The New England Journal of Medicine OCTOBER 29, 2020

Osimertinib as Adjuvant Therapy in Patients with Resected EGFR-Mutated Non–Small-Cell Lung Cancer (ADAURA)

Wu YL, Tsuboi M, He J, et al. (ADAURA Investigators)

Bottom Line

The ADAURA trial demonstrated that adjuvant osimertinib significantly improves disease-free survival (DFS) and overall survival (OS) in patients with completely resected, EGFR-mutated stage IB to IIIA non-small-cell lung cancer.

Key Findings

1. In patients with stage II to IIIA disease, adjuvant osimertinib demonstrated a substantial reduction in the risk of disease recurrence or death (Hazard Ratio [HR] 0.17; 99.06% CI, 0.11 to 0.26; P < 0.001).

2. In the overall study population (stage IB to IIIA), osimertinib significantly improved DFS with an HR of 0.20 (99.12% CI, 0.14 to 0.30; P < 0.001).

3. Long-term follow-up demonstrated a statistically significant overall survival benefit, with a 51% reduction in the risk of death (HR 0.49; 95% CI, 0.33 to 0.73; P = 0.0004) in the stage II-IIIA patient cohort.

4. Osimertinib treatment substantially reduced the risk of central nervous system (CNS) recurrence, with a CNS DFS hazard ratio of 0.18 (95% CI, 0.10 to 0.33) in the stage II-IIIA population.

5. The safety profile was consistent with known side effects of osimertinib, with diarrhea, paronychia, and dry skin being the most common adverse events, leading to treatment discontinuation in 11% of the osimertinib group.

Study Design

Design

RCT

Double-Blind

Sample

682

Patients

Duration

3 yr

Median

Setting

Multicenter, International

Population Patients with completely resected stage IB, II, or IIIA non-small-cell lung cancer harboring EGFR exon 19 deletions or L858R mutations.

Intervention Osimertinib 80 mg once daily for 3 years.

Comparator Placebo once daily for 3 years.

Outcome Investigator-assessed disease-free survival in patients with stage II to IIIA disease.

Study Limitations

• The trial was unblinded early by the Independent Data Monitoring Committee due to overwhelming efficacy, which can sometimes influence subsequent reporting and follow-up.

• Adjuvant chemotherapy was permitted at the investigator's discretion, introducing heterogeneity in the background treatment, although this reflects real-world practice.

• While OS data is now mature, the initial primary analysis was based on DFS, which is a surrogate endpoint for overall survival.

• The benefit in the stage IB subgroup was less pronounced than in more advanced stages, raising questions regarding the optimal patient selection within the stage IB category.

Clinical Significance

Osimertinib is now established as the standard of care for adjuvant treatment in resected, EGFR-mutated stage IB-IIIA NSCLC, providing a significant survival benefit and reduced risk of distant, specifically CNS-related, recurrence.

Historical Context

Prior to ADAURA, adjuvant EGFR-TKI trials (such as ADJUVANT/CTONG) showed mixed results regarding survival, and there was no approved targeted therapy in the adjuvant setting for early-stage NSCLC. ADAURA shifted the paradigm by utilizing a third-generation TKI with superior CNS penetration and efficacy in an adjuvant setting, effectively targeting oncogenic drivers post-resection.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Osimertinib is classified as a third-generation EGFR tyrosine kinase inhibitor (TKI). How does its mechanism of action and binding affinity differ from first-generation TKIs like erlotinib, and why is this clinically relevant for patient side-effect profiles?

Key Response

Osimertinib binds irreversibly to the cysteine 797 residue in the ATP-binding pocket of the EGFR mutant protein. Unlike first-generation TKIs, it is highly selective for sensitizing mutations (Ex19del, L858R) and the T790M resistance mutation, while significantly sparing wild-type EGFR. This selectivity results in fewer 'off-target' skin and gastrointestinal toxicities compared to earlier generations.

Resident

In a patient with resected Stage IIB EGFR-mutated NSCLC who has just completed four cycles of adjuvant cisplatin-based chemotherapy, what is the level of evidence and the specific recommendation for adjuvant osimertinib according to the ADAURA results?

Key Response

Based on the ADAURA trial, adjuvant osimertinib is recommended (80 mg daily) for up to 3 years. The trial demonstrated a significant disease-free survival (DFS) benefit (HR 0.17 for Stage II-IIIA) and a subsequent overall survival (OS) benefit (HR 0.49). It is now considered the standard of care for resected Stage IB-IIIA EGFR-mutated NSCLC, regardless of whether the patient received prior adjuvant chemotherapy.

