Background: EGFR-TKI is the recommended treatment for patients with advanced NSCLC who have an EGFR-TKI-sensitizing mutation (EGFRm). However, most patients develop resistance, and in ~60% of cases the EGFR T790M mutation is the cause. AZD9291 is an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M mutations. Preliminary data from a Phase I/II study demonstrated clinical activity and a manageable tolerability profile for AZD9291 as first-line treatment of patients with EGFRm advanced NSCLC. Methods: This Phase III, double-blind, randomized study (FLAURA, NCT02296125) is designed to assess the efficacy and safety of AZD9291 (80 mg qd, orally) versus standard of care (SoC) EGFR-TKI (gefitinib [250 mg qd, orally] or erlotinib [150 mg qd, orally]) in treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC. Eligible patients must have pathologically confirmed adenocarcinoma harboring an EGFR Ex19del or L858R mutation, alone or in combination with another EGFRm, determined by local (accredited laboratory) or central testing. Patients ≥ 18 years of age ( ≥ 20 in Japan), WHO performance status 0–1, will be randomized 1:1 to receive either AZD9291 or SoC EGFR-TKI, stratified by mutation status (Ex19del or L858R) and race (Asian versus non-Asian), until RECIST v1.1 defined progression or a discontinuation criterion is met. Patients may continue randomized treatment beyond RECIST defined progression if they continue to show clinical benefit, as judged by the Investigator. The primary objective is to compare progression-free survival (PFS) for AZD9291 to SoC EGFR-TKI. PFS in patients with tumors harboring T790M is a key secondary objective. Additional secondary objectives include PFS by Ex19del or L858R detectable in circulating tumor DNA, objective response rate, duration of response, disease control rate, depth of response, overall survival, PK, health-related quality of life, patient satisfaction with treatment, and the safety and tolerability profile of AZD9291 compared with SoC EGFR-TKI. The study was opened to accrual in November 2014. Clinical trial information: NCT02296125