Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC

Author(s): Masahiro Tsuboi, M.D., Roy S. Herbst, M.D., Ph.D., Thomas John, M.B., B.S., Ph.D., Terufumi Kato, M.D., Margarita Majem, M.D., Ph.D., Christian Grohé, M.D., Jie Wang, M.D., Ph.D., Jonathan W. Goldman, M.D., Shun Lu, M.D., Wu-Chou Su, M.D., Filippo de Marinis, M.D., Frances A. Shepherd, M.D., Ki Hyeong Lee, M.D., Ph.D., Nhieu Thi Le, M.D., Arunee Dechaphunkul, M.D., Dariusz Kowalski, M.D., Ph.D., Lynne Poole, M.Sc., Ana Bolanos, M.D., Yuri Rukazenkov, M.D., Ph.D., and Yi-Long Wu, M.D. for the ADAURA Investigators*

Source: N Engl J Med 2023; 389:137-147 DOI: 10.1056/NEJMoa2304594

Dr. Anjan Patel's Thoughts

The ADAURA trial reported its 5-year data at the plenary session of ASCO. No surprise, given the 3-year data was very compelling, adjuvant Osimertinib should be considered SOC for EGFR-mutated stage IB – IIIA NSCLC patients.

BACKGROUND

Among patients with resected, epidermal growth factor receptor (EGFR)–mutated, stage IB to IIIA non–small-cell lung cancer (NSCLC), adjuvant osimertinib therapy, with or without previous adjuvant chemotherapy, resulted in significantly longer disease-free survival than placebo in the ADAURA trial. We report the results of the planned final analysis of overall survival.

METHODS

In this phase 3, double-blind trial, we randomly assigned eligible patients in a 1:1 ratio to receive osimertinib (80 mg once daily) or placebo until disease recurrence was observed, the trial regimen was completed (3 years), or a discontinuation criterion was met. The primary end point was investigator-assessed disease-free survival among patients with stage II to IIIA disease. Secondary end points included disease-free survival among patients with stage IB to IIIA disease, overall survival, and safety.

RESULTS

Of 682 patients who underwent randomization, 339 received osimertinib and 343 received placebo. Among patients with stage II to IIIA disease, the 5-year overall survival was 85% in the osimertinib group and 73% in the placebo group (overall hazard ratio for death, 0.49; 95.03% confidence interval [CI], 0.33 to 0.73; P<0.001). In the overall population (patients with stage IB to IIIA disease), the 5-year overall survival was 88% in the osimertinib group and 78% in the placebo group (overall hazard ratio for death, 0.49; 95.03% CI, 0.34 to 0.70; P<0.001). One new serious adverse event, pneumonia related to coronavirus disease 2019, was reported after the previously published data-cutoff date (the event was not considered by the investigator to be related to the trial regimen, and the patient fully recovered). Adjuvant osimertinib had a safety profile consistent with that in the primary analysis.

CONCLUSIONS

Adjuvant osimertinib provided a significant overall survival benefit among patients with completely resected, EGFR-mutated, stage IB to IIIA NSCLC. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)

Author Affiliations

From the Department of Thoracic Surgery and Oncology, National Cancer Center Hospital East, Kashiwa (M.T.), the Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama (T.K.) — both in Japan; the Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, CT (R.S.H.); the Department of Medical Oncology, Peter MacCallum Cancer Centre, and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia (T.J.); the Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona (M.M.); Klinik für Pneumologie, Evangelische Lungenklinik Berlin Buch, Berlin (C.G.); Cancer Hospital, Chinese Academy of Medical Sciences, Beijing (J.W.), Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai (S.L.), and Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou (Y.-L.W.) — all in China; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (J.W.G.); the Department of Oncology, National Cheng Kung University, Tainan, Taiwan (W.-C.S.); the Division of Thoracic Oncology, European Institute of Oncology, IRCCS, Milan (F.M.); the Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre (F.A.S.), and Oncology Research and Development, AstraZeneca (A.B.) — both in Toronto; the Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, South Korea (K.H.L.); Ho Chi Minh City Oncology Hospital, Binh Thanh District, Ho Chi Minh City, Vietnam (N.T.L.); the Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand (A.D.); the Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (D.K.); and Oncology Biometrics (L.P.), and Oncology Research and Development (Y.R.), AstraZeneca, Cambridge, United Kingdom.

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC

The combination therapy demonstrated improved overall survival (a 25% reduction in mortality) but was associated with increased toxicity, including skin rash and venous thromboembolic events (VTEs). Single-agent osimertinib may lose its role as monotherapy for EGFR-mutated NSCLC, as the FLAURA2 trial showed that combining osimertinib with chemotherapy yielded better outcomes than osimertinib alone.

Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small Cell Lung Cancer

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.