The signal that changes everything: understanding MRD in oncology drug development

Biotech The signal that changes everything: understanding MRD in oncology drug development Sponsored By Natera Sep 14, 2026 8:00am Biotech In oncology, this question shapes almost every treatment decision after therapy. Yet imaging and clinical response criteria may not reliably answer it when the disease signal is too faint to detect. Molecular residual disease (MRD) assays detect circulating tumor DNA (ctDNA), fragments of tumor-derived genetic material shed into the bloodstream.

They reveal residual disease at the molecular level sooner than persistence or recurrence can be detected by conventional tools such as imaging, creating a window of opportunity for earlier intervention. Once treatment begins, ctDNA clearance — the transition from detectable to undetectable ctDNA during or after treatment — and ctDNA dynamics in general can offer an early read on treatment response. MRD can change trial decisionsFor biopharma teams, MRD can change how trials are designed, enrolled, and evaluated.

By identifying molecular recurrence before radiographic recurrence, drug developers can now design Treatment on MRD (TOMR) trials that enroll patients earlier, target disease when tumor burden is still low, and expand the intervention window before clinical relapse. fierce_article_figure_1_1_1_1.png Figure 1. Serial ctDNA monitoring tracks disease activity over time from diagnosis through treatment and recurrence.

(A) Imaging indicates complete response, while ctDNA becomes detectable, a discordant signal. Patient was persistently ctDNA negative before turning positive. (B) Imaging shows only partial response, while ctDNA has cleared to undetectable levels, indicating molecular response.

The window to treat on molecular recurrenceIn TOMR trials, ctDNA-positive, imaging-negative patients are identified and enrolled when the potential for a durable response may be highest. This defines a higher-risk population than an all-comer study design, enabling a more focused evaluation of treatment effect. IMvigor011 shows what MRD-guided enrollment makes possible.

By enrolling only ctDNA-positive, imaging-negative patients, the trial demonstrated a 55% median OS improvement and 2x median DFS improvement in the atezolizumab arm — results that had not been seen in earlier all-comer approaches. The MRD-guided design also required ~70% fewer randomized patients and cut the time from final enrollment to interim analysis from 16 months to 6.7 months.1 Assess treatment response within weeks instead of monthsctDNA clearance — the transition from detectable to undetectable ctDNA levels — can serve as an early indicator of treatment response ahead of imaging.Multiple studies across tumor types have demonstrated that early ctDNA clearance, within weeks of treatment initiation, is associated with long-term outcomes. For example, in the neoadjuvant setting, ctDNA clearance during or after neoadjuvant therapy predicted event- or disease-free survival.2,3 In advanced disease, achieving ctDNA clearance as early as two cycles into immune checkpoint inhibitor treatment was associated with 100% overall survival (OS) at a median follow-up of 25 months from first clearance.⁴For drug development, this means ctDNA clearance can serve as an early indicator of treatment response, enabling faster go/no-go decisions and potentially supporting regulatory milestones before conventional endpoints mature.

In Allogene Therapeutics’ pivotal Phase 2 ALPHA3 trial evaluating an investigational allogeneic CAR T product as a 1L consolidation treatment for LBCL patients, MRD clearance data at Day 45 was compelling enough to support both RMAT and Fast Track designations for cemacabtagene ansegedleucel (cema-cel) from the FDA.5,6 fierce_article_figure_2_alpha3_1.png Figure 2. MRD analysis performed using Natera's Clarity™ utilizing Phased Variant Technology5Assay sensitivity determines actionabilityAt very low tumor burden, an MRD assay can miss disease that remains present — when ctDNA volumes fall below the assay's analytical limit of detection. In one pan-cancer study, nearly 50% of MRD-positive cases were detected at or below 100 ppm — levels that would be missed by less sensitive assays, compromising patient identification and enrollment.7Since ctDNA shedding varies by cancer type and can be lower after treatment, the consequences of insufficient sensitivity compound across every application — from identifying patients early enough to enroll, to determining whether ctDNA clearance reflects genuine treatment response or disease that simply falls below the detection threshold.

More signal, less noise: Improving confidence in MRD detectionAt low disease burden, when MRD matters most, ctDNA signals need to be amplified before they can be quantified. This creates a problem as background healthy DNA is also amplified, creating noise. The SignateraTM Genome MRD assay cuts through the noise using Phased Variant Technology, which detects two or more tumor-specific mutations occurring together on the same DNA fragment.8 Because sequencing errors are unlikely to reproduce the same pattern across multiple nearby mutations, error rates fall from approximately 1 in 10,000 for standard single-nucleotide variants to fewer than 1 in 100 million, enabling a limit of detection down to 0.1 PPM.9,10For trial teams, that confidence at the low end of detection means more reliable enrollment, more credible clearance endpoints, and earlier development decisions based on actionable efficacy signals.

fierce_article_figure_3_1.png Figure 3. Phased Variant Technology provides confidence across tracked variants, enabling market-leading detection.8,9,10MRD is reshaping oncology drug developmentMRD is reshaping how oncology trials are designed — from who gets enrolled, to when treatment starts, to how early efficacy can be measured. Whether MRD results can be acted on depends on assay sensitivity, particularly at low levels of disease burden.

Learn more about how phased variants enable detection down to 0.1 PPM.10 Powles T, et al. ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med.

2025;393:2395–2408. Van der Heijden MS, et al. ctDNA in patients with MIBC who received perioperative durvalumab in NIAGARA.

J Clin Oncol. 2025;43(suppl 17):4503.Magbanua MJM, et al. Clinical significance and biology of ctDNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy.

Cancer Cell. 2023. doi:10.1016/j.ccell.2023.03.007Bratman SV, Yang SYC, Iafolla MAJ, et al.

Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer. 2020;1(9):873–881.Allogene Therapeutics, ALPHA3 interim futility analysis.

press release (April 13, 2026).Allogene Therapeutics, FDA grants RMAT and Fast Track designations to cema-cel. Press release (July 29, 2026).George M, Schwartz G, McHayleh W, et al. Clinical performance of Signatera Genome assay in a cohort of patients with solid tumors.

J Clin Oncol. 2025;43(16_suppl):3142. Phased Variant Technology is included in Signatera™ Genome (RUO), CLARITY™ Fixed (RUO, CLIA), and CLARITY™ Heme (RUO, CLIA)Kurtz DM, et al.

Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA. Nat Biotechnol. 2021;39(12):1537-1547.Cabel et al.

ESMO 2024, using CLARITY™ Fixed Research Use Only (RUO) assay. The editorial staff had no role in this post's creation. Biotech