Longer-Term Follow-up From ADAURA Supports Adjuvant Osimertinib as Standard of Care for EGFR-Mutated Stage IB to IIIA NSCLC

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With longer-term follow-up, adjuvant treatment with osimertinib led to a 77% reduction in the risk of disease recurrence or death following complete resection vs placebo-treated patients with EGFR-mutated, stage II to IIIA non–small cell lung cancer (NSCLC). Disease-free survival was improved regardless of prior adjuvant chemotherapy or disease stage, according to updated findings from the phase III ADAURA trial presented at the European Society for Medical Oncology (ESMO) Congress 2022.1

Exploratory analysis showed that adjuvant osimertinib reduced the risk of recurrence in the central nervous system (CNS) by 76% in patients with stage II to IIIA disease.

In the overall trial population, which included patients with stage IB to IIIA EGFR-mutated NSCLC, adjuvant osimertinib reduced the risk of disease progression or death by 73% vs placebo.

At a median follow-up of 44.2 months for the osimertinib-treated group and 19.6 months for the placebo-treated group, median disease-free survival was 65.8 months vs 21.9 months, respectively, in the analysis of 470 patients with stage II/IIIA disease.

In the overall population of 682 patients (including patients with stage IA disease), the median disease-free survival was 65.8 months for adjuvant osimertinib vs 28.1 months for placebo, translating to a 73% reduction in the risk of disease recurrence or death. In this group, the median follow-up for the osimertinib group was 44.2 months) and 27.7 months for those given placebo.

Masahiro Tsuboi, MD

Masahiro Tsuboi, MD

Subgroup analysis showed that osimertinib had more favorable results over placebo across all prespecified subgroups; prior adjuvant therapy (yes or no); and stage I, II, or III disease.

“These updated data reinforce adjuvant osimertinib as the standard of care for patients with EGFR-mutated, stage IB to IIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy,” said principal author Masahiro Tsuboi, MD, National Cancer Center Hospital East, Kashiwa, Japan.

Primary Analysis

ADAURA enrolled 682 patients with confirmed primary nonsquamous NSCLC and EGFR exon 19 deletion or L858R mutation following complete resection with negative surgical margins. All patients were aged 18 years or older and had a World Health Organization (WHO) performance status (PS) of 0 or 1. Key stratification factors were disease stage (IB vs II vs IIIA), EGFR mutational status (exon 19 deletion vs L858R), and race (Asian vs non-Asian).

Patients were randomly assigned in a 1:1 ratio to receive osimertinib at 80 mg/d or placebo once per day. The planned treatment duration was 3 years, and treatment was continued until disease recurrence or unacceptable toxicity.

The primary endpoint was investigator-assessed disease-free survival in patients with stage II/IIIA disease. Secondary endpoints included disease-free survival in the overall population; disease-free survival at 2, 3, 4, and 5 years; overall survival; safety; and health-related quality of life. Prespecified exploratory endpoints included patterns of recurrence and time to CNS disease recurrence or death.

Findings from the primary analysis, with a data cutoff of January 17, 2020, showed that treatment with adjuvant osimertinib led to a highly statistically significant and clinically meaningful improvement in disease-free survival compared with placebo in both the stage II/IIA population (P < .001) and the overall population (P < .001).3 Based on these findings, adjuvant osimertinib was approved by the U.S. Food and Drug Administration for the treatment of patients with NSCLC whose tumors harbor an EGFR exon 19 deletion or exon 21 L858R mutation.2

Updated Analysis

At the 2022 ESMO Congress, Dr. Tsuboi presented an updated analysis of the primary trial with at least 2 years of additional follow-up, during which all participants had the opportunity to receive the full 3 years of adjuvant osimertinib.

Baseline demographic and disease characteristics were generally well balanced between the investigative and control arms. The median age of patients was about 63 years, and about 70% were female. The majority of patients across both arms were never-smokers (68% vs 75%, respectively), Asian (64% in both arms) and were WHO PS of 0 (63% vs 64%, respectively). Almost all patients had adenocarcinoma (> 95%), and about 60% received adjuvant chemotherapy. Disease stage was balanced across both arms.

