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.

Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non–Small Cell Lung Cancer: Results From CHRYSALIS-2

The CHRYSALIS-2, the cohort C analysis of patients with atypical EGFR mutations showed meaningful and durable activity. Atypical mutations can be difficult to deal with as a clinician, and having concrete data on these (S768I, L861Q and G719ZX) mutations gives assurance that this doublet is active. Overall response rate (ORR) was 52% and median progression-free survival (PFS) was 11.1 months in refractory patients and 19.5 months in the treatment-naive population.

Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC

The final overall survival (OS) analysis from the FLAURA2 confirms the well-published findings that Osi + chemo improves survival over Osi monotherapy. OS difference was about 10 months at 47 vs 37 months, with a predictable toxicity tradeoff.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer

This update demonstrated that encorafenib plus binimetinib was associated with the longest median overall survival (mOS) reported to date among targeted therapies in patients with treatment-naïve BRAF V600E–mutant metastatic NSCLC (mNSCLC). Median OS was 47.6 months in treatment-naïve patients. By the way check the authors there 😊.

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.