Treatment with osimertinib (Tagrisso®; AstraZeneca; previously known as AZD9291) after surgery significantly lowered the risk of death in adults with completely resected EGFR-mutated (EGFRm) stage IB, II, or IIIA non-small cell lung cancer (NSCLC).

This is a conclusion based on the findings of the international ADAURA study ( identifier: NCT02511106), funded by AstraZeneca. The results of the study were presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 2 – 6, 2023 in Chicago, Illinois. [1]

Lung cancer is the leading cause of global cancer death, accounting for almost 1.8 million deaths every year. EGFRm lung cancer represents approximately 30–40% of lung cancer cases in Asia and around 10–25% of lung cancers in the United States (U.S.) and Europe. Despite the use of chemotherapy after the removal of a tumor using surgery, disease recurrence rates in stage IB–IIIA NSCLC are high and increase with disease stage.

Osimertinib, a third-generation, central nervous system (CNS)-active epidermal growth factor receptor (EGFR-) tyrosine kinase inhibitor (TKI), is the first targeted agent to be approved by the U.S. Federal Drug Administration as an adjuvant treatment for resected stage IB–IIIA (AJCC/UICC 7th edition) EGFRm NSCLC.

Study design
ADAURA is a global study conducted in 26 different countries across Europe, the Asia-Pacific, North America, and South America. Approximately two-thirds of patients in the study were women.

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Participating patients were aged between 30 and 86 years, with an average age of 64 years in the osimertinib group and 62 years in the placebo group. Approximately two-thirds of patients had no history of smoking and approximately two-thirds of patients were Asian.

In total, 682 patients were randomized 1:1 to receive osimertinib (n = 339) 80 mg once daily or placebo (n = 343) until disease recurrence, treatment completion at three years, or a discontinuation criterion was met. The primary endpoint was DFS in stage II IIIA, and key secondary endpoints were DFS in stage IB IIIA, OS, and safety.

Recently published data shows that the majority of adverse events (AE) were not serious and were mild or moderate in severity.  Also, overall rates of dose reductions and treatment discontinuation were as expected based on existing data for osimertinib. Overall, 66% (n = 222) of participants in the osimertinib group and 41% (n = 139) of participants in the placebo group completed the planned treatment duration of 3 years.

Adverse events led to treatment discontinuation for 13% (n = 43) of participants in the osimertinib group and 3% (n = 9) of participants in the placebo group.

Key Findings
The study results demonstrated that treatment with adjuvant osimertinib significantly improved overall survival (OS) vs placebo. In patients with stage II IIIA disease, OS HR was 0.49 (95% CI 0.33, 0.73; p = 0.0004; 100/470 events, 21% maturity).

Median followup for OS in stage II IIIA was 59.9 months (osimertinib) and 56.2 months (placebo). In the overall population (stage IB IIIA), OS HR was 0.49 (95% CI 0.34, 0.70; p < 0.0001; 124/682 events, 18% maturity).

In this final OS analysis of the ADAURA study, with a median follow-up for OS of 60.4 months (osimertinib) and 59.4 months (placebo) 88% of patients with IB–IIIA NSCLC who were given osimertinib following the removal of their tumor were still alive 5 years after surgery compared to 78% of patients treated with a placebo.

Overall, there was a 51% lower risk of death for those who received osimertinib compared to those who received placebo (p < 0.0001). This survival benefit with adjuvant osimertinib was observed consistently in an exploratory analysis across all study subgroups, including in those with stage IB, II, and IIIA NSCLC. Adjuvant chemotherapy had been given to 60% of study participants before assignment to the study’s treatment groups, and the survival benefit of osimertinib was seen regardless of whether prior adjuvant chemotherapy was received.

The ADAURA study is the first global phase 3 study to find both statistically significant disease-free-survival (DFS)—or the amount of time after treatment in which no sign of cancer is found—and statistically significant OS benefit using osimertinib in people with EGFRm stage IB–IIIA NSCLC.

“Overall survival has historically been considered the gold standard efficacy endpoint for randomized adjuvant clinical trials. The results of the ADAURA trial will broaden treatment access for patients with EGFR-mutated non-small cell lung cancer,” said Roy S. Herbst, MD, PhD, deputy director of Yale Cancer Center, assistant dean for translational research at Yale School of Medicine, and lead author of the study.

“Together with the practice-changing disease-free survival data from our primary analysis, the overall survival benefit instills confidence that adjuvant osimertinib is the standard of care for patients with resected EGFRm stage IB–IIIA non-small-cell lung cancer. This further reinforces the need to identify these patients with available biomarkers at the time of diagnosis and before treatment begins,” Herbst added.

Next Steps
Future analyses from ADAURA are underway, and they may provide more information, including tumor and circulating tumor DNA molecular profiling for minimal residual disease. Osimertinib is also currently being evaluated in other stages of NSCLC, including neo- adjuvant treatment.

Clinical trials
AZD9291 Versus Placebo in Patients With Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy. (ADAURA) – NCT02511106

Highlights of Prescribing Information
Osimertinib (Tagrisso®; AstraZeneca)[Prescribing Information]

[1] Herbst RS, Tsuboi M, John T, Kato T, Majem M, Grohé C, Wang J, Goldman JW, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR‑mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). J Clin Oncol 41, 2023 (suppl 17; abstr LBA3) DOI 10.1200/JCO.2023.41.17_suppl.LBA3
[2] Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. doi: 10.1056/NEJMoa1411817. PMID: 25923549.

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