The updated analysis showed that in the population of patients with stage II/IIIA disease, the 24-month disease-free survival rates with osimertinib and placebo were 90% and 46%, respectively; at 36 months, these rates were 84% vs 34%, respectively; and at 48 months, 70% vs 39%, respectively. In the overall study population, the 24-, 36-, and 48-month disease-free rates in the osimertinib and placebo arms were 90% and 55%, respectively; 85% and 44%, respectively; and 73% and 38%, respectively.

In the overall population, there were fewer recurrences in the osimertinib arm than in the placebo arm (27% vs 60%, respectively). In the osimertinib-treated group, the most frequent first sites of recurrence were (in descending order): lung (12%), lymph nodes (6%), and CNS (6%). In the placebo arm, the most frequent sites were also lung (26%), lymph nodes (17%), and CNS (11%).

A total of 63 patients experienced CNS disease-free survival events; 22 in the osimertinib arm and 41 in the placebo arm. Median CNS disease-free survival was not reached in either arm. The 24-month CNS disease-free survival rates in the osimertinib and placebo arms were 98% and 81%, respectively; at 36 months, these rates were 97% and 77%, respectively; and at 48 months, these rates were 90% and 75%, respectively.

The estimated probability of CNS recurrence at 36 months in the osimertinib arm was 2% vs 13% in the placebo arm. The cumulative incidence of CNS recurrence was consistently lower in the osimertinib arm vs the placebo arm.

Adverse Events

No new safety concerns emerged with longer follow-up of ADAURA. Any-grade adverse effects were reported in 98% of those on the osimertinib arm) vs 90% of those on the placebo arm. Grade 3 or higher adverse events occurred in 23% and 14% of patients, respectively. Serious adverse events were reported in 20% of the osimertinib arm and 14% of the placebo arm.

Adverse events leading to treatment discontinuation occurred in 13% of the investigative arm vs 3% of the control arm. Dose reductions due to adverse events occurred in 12% and 1% of patients, respectively, and 27% and 13% of patients, respectively, had an adverse event leading to dose interruption. Deaths due to an adverse event were reported in one patient in the osimertinib arm and two patients in the placebo arm.

Treatment-related adverse events occurred in 91% and 58% of patients in the osimertinib and placebo arms, respectively; grade 3 or higher treatment-related adverse events were reported in 11% and 2% of patients, respectively. Serious adverse events occurred in 3% percent of patients in the osimertinib arm and 1% of those in the placebo arm.

Interstitial lung disease was reported in 3% of those in the osimertinib arm, and all cases were grade 1 or 2 in severity. QTc prolongation was observed in 9% and 2% of patients in the osimertinib and placebo arms, respectively.

Further studies of osimertinib will explore treatment duration, subsequent treatment use, and overall survival benefit. The global phase III ADAURA2 trial will evaluate osimertinib in patients with EGFR-mutated, stage I A-C following tumor resection. 

DISCLOSURES: Dr. Tsuboi has received honoraria from Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical Co Ltd, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical Co Ltd, Merck Sharp & Dohme, Bristol Myers Squibb KK, and Teijin Pharma; has served as a consultant or advisor for AstraZeneca KK, Chugai Pharmaceutical Co Ltd, Merck Sharp & Dohme, and Novartis; and has received research funding from Boehringer Ingelheim Japan, Merck Sharp & Dohme, AstraZeneca KK, ONO Pharmaceutical Co Ltd., Bristol Myers Squibb KK, and Eli Lilly Japan.


1. Tsuboi M, Wu Y0L, Grohe C, et al: Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA. 2022 ESMO Congress. Abstract LBA47. Presented September 11, 2022.

2. Wu Y-L, Tsuboi M, He J, et al: Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med 383:1711-1723, 2020.

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“Adjuvant osimertinib has been adopted widespread as a standard of care as a result of the primary results of ADAURA,” said formal discussant Sanjay Popat, FRCP, PhD, medical oncologist and lung specialist at the Royal Marsden Hospital, NHS Foundation Trust, London.