An exploratory analysis of patients with resected EGFR-mutated stage IB-IIIA non-small cell lung cancer (NSCLC), included in the ADAURA study, suggests that plasma-based, tumour-informed molecular residual disease (MRD) analysis may predict disease recurrence during adjuvant treatment with osimertinib and during posttreatment follow-up. The researchers also showed that a disease-free survival (DFS) and MRD event-free status was maintained for most patients during adjuvant osimertinib and over 24 months posttreatment.
These observations suggest that MRD monitoring may inform clinical intervention, including restarting or intensifying treatment. Prospective studies to understand the optimal frequency of MRD monitoring following adjuvant treatment completion and the appropriate clinical interventions following MRD detection are warranted before this can be applied routinely to the real-world clinical setting according to Dr. Roy S. Herbst of the Medical Oncology and Hematology, Yale School of Medicine and Yale Cancer Center in New Haven, CT, US, Dr. Yi-Long Wu of the Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University in Guangzhou, China and colleagues, who published the findings on 17 March 2025 in the Nature Medicine.
Adjuvant osimertinib for a duration of 3 years is recommended for patients with resected EGFR-mutated stage IB–IIIA NSCLC, based on significant DFS and overall survival improvement reported in the phase III ADAURA study. A trend toward an increased DFS event rate after completion of 3 years adjuvant treatment in ADAURA suggests that some patients may benefit from longer adjuvant osimertinib treatment.
The standard surveillance paradigm following curative intent therapies includes serial radiographic imaging; however, this detects only macroscopic disease, is confounded by changes in normal tissue after treatment and the optimal scan frequency for surveillance is uncertain. MRD, the detection of ctDNA after treatment with curative intent, could be a biomarker for early disease recurrence, with the potential to inform treatment and prognosis.
Due to low tumour burden, and a concomitant low fraction of ctDNA in patients with early-stage disease, robust detection of ctDNA can be challenging. However, recent advances in next-generation sequencing have improved the limit of detection for ctDNA and increased the feasibility of successfully building bespoke tumour-informed MRD assays and applying them in this setting. A successful technological strategy, generally referred to as tumour-informed MRD testing, leverages the genomic profile from the patient’s tumour to track an individualised set of tumour-specific alterations longitudinally in plasma ctDNA samples.
The study team explored whether tumour-informed, ctDNA-based, MRD could predict recurrence in an exploratory post hoc analysis of 220 patients, of whom 112 received osimertinib and 108 received placebo in the ADAURA study. MRD preceded imaging DFS events in this study by a median of 4.7 months (95% confidence interval [CI] 2.2-5.6). DFS and MRD event-free rate at 36 months was 86% versus 36% for patients in the osimertinib versus placebo groups (hazard ratio 0.23, 95% CI 0.15-0.36).
In the osimertinib group, DFS or MRD events were detected in 28 patients (25%); most events occurred following osimertinib cessation (19 of 28, 68%) and within 12 months of stopping osimertinib (11 of 19, 58%). At 24 months after osimertinib, the DFS and MRD event-free rate was 66%. In this study, MRD preceded DFS events in most patients across both arms. DFS and MRD event-free status was maintained for most patients during adjuvant osimertinib treatment and posttreatment follow-up, with most MRD or DFS events occurring after osimertinib treatment discontinuation or completion.
Understanding the predictive role and clinical utility of MRD detection is crucial to further improve outcomes for patients undergoing treatment for early and locally advanced NSCLC. The authors concluded that MRD detection could potentially identify patients who may benefit from longer adjuvant osimertinib, although this requires clinical confirmation.
Reference
Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB–IIIA non-small-cell lung cancer. Nature Medicine; Published online 17 March 2025. DOI: https://doi.org/10.1038/s41591-025-03577-y