“We have been using one-size-fits-all adjuvant chemotherapy for every patient with lung cancer despite a decade of advances in targeted treatments for select groups of patients that result in dramatically better outcomes. In a first for the lung cancer field, adjuvant osimertinib unequivocally improves survival in people with resected EGFR-mutated non-small cell lung cancer. This should be the new standard of care for these patients,” said Nathan Pennell, MD, PhD, FASCO, ASCO Expert.
ALEXANDRIA, Va. — Treatment with osimertinib (Tagrisso®) 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), according to the findings of an international study. The research will be presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.
Study at a Glance
Non-small cell lung cancer (NSCLC)
Adults with EGFR-mutated (EGFRm) stage IB, II, or IIIA NSCLC where the tumor has been completely removed by surgery
Adjuvant osimertinib treatment for EGFRm stage IB–IIIA NSCLC dramatically improves survival when added to the standard treatment of surgery with or without chemotherapy, reinforcing adjuvant osimertinib as the current standard of care in these patients.
In this final overall survival (OS) analysis of the ADAURA study, 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.
ADAURA is the first global phase III 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.”
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 is a third-generation, central nervous system (CNS)-active EGFR-tyrosine kinase inhibitor (TKI) and is the first targeted agent to be approved by the U.S. Federal Drug Administration as an adjuvant treatment for resected stage IB–IIIA EGFRm NSCLC.
About the Study
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. 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 IIꟷIIIA, and key secondary endpoints were DFS in stage IBꟷIIIA, OS, and safety.
In data published recently, the majority of adverse events were not serious and were mild or moderate in severity, and 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.
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 before surgery.
This study was funded by AstraZeneca.
View the full embargoed abstract:
LBA3: Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFRmutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC).
Authors: Roy S. Herbst, Masahiro Tsuboi, Tom John, Terufumi Kato, Margarita Majem, Christian Grohé, Jie Wang, Jonathan W. Goldman, Shun Lu, Wu-Chou Su, Filippo de Marinis, Frances A. Shepherd, Ki Hyeong Lee, Nhieu Le, Arunee Dechaphunkul, Dariusz M. Kowalski, Lynne Poole, Marta Stachowiak, Yuri Rukazenkov, Yi-Long Wu; Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, CT; Department of Thoracic Surgery and Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia; Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan; Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Klinik für Pneumologie - Evangelische Lungenklinik Berlin Buch, Berlin, Germany; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA; Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; Department of Oncology, National Cheng Kung University, Tainan, Taiwan; Thoracic Oncology Division, European Institute of Oncology (IEO), IRCCS, Milan, Italy; Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, ON; Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea, Republic of (South); Ho Chi Minh City Oncology Hospital, Binh Thanh District, Ho Chi Minh City, Viet Nam; Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand; Department of Lung Cancer and Thoracic Tumours, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland; Oncology Biometrics, AstraZeneca, Cambridge, United Kingdom; Late Oncology Research & Development, AstraZeneca, Warsaw, Poland; Oncology Research & Development, AstraZeneca, Cambridge, United Kingdom; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Background: Osimertinib is a third-generation, central nervous system (CNS) active EGFRTKI, that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. In the primary analysis from the Phase III ADAURA study (NCT02511106), adjuvant osimertinib demonstrated a clinically meaningful, statistically significant, and practice-changing diseasefree survival (DFS) benefit vs placebo in patients with completely resected EGFRm (ex19del/L858R) NSCLC ± adjuvant chemotherapy. In an updated DFS analysis, with 2 years additional follow-up, DFS and CNS DFS benefit with adjuvant osimertinib were sustained (stage IIꟷIIIA DFS hazard ratio [HR] 0.23; 95% confidence interval [CI] 0.18, 0.30; stage IBꟷIIIA DFS HR 0.27; 95% CI 0.21, 0.34; stage IIꟷIIIA CNS DFS HR 0.24; 95% CI 0.14, 0.42), with a tolerable safety profile observed over the extended treatment duration. Here, we report the planned final overall survival (OS) analysis from ADAURA. Methods: Eligible patients (aged ≥18 years [≥20 in Japan and Taiwan], WHO PS 0/1 with completely resected EGFRm (ex19del/L858R) stage IB, II or IIIA [AJCC/UICC 7th edition] NSCLC; adjuvant chemotherapy allowed) were randomized 1:1 to osimertinib 80 mg once daily or placebo until disease recurrence, treatment completion (3 years), or a discontinuation criterion was met. The primary endpoint was investigator-assessed DFS in stage IIꟷIIIA. Key secondary endpoints: DFS in stage IBꟷIIIA, OS and safety. Data cut-off: January 27, 2023. Results: Globally, 682 patients were randomized; osimertinib n = 339, placebo n = 343. Adjuvant osimertinib significantly improved OS vs placebo. In patients with stage IIꟷIIIA disease, OS HR was 0.49 (95% CI 0.33, 0.73; p = 0.0004; 100/470 events, 21% maturity); 5year OS rate was 85% with osimertinib vs 73% with placebo. Median followup for OS in stage IIꟷIIIA was 59.9 months (osimertinib) and 56.2 months (placebo). In the overall population (stage IBꟷIIIA), OS HR was 0.49 (95% CI 0.34, 0.70; p < 0.0001; 124/682 events, 18% maturity); 5-year OS rate was 88% with osimertinib vs 78% with placebo, with a median follow-up for OS of 60.4 months (osimertinib) and 59.4 months (placebo). Median OS was not reached in either population or treatment group. Conclusions: Adjuvant osimertinib demonstrated an unprecedented, highly statistically significant and clinically meaningful OS benefit in patients with EGFRm stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. ADAURA is the first global Phase III study to demonstrate a statistically significant DFS and OS benefit with targeted treatment for patients with EGFRm stage IB–IIIA NSCLC.
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