Treatment with any of the following: - Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC. - Prior treatment with an EGFR-TKI. - Major surgery within 4 weeks of the first dose of study drug. - Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug. - Patients currently receiving medications or herbal supplements known to be potent inducers of cytochrome P450 (CYP) 3A4. - Alternative anti-cancer treatment - Treatment with an investigational drug within five half-lives of the compound or any of its related material. - Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of study drug. - Spinal cord compression, symptomatic and unstable brain metastases, except for those patients who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids. - Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). - Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9291. - Any of the following cardiac criteria: • Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTcF value. • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG. • Any patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval. - Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. - Involvement in the planning and/or conduct of the study.