Fellow

The ADAURA trial demonstrated a remarkable reduction in CNS recurrence (HR 0.18). How does the pharmacokinetic profile of osimertinib explain this finding, and how should this data influence your surveillance strategy for patients on adjuvant therapy?

Key Response

Osimertinib has superior blood-brain barrier penetration and higher CNS distribution compared to gefitinib or erlotinib, as evidenced by its high brain-to-plasma ratio. Because it effectively suppresses micrometastatic CNS disease, some clinicians may extend the interval between brain MRIs, though vigilant monitoring remains necessary since recurrence risk remains after the 3-year treatment window concludes.

Attending

The OS benefit in ADAURA was significant across all stages, but the magnitude of DFS benefit was most pronounced in Stage IIIA. How do you approach the shared decision-making process for a Stage IB patient regarding the 3-year duration of therapy and the potential for 'financial toxicity' and long-term side effects?

Key Response

This involves balancing a high Hazard Ratio for survival against the absolute risk reduction, which is lower in Stage IB than in Stage IIIA. The discussion must address the 'cost of cure' versus the 'cost of suppression,' as 3 years of therapy is expensive and can cause chronic low-grade diarrhea or paronychia. The OS benefit (HR 0.44 for Stage IB-IIIA) provides a strong argument for therapy, but patient preference regarding 3 years of daily medication is paramount.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critically analyze the use of Disease-Free Survival (DFS) as the primary endpoint in ADAURA. Does the eventual confirmation of Overall Survival (OS) benefit in this trial validate DFS as a robust surrogate for OS in the adjuvant TKI setting, or are there confounding factors related to post-progression therapy?

Key Response

While ADAURA showed an OS benefit, the surrogacy of DFS remains debated in the TKI era. A major confounding factor is 'crossover': if patients in the placebo arm did not receive osimertinib upon recurrence (the current standard for metastatic disease), the OS benefit might be an artifact of inferior salvage therapy rather than the timing of the TKI. Researchers must analyze the 'post-recurrence' treatment data to confirm if adjuvant use is truly superior to early salvage use.

Journal Editor

The ADAURA trial reported an OS Hazard Ratio of 0.49. However, the trial design allowed for a 3-year treatment duration. As a reviewer, what concerns would you raise regarding the Kaplan-Meier curve morphology after the 36-month mark, and what does this imply about the trial's ability to claim 'cure' versus 'disease suppression'?

Key Response

A reviewer would look for a 'catch-up' phenomenon where the DFS curves begin to converge after treatment cessation at 36 months. If the curves stay parallel, it suggests a curative effect (elimination of micrometastatic clones). If they converge, it suggests osimertinib was merely suppressing growth. Long-term follow-up beyond the 3-year mark is essential to determine if we are extending the time to recurrence or actually increasing the cure fraction.

Guideline Committee

Current NCCN and ASCO guidelines have been updated to include adjuvant osimertinib as a Category 1 recommendation. How should the committee address the sequence of chemotherapy and TKI, and is there any subgroup where chemotherapy can be safely omitted in favor of immediate TKI start?

Key Response

Guidelines (NCCN Version 1.2024) state that patients should receive adjuvant chemotherapy if they are candidates for it, followed by osimertinib. However, for patients who are not candidates for platinum-based doublets due to comorbidities, ADAURA provides evidence for using osimertinib alone. The committee must emphasize that TKI therapy is not a replacement for chemotherapy in eligible patients, as the two modalities may have additive or synergistic effects on different clonal populations.

Clinical Landscape

Noteworthy Related Trials

2013

BR.19 Trial

n = 503 · J Clin Oncol

Tested

Gefitinib

Population

Completely resected stage IB-IIIA NSCLC

Comparator

Placebo

Endpoint

Overall survival

Key result: Gefitinib did not improve overall survival or disease-free survival in the unselected resected NSCLC population.

2014

SELECT Trial

n = 41 · J Clin Oncol

Tested

Erlotinib

Population

Resected stage IA-IIIA EGFR-mutated NSCLC

Comparator

None (single-arm)

Endpoint

2-year disease-free survival

Key result: The 2-year disease-free survival was 88%, suggesting that adjuvant EGFR TKI therapy could be beneficial in specifically mutation-positive populations.

2015

RADIANT Trial

n = 973 · Lancet Oncol

Tested

Erlotinib

Population

Stage IB-IIIA NSCLC with EGFR protein expression or amplification

Comparator

Placebo

Endpoint

Disease-free survival

Key result: Erlotinib did not significantly improve disease-free survival in patients selected based on EGFR IHC or FISH positivity.

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