AS REPORTED in The New England Journal of Medicine by Jean-Charles Soria, MD, PhD, of Gustave Roussy Cancer Campus and University Paris-Sud, and colleagues, the phase III FLAURA trial has shown a significant progression-free survival benefit with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) vs standard EGFR TKIs in previously untreated advanced EGFR-mutant non–small cell lung cancer (NSCLC).1 Osimertinib selectively inhibits both EGFR TKI–sensitizing and EGFR T790M resistance mutations.
IN THE DOUBLE-BLIND TRIAL, 556 patients from 132 sites in 29 countries with advanced EGFR exon 19 deletion or L858R mutation were randomized between December 2014 and March 2016 to receive osimertinib at 80 mg once daily (n = 279) or standard TKI treatment consisting of gefitinib (Iressa) at 250 mg once daily or erlotinib (Tarceva) at 150 mg once daily (n = 277). The standard TKI was selected by trial site, except in the United States, where all sites used erlotinib. Randomization was stratified according to tumor EGFR mutation status (exon 19 deletion or L858R) and race (Asian or non-Asian).
Treatment continued until disease progression, unacceptable side effects, or withdrawal of consent. Treatment beyond disease progression was permitted in the setting of continued clinical benefit. A protocol amendment allowed patients in the standard TKI group to cross over to osimertinib after blinded confirmation of disease progression and post–disease progression documentation of T790M-positive mutation status. The primary endpoint was investigator-assessed progression-free survival.
“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.”— Jean-Charles Soria, MD, PhD
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For the osimertinib vs standard TKI groups, the median age was 64 years in both; 64% vs 62% were female; 62% in both were Asian and 36% in both were white; 65% vs 63% were never smokers; all but one patient had World Health Organization performance status of 0 or 1; 99% vs 98% had adenocarcinoma histology; 95% in both had metastatic disease, with 34% vs 37% having visceral metastases and 19% vs 23% having central nervous system (CNS) metastases; and 63% in both had exon 19 deletion and 37% in both had L858R mutation. In the standard TKI group, 66% of patients received gefitinib and 34% received erlotinib.
AT DATA CUTOFF, the median duration of total treatment exposure was 16.2 months in the osimertinib group vs 11.5 months in the standard-TKI group, with 51% and 23% of patients continuing to receive study treatment.
Median progression-free survival was 18.9 months in the osimertinib group vs 10.2 months in the standard-TKI group (hazard ratio [HR] = 0.46, P < .001). A consistent benefit of osimertinib was observed across all predefined subgroups, including Asian (HR = 0.55, 95% confidence interval [CI] = 0.42–0.72) and non-Asian patients (HR = 0.34, 95% CI = 0.23–0.48), patients with exon 19 deletion (HR = 0.43, 95% CI = 0.32–0.56) and those with L858R mutation (HR = 0.51, 95% CI = 0.36–0.71), and according to smoking history (HR = 0.48, 95% CI = 0.34–0.68) or never smoking (HR = 0.45, 95% CI = 0.34–0.59). Median progression-free survival was 15.2 vs 9.6 months among patients with CNS metastases (HR = 0.47, P < .001) and 19.1 vs 10.9 months among those without CNS metastases (HR = 0.46, P < .001).
Objective response was observed in 80% vs 76% of patients (odds ratio = 1.27, P = .24). The median duration of response was 17.2 vs 8.5 months. Data on overall survival were immature at interim analysis (25% maturity). The survival rate at 18 months was 83% vs 71% (HR = 0.63, P = .007; nonsignificant in the interim analysis). After disease progression, 29% of the osimertinib group and 47% of the standard-TKI group received a first subsequent anticancer therapy; of them, 43% in the standard-TKI group received osimertinib.
ADVERSE EVENTS of grade ≥ 3 occurred in 34% of the osimertinib group vs 45% of the standard-TKI group, with the most common in the osimertinib group being decreased appetite (3%). Changes in QT interval were observed in 10% vs 5% of patients, with no fatal cases of torsades de pointes or prolonged QT interval in either group. Interstitial lung disease was reported in 4% vs 2%. Serious adverse events occurred in 22% vs 25%. Serious adverse events included QT prolongation in one osimertinib patient and interstitial lung disease in six osimertinib and four standard-TKI patients. Adverse events led to dose interruption in 25% vs 24%, dose reduction in 4% vs 5%, and discontinuation of treatment in 13% vs 18%.
Adverse events led to death in 6 patients in the osimertinib group (2%; pneumonia, respiratory tract infection, cerebral infarction, myocardial infarction, pulmonary embolism, and intestinal ischemia in 1 patient each) and in 10 patients in the standard-TKI group (4%; sepsis in 2 patients and pneumonia, endocarditis, cognitive disorder and pneumonia, peripheral artery occlusion, dyspnea, hemoptysis, diarrhea, gastrointestinal hemorrhage, respiratory failure, circulatory collapse, and death not further specified in 1 each). None of the deaths in the osimertinib group and one death in the standard-TKI group (due to diarrhea) was considered possibly related to study treatment.
The investigators concluded: “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.” ■
DISCLOSURE: The study was funded by AstraZeneca. For full disclosures of the study authors, visit www.nejm.org.
1. Soria JC, Ohe Y, Vansteenkiste J, et al: Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378:113-125, 2018.
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Dr. Ramalingam is Professor of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta.
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