Molecular Residual Disease Testing After Surgery for EGFR-Mutant Lung Cancer

The Osimertinib Revolution in EGFR-Mutated Lung Cancer

For patients with surgically resected EGFR-mutated non-small-cell lung cancer (NSCLC), adjuvant (postoperative) treatment changed fundamentally with the ADAURA study. This large clinical trial showed that the EGFR inhibitor osimertinib (tagrisso) significantly improved disease-free survival compared with placebo. Osimertinib for up to 3 years after surgery is therefore recommended as standard adjuvant treatment for EGFR-mutated NSCLC.

MRD and Predicting Disease Recurrence

In a recent study published in Nature Medicine , patients enrolled in ADAURA underwent advanced follow-up to investigate whether molecular residual disease (MRD) (Molecular Residual Disease, MRD), based on circulating tumor DNA (ctDNA) detected after surgery, could predict cancer recurrence.

The ADAURA study showed that osimertinib benefits patients. But the key question remained: Were they truly cured, or would their cancer return? Detecting MRD offers a more personalized approach for patients with EGFR mutations. We are beginning to understand which patients benefit and when, and how to target treatment more precisely.

MRD-Positive Patients Are at Higher Risk

This further analysis evaluated 220 ADAURA participants (112 receiving osimertinib and 108 placebo). Although few were MRD-positive at randomization, MRD positivity was associated with poor clinical outcomes in both treatment groups.

If MRD detection is validated for clinical use, it could help identify high-risk patients and guide strategies such as intensifying or restarting adjuvant osimertinib. MRD may also identify patients at low risk of recurrence, allowing them to avoid unnecessary treatment and possible adverse effects.

Effects of Osimertinib on Molecular and Clinical Recurrence

(a) Time Between MRD Detection and a Disease-Free Survival Event

This analysis included 62 patients across both treatment groups who had a post-randomization disease-free survival (DFS) event and detectable MRD (Molecular Residual Disease). Each point on the graph represents a patient.

• Central vertical line: Shows the median time between MRD detection and the DFS event.
• Whiskers: Represent the minimum and maximum times between MRD detection and the DFS event.
• Box boundaries: Represent the upper and lower quartiles.
• In this study: MRD was detected before the DFS event by a median 4.7 months (95% CI, 2.2–5.6 months) .

(b) Kaplan-Meier Analysis: Patients Without DFS or MRD Events

In the MRD analysis population, this analysis shows the time from randomization to a DFS event (clinical recurrence or death) or a post-randomization MRD event, whichever occurred first.

Kaplan-Meier Curve Details:

• Blue line: Osimertinib group
• Yellow line: Placebo group
• Planned treatment duration: 36 months
• Percentages of patients without DFS or MRD events:
  • Osimertinib Group (112 patients)
    • At month 24: 91% (84-95)
    • At month 36: 86% (78-92)
  • Placebo Group (108 patients)
    • At month 24: 46% (36-55)
    • At month 36: 36% (27-45)
• Hazard ratio (HR - Hazard Ratio, 95% CI): 0.23 (0.15-0.36)

This analysis was calculated using an unadjusted Cox proportional hazards model.

(c) DFS or MRD Events in the Osimertinib and Placebo Groups

This graph shows DFS or MRD events in patients in the osimertinib group occurring during treatment and after treatment ended .

Osimertinib Group (112 patients)

• 75%: Patients without an MRD or DFS event
• 8%: Patients with an MRD/DFS event during treatment
• 17%: Patients with an MRD/DFS event after treatment
  • Within this group:
    • 58%: The event occurred within 12 months
    • 37%: The event occurred between 12-24 months
    • 5%: The event occurred after 24 months

Placebo Group (108 patients)

• 31%: Patients without an MRD or DFS event
• 69%: Patients with an MRD or DFS event

The Future of Real-Time Monitoring: MRD

MRD detection is a revolutionary development in clinical oncology:

MRD detection will be the approach of the future, enabling real-time patient monitoring. The data are strong, and we are excited to incorporate this approach into future studies.

In conclusion, MRD detection after surgery for EGFR-mutated NSCLC could improve clinical outcomes by allowing more personalized adjuvant osimertinib treatment. This additional ADAURA analysis again highlights the importance of individualized oncology treatment. Future studies will clarify how MRD can be used in clinical practice.