The current standard of care for patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)–sensitizing mutations is treatment with a first-generation or second-generation EGFR-TKI such as gefitinib, erlotinib, or afatinib.1,2 Treatment with EGFR-TKIs in this patient population has extended progression-free survival relative to chemotherapy as initial therapy3-5; a meta-analysis of six randomized trials involving patients who had not previously received treatment showed a median progression-free survival of 11.0 months with EGFR-TKIs (gefitinib or erlotinib) versus 5.6 months with chemotherapy.6 The phase 3 studies of first-generation and second-generation EGFR-TKIs showed a median progression-free survival of 9 to 13 months,3-5,7-10 and the EGFR p.Thr790Met point mutation (EGFR T790M) is detected in 50% or more of the patients who have disease progression.11,12
Osimertinib is an oral, third-generation, irreversible EGFR-TKI that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations, with lower activity against wild-type EGFR.13,14 On the basis of positive results from the AURA clinical program,15-17 osimertinib is approved worldwide for the treatment of patients with metastatic T790M-positive NSCLC who have disease progression during or after EGFR-TKI therapy. Preclinical data support the ability of osimertinib to cross the blood–brain barrier and penetrate the central nervous system (CNS).18Previous studies in which osimertinib was given as a second-line treatment have shown superior efficacy in the CNS as compared with platinum chemotherapy.15,19
Preclinical data13,20,21 and phase 1 clinical data from the AURA trial22 suggest that osimertinib may also be an effective first-line therapy for patients with EGFR mutation–positive advanced NSCLC. A median progression-free survival of 20.5 months was recently reported in a group of 60 patients with previously untreated EGFR mutation–positive advanced NSCLC who received osimertinib (80 mg or 160 mg daily).22 The phase 3 FLAURA trial assessed the efficacy and safety of osimertinib in patients with previously untreated EGFR mutation–positive advanced NSCLC as compared with the standard EGFR-TKIs, gefitinib or erlotinib.