Liquid Biopsy as a Tool to Evaluate Resistance to First and Third (AZD9291) (EGFR) (TKIs) in (EGFR) Mutant NSCLC

Inclusion Criteria:

1. Age \>18 years
2. Both sexes
3. Histologically or cytologically documented NSCLC
4. Stage 3b (IIIb) not amenable to radical therapy or stage IV
5. Presence of EGFR activating mutations (exon 19 deletion or L858R in exon 21)
6. First or second line treatment with EGFR TKIs
7. Performance status (ECOG): 0-1
8. Measurable or evaluable disease
9. Adequate organ function tests (Hb\>=10g/dL, white blood cell (WBC) \>=3.0 x 10\^9/L, neutrophils count \>=1.5 x 10\^9/L, platelets≥100 x 10\^9/L, Creatinine clearance \>=50 mL/min, Total bilirubin=\<1.5 X UNL, aspartate aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline phosphatase (ALP) =\<2.5 x UNL)
10. Normal QT interval in ECG
11. Central nervous system (CNS) metastases are allowed provided that they have been irradiated and the patient is clinically stable
12. Women of child bearing potential and all men will be required to use adequate contraceptive measures
13. Life expectancy of at least 3 months
14. Written informed consent

Exclusion Criteria:

1. History of serious drug allergy
2. Refractory nausea, vomiting and chronic gastrointestinal diseases
3. 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 QTc value.
   * Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG.
   * 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.
4. Severe or uncontrolled systemic liver disease, including those with known hepatitis B, hepatitis C, and Human Immunodeficiency virus (HIV) infection
5. Interstitial lung disease or pulmonary fibrosis
6. Pregnancy, lactation or other concomitant serious medical condition
7. Other concurrent active malignancy