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Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer
Jean-Charles Soria1, Yuichiro Ohe1, Johan Vansteenkiste1
1From Gustave Roussy Cancer Campus and University Paris-Sud, Orsay, France (J.-C.S., D.P.); the Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo (Y.O.), the Department of Thoracic Oncology, Osaka International Cancer Institute (F.I.), and the Department of Thoracic Oncology, Kansai Medical University Hospital (T.K.), Osaka, the Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama (N.N.), and the Research Institute for Diseases of the Chest, Graduate School of Medical Science, Kyushu University, Fukuoka (I.O.) - all in Japan; the Respiratory Oncology Unit, University Hospital KU Leuven, Leuven, Belgium (J.V.); Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok (T.R.), the Oncology Unit, Department of Medicine, Chiang Mai University, Chiang Mai (B.C.), and the Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai (A.D.) - all in Thailand; the Division of Medical Oncology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheong-ju (K.H.L.), the Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (B.C.C.), and the Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon (E.K.C.) - all in South Korea; Pulmonary Hospital of Tongji University, Shanghai (C.Z.), and Jilin Provincial Cancer Hospital, Changchun (Y.C.) - both in China; Hospital Umum Sarawak, Kuching, Malaysia (P.J.V.); National Cheng Kung University, Tainan, Taiwan (W.-C.S.); the Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (J.E.G.); the Department of Oncology, University College London Hospitals Biomedical Research Centre, and the Cancer Research UK Lung Cancer Centre of Excellence, London (S.-M.L.), and AstraZeneca, Cambridge (R.H., M.M., Y.R.) - all in the United Kingdom; and Emory University School of Medicine, Winship Cancer Institute, Atlanta (S.S.R.).
Background:
Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC).
Methods:
In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival.
Results:
The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%).
Conclusions:
Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).
Insights
Osimertinib significantly improves progression-free survival in patients with EGFR-mutated non-small-cell lung cancer compared to standard therapies. This third-generation EGFR-TKI also demonstrated a favorable safety profile.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths worldwide.
- Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized NSCLC treatment for patients with activating EGFR mutations.
- Acquired resistance to standard EGFR-TKIs, often through the T790M mutation, poses a significant clinical challenge.
Purpose of the Study:
- To evaluate the efficacy and safety of osimertinib, a third-generation irreversible EGFR-TKI, versus standard EGFR-TKIs as a first-line treatment for patients with EGFR mutation-positive advanced NSCLC.
- To compare progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and overall survival (OS) between osimertinib and standard EGFR-TKIs.
- To assess the safety and tolerability profiles of osimertinib and standard EGFR-TKIs in this patient population.
Main Methods:
- A double-blind, randomized, phase 3 clinical trial (FLAURA) was conducted.
- 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC were enrolled.
- Patients were randomized 1:1 to receive either osimertinib (80 mg once daily) or a standard EGFR-TKI (gefitinib 250 mg once daily or erlotinib 150 mg once daily).
Main Results:
- Osimertinib demonstrated significantly longer median progression-free survival (18.9 months vs. 10.2 months; P<0.001).
- The objective response rate was similar between groups (80% for osimertinib vs. 76% for standard EGFR-TKIs), but the median duration of response was longer with osimertinib (17.2 months vs. 8.5 months).
- Grade 3 or higher adverse events were less frequent with osimertinib (34% vs. 45%), indicating a favorable safety profile.
Conclusions:
- Osimertinib is superior to standard EGFR-TKIs as a first-line treatment for patients with EGFR mutation-positive advanced NSCLC.
- Osimertinib offers improved efficacy with a comparable or better safety profile, including lower rates of serious adverse events.
- These findings support osimertinib as a new standard of care in the first-line treatment setting for this patient group.
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