Tumor-informed Molecular Residual Disease (MRD) Analysis from the ADAURA Study of Adjuvant Osimertinib (Tagresso) in Resectable Stage IB-IIIA EGFR-mutant Non-small Cell Lung Cancer (NSCLC)

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The ADAURA trial is a phase III, randomized, placebo-controlled study for patients with completely resected stage IB to IIIA NSCLC harboring EGFR L858R or exon 19 deletion, with or without adjuvant chemotherapy. Adjuvant osimertinib demonstrated significant disease-free survival (DFS) and overall survival (OS) benefits compared to placebo in resected early-stage NSCLC.

ADAURA adopted RaDaR tumor-informed molecular residual disease (MRD) analysis to explore the biomarker of disease recurrence using a tumor-specific high-depth ctDNA NGS panel, averaging 33 variants per panel. ctDNA sampling started at the beginning of the planned 3-year adjuvant treatment and continued during post-treatment follow-up. A total of 220 patients with successful MRD panel builds were analyzed in the MRD analysis set (n=112 osimertinib; n=108 placebo). An MRD detected classification was made when plasma ctDNA was positive for more than one variant detected in the ctDNA panel, regardless of MRD status at baseline. MRD analysis was planned to evaluate MRD clearance (baseline ctDNA positive after 24 weeks from randomization) and MRD detected on-study (first detected MRD sample post-baseline or after MRD clearance, if applicable).

The MRD analysis set showed similar outcomes to the overall ADAURA population, with a hazard ratio of 0.19 for DFS and 0.42 for OS in the MRD set, compared to 0.27 and 0.49 in the overall set, respectively. MRD events were detected in 68 patients, with 13% (15/112) in the osimertinib arm and 49% (53/108) in the placebo arm. Baseline MRD positivity indicated poor outcomes, but 80% (4/5) of patients who received osimertinib achieved ctDNA clearance. MRD positivity identified recurrence with a median lead time of 4.7 months. The concordance of MRD with DFS showed 65% positive percentage agreement (PPA) and 95% negative percentage agreement (NPA). The DFS and MRD event-free rates in the osimertinib arm were 91% and 86% at 24 and 36 months, respectively, compared to 46% and 36% in the placebo arm, with a hazard ratio of 0.23. Of the patients receiving osimertinib, 75% (84/112) maintained a DFS/MRD event-free status during treatment and post-treatment follow-up. In contrast, 69% of patients in the placebo arm experienced MRD/DFS events. Half of the patients (58%; 11/19) experienced DFS/MRD events in the post-treatment follow-up period within 12 months after discontinuing osimertinib. At 24 months post-osimertinib treatment, the DFS/MRD event-free rate was 66%. Tumor-informed MRD analysis demonstrated predictive value for maintaining the DFS/MRD event-free rate with adjuvant osimertinib, highlighting the potential for monitoring and personalized patient care in patients with resectable stage IB to IIIA EGFR-mutated NSCLC.

Reference:

Tom John et al., Molecular residual disease (MRD) analysis from the ADAURA trial of adjuvant (adj) osimertinib in patients (pts) with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). JCO 42, 8005-8005(2024).

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