Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC

Author(s): Shun Lu, M.D., Terufumi Kato, M.D., Xiaorong Dong, M.D., Ph.D., Myung-Ju Ahn, M.D., Le-Van Quang, M.D., Nopadol Soparattanapaisarn, M.D., Takako Inoue, M.D., Chih-Liang Wang, M.D., Meijuan Huang, M.D., James Chih-Hsin Yang, M.D., Ph.D., Manuel Cobo, M.D., Mustafa Özgüroğlu, M.D., Ignacio Casarini, M.D., Dang-Van Khiem, M.D., Virote Sriuranpong, M.D., Ph.D., Eduardo Cronemberger, M.D., Toshiaki Takahashi, M.D., Ph.D., Yotsawaj Runglodvatana, M.D., Ming Chen, M.D., Ph.D., Xiangning Huang, Ph.D., Ellie Grainger, M.Sc., Dana Ghiorghiu, M.D., Ph.D., Toon van der Gronde, Pharm.D., Ph.D., and Suresh S. Ramalingam, M.D., for the LAURA Trial Investigators*

Source: N Engl J Med 2024;391:585-597

Dr. Maen Hussein's Thoughts

Osimertinib in adjuvant, now after chemotherapy and radiation, next… Neoadjuvant??? Trials are ongoing. This is here till progression.

BACKGROUND

Osimertinib is a recommended treatment for advanced non–small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC.

METHODS

In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review.

RESULTS

A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P=0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged.

CONCLUSIONS

Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.)

Author Affiliations

From the Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai (S.L.), the Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (X.D.), the Division of Thoracic Tumor Multimodality Treatment and Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (M.H.), the Department of Radiotherapy, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), the Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou (M. Chen) — all in China; the Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama (T.K.), the Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka (T.I.), and the Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka (T.T.) — all in Japan; the Department of Hematology–Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (M.-J.A.); the Department of Oncology, Hanoi Medical University (L.-V.Q.), and the Department of Oncology, Vietnam National Lung Hospital (D.-V.K.) — both in Hanoi; the Faculty of Medicine, Siriraj Hospital, Mahidol University (N.S.), the Division of Medical Oncology, Faculty of Medicine, Chulalongkorn University and the King Chulalongkorn Memorial Hospital (V.S.), and the Faculty of Medicine, Vajira Hospital, Navamindradhiraj University (Y.R.) — all in Bangkok, Thailand; the Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Linkou Chang Gung Memorial Hospital, Medical College of Chang Gung University, Taoyuan (C.-L.W.), and the Department of Oncology, National Taiwan University Hospital, and the National Taiwan University Cancer Center, Taipei (J.C.-H.Y.) — all in Taiwan; Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga, Málaga, Spain (M. Cobo); the Department of Internal Medicine, Division of Medical Oncology, Clinical Trial Unit, Istanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Istanbul, Turkey (M.Ö.); Servicio Oncología, Hospital Bernardo Houssay, Mar del Plata, Buenos Aires (I.C.); Centro de Pesquisa Clínica, Centro Regional Integrado de Oncologia, Fortaleza, Brazil (E.C.); Biometrics, Late-Stage Development, Oncology Research and Development, AstraZeneca, Cambridge, United Kingdom (X.H., E.G.); Late-Stage Development, Oncology Research and Development, AstraZeneca, Baar, Switzerland (D.G.); Late-Stage Development, Oncology Research and Development, AstraZeneca, New York (T.G.); and the Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta (S.S.R.).

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.