safe to defer adjuvant treatment until MRD becomes detectable? As Moshkevich explained, oncologists have been historically trained to start systemic therapy within 6 to 8 weeks of surgery, with the belief that delays reduce efficacy.

IMvigor011 challenges that assumption. “This is the first time that we've shown it's safe to defer that treatment and to treat them later only when the MRD status becomes positive,” Moshkevich said. “And the big question that's been answered is that the efficacy of the treatment remains at the same level, even if you start that treatment later instead of starting it early.”

This concept, called Treatment on MRD (TOMR), was a theme across Natera's 35 abstracts at ASCO and is now being embedded in its next generation of clinical trials.³ Moshkevich described the newly announced SIGNAL ER-101 trial (NCT07214532), which targets patients with intermediate-risk early breast cancer currently managed with CDK4/6 inhibitors for 2 to 3 years after completing surgery and chemotherapy.⁴

The benefit of that therapy in the intermediate-risk population is modest—approximately 3% improvement in invasive disease-free survival⁵—but carries a price tag that can exceed $400,000 per patient. “We think we're going to reduce CDK4/6 inhibition for over two-thirds, maybe over three-quarters of patients, with no impact to outcomes," he said.

At ASCO, Natera best demonstrated this concept with the GALAXY study in colorectal cancer; in one analysis, patients who initially had negative results with Signatera but later had positive results derived a substantial benefit from adjuvant chemotherapy (HR, 0.3), showing Signatera can identify a subset of patients with early molecular recurrence who could benefit from adjuvant therapy.^3,6

“These results underscore the critical role of both the 4- and 12-week postsurgery time points for risk stratification and indicate that early ctDNA dynamics can identify a subgroup of initially ctDNA-negative patients who may benefit from delayed [adjuvant therapy],” the investigators wrote.⁶

As with IMvigor011, patients who remained with negative status throughout had excellent outcomes regardless of adjuvant therapy, showing the potential for patients to avoid unnecessary treatment.⁶

Elsewhere in colorectal cancer, Moshkevich said, Natera is partnering with Exelixis on the STELLAR-316 trial,⁷ enrolling patients who develop positive results with Signatera after surgery and testing zanzalintinib against zanzalintinib plus immunotherapy vs placebo.

Turning the Corner on Payer Coverage

For Natera and others in the testing arena, payer coverage remains uneven. Moshkevich acknowledged that coverage can be a challenge but expressed optimism that the FDA approval, combined with anticipated updates in the guidelines from the National Comprehensive Cancer Network, should yield progress in both commercial and employer plan coverage.

But if results show the potential for avoiding unnecessary treatment, do payers see the value?

“For payers, that’s the huge opportunity,” Moshkevich said.

The health economics of MRD-guided de-escalation are difficult to argue against. With IMvigor011, for example, he said, “For half of the patients in the study, they never got treated after surgery because they never turned positive, and those patients avoided a year of immunotherapy, which can cost upwards of $200,000 when you layer everything in.”

Natera has estimated that implementing a TOMR strategy in stage II and III colorectal cancer could reduce overall management costs by approximately 43%, and Moshkevich said those analyses are ongoing.

Other Results at ASCO

An impressive real-world meta-analysis involving 18 studies, 3000 patients, and 15 tumor types produced findings highlighting the consistency of the link between Signatera positivity and increased risk of recurrence or disease progression.⁸ In the adjuvant window (post surgery), a positive reading was significantly associated with increased risk of recurrence or death (HR, 8.15), whereas in the surveillance setting, the link was even stronger (HR, 18.30).

In addition, results showed the Signatera test spotted cancer ahead of other methods. “Across studies, ctDNA detection during surveillance preceded radiographic or clinical recurrence by a median of 3.20 months (95% CI: 2.50-4.10, P < .0001, n = 10), although this varied substantially by study/tumor type,” investigators wrote.⁸

ASCO also saw the launch of Annotation, a new digital platform that layers clinical context—surgeries, scans, treatments—onto a patient's Signatera result over time. "Patients and physicians spend hours creating these types of charts," Moshkevich said. "Natera can just do that with the software at the click of a button."

Moshkevich predicted that it will not be long before monitoring becomes the norm. “MRD testing and monitoring will become as standard and ubiquitous as a CT scan is today for following patients with cancer from diagnosis through treatment through surveillance.”

References

1. Signatera CDx approved by the FDA as a companion diagnostic in muscle-invasive bladder cancer (MIBC). News release. Natera Inc. May 15, 2026. Accessed June 19, 2026. https://www.natera.com/company/news/signatera-cdx-approved-by-the-fda-as-a-companion-diagnostic-in-muscle-invasive-bladder-cancer-mibc/
2. Powles T, Kann AG, Castellano D, et al; IMvigor011 Investigators. ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med. 2025;393(24):2395-2408. doi:10.1056/NEJMoa2511885
3. Natera to present 35 studies at ASCO, extending clinical data leadership in oncology. News release. Natera Inc. May 21, 2026. Accessed July 19, 2026. https://investor.natera.com/news/news-details/2026/Natera-to-Present-35-Studies-at-ASCO-Extending-Clinical-Data-Leadership-in-Oncology/default.aspx
4. Lipsyc-Sharf M, Mahtani RL, Parsons HA, et al. SIGNAL-ER-101: Signatera-guided CDK4/6 inhibitor therapy in breast cancer. J Clin Oncol. 2026;44(suppl 16):TPS648. doi:10.1200/JCO.2026.44.16_suppl.TPS648
5. Johnston S, Martin M, O’Shaughnessy J, et al. Overall survival with abemaciclib in early breast cancer. Ann Oncol. 2026;37(2):155-165. doi:10.1016/j.annonc.2025.10.005
6. Yokota M, Bando H, Nakamura Y, et al. Benefit of adjuvant chemotherapy in resected stage I-IV CRC patients based on ctDNA dynamics across two timepoints: results from GALAXY study. J Clin Oncol. 2026;44(suppl 16):102. doi:10.1200/JCO.2026.44.16_suppl.102
7. Exelixis announces clinical development collaboration with Merck for phase 3 STELLAR-316 pivotal trial for patients with colorectal cancer. News release. Exelixis Inc. May 19, 2026. Accessed June 19, 2026. https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-clinical-development-collaboration-merck
8. Kopetz S, Laliotis G, Abdelrahim M, et al. Prognostic value of circulating tumor DNA (ctDNA) for recurrence detection across solid tumors: a real-world meta-analysis. J Clin Oncol. 2026;44(suppl 16):11177. doi:10.1200/JCO.2026.44.16_suppl.11177