A post hoc analysis of the phase 3 ADAURA trial has revealed that plasma-based, tumor-informed minimal residual disease (MRD) analysis may effectively predict disease recurrence in patients with resected EGFR-mutated non-small cell lung cancer (NSCLC) during and after adjuvant osimertinib treatment. The findings, published in Nature Medicine, suggest that MRD monitoring could potentially guide clinical intervention decisions, including treatment extension or intensification.
MRD Detection Predicts Recurrence Before Clinical Evidence
The exploratory analysis examined 220 patients from the ADAURA trial with successfully designed and validated RaDaR panels for MRD detection. Results showed that MRD positivity preceded disease-free survival (DFS) events by a median of 4.7 months (95% CI: 2.2–5.6), providing an early warning system for potential recurrence.
At baseline before treatment initiation, 8% of patients had detectable MRD, including 4% in the osimertinib group and 12% in the placebo group. Among these 18 MRD-positive patients, 7 (39%) had stage II disease, and 11 (61%) had stage IIIA disease. Nearly all patients (17 of 18) with MRD detected at randomization eventually experienced a DFS event.
"This exploratory analysis of patients from the ADAURA trial suggests that plasma-based, tumor-informed MRD analysis may predict disease recurrence during adjuvant treatment and during posttreatment follow-up," explained lead investigator Roy S. Herbst, MD, PhD, Ensign Professor of Medical Oncology and Pharmacology at Yale School of Medicine and deputy director of the Yale Cancer Center.
Significant Benefit with Osimertinib Despite Post-Treatment Recurrence Risk
The ADAURA trial enrolled patients 18 years and older with postsurgical stage IB, II, or IIIA EGFR-mutant NSCLC, randomizing them to receive either 80 mg of once-daily osimertinib or placebo for up to 3 years. Plasma samples were collected at randomization and at regular intervals during treatment and follow-up.
When combining DFS and MRD events as a composite endpoint, the 36-month event-free rates were 86% (95% CI, 78%-92%) with osimertinib versus 36% (95% CI, 27%-45%) with placebo, demonstrating a hazard ratio of 0.23 (95% CI, 0.15-0.36) favoring osimertinib.
However, the analysis revealed a concerning pattern: 25% of patients in the osimertinib group still experienced DFS or MRD events, with 68% of these events occurring after treatment discontinuation or completion. More troublingly, 58% of post-treatment events occurred within the first year after stopping therapy.
Implications for Extended Adjuvant Therapy
The findings raise important questions about the optimal duration of adjuvant osimertinib therapy. At 24 months post-treatment, the DFS and MRD event-free rate in the osimertinib group had declined to 66%, suggesting a significant proportion of patients may benefit from extended treatment.
"We also show that DFS and MRD event-free status was maintained for most patients during adjuvant osimertinib treatment and over 24 months posttreatment," Dr. Herbst noted. "These observations suggest that MRD monitoring may inform clinical intervention, including restarting or intensifying treatment."
Study Design and Methodology
The ADAURA trial's primary endpoint was DFS among patients with stage II or IIIA disease, with secondary endpoints including DFS among those with stage IB to IIIA disease. The exploratory endpoint specifically assessed the feasibility of circulating tumor DNA (ctDNA) profiling for MRD detection in early-stage NSCLC after surgery with or without chemotherapy.
Plasma samples were collected before dosing on day 1 of randomization, at 12-week intervals for up to 36 months during treatment, and then at weeks 12 and 24 during post-treatment follow-up. Additional samples were collected every 52 weeks until disease recurrence, death, or study end.
Future Directions
While these results are promising, further clinical studies are needed to confirm the role of MRD monitoring in guiding treatment decisions for patients with EGFR-mutated NSCLC. The findings highlight the potential of ctDNA-based MRD detection to optimize long-term management strategies, particularly regarding the duration of adjuvant therapy.
The study demonstrates that MRD detection could serve as an early indicator of recurrence risk, potentially allowing for more personalized treatment approaches that extend beyond the current standard 3-year adjuvant therapy period for high-risk patients.
