Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity

Inclusion Criteria:

* Subjects must be willing to have a biopsy of relapsed disease. Consent will be obtained through the TRACERx study or with the 'trial entry tissue collection' consent form(non-TRACERx patients). Procurement of the biopsy sample is not necessary at the time of trial registration. However, patients must undergo a biopsy prior to commencement of afatinib.
* Patients must have tumours harbouring a sensitising EGFR mutation or HER2 mutation in at least one biopsy at recurrence, or region of the primary sample.
* Non-TRACERx patients must have at least two archival tissue/DNA samples of their disease available.
* Written informed consent for DARWIN1.
* ECOG performance status 0-3
* No previous exposure to an EGFR TKI (other than afatinib) or HER2 targeted therapy
* Measurable disease by RECIST v1.1. Patients without measurable disease may be eligible following discussion with the CI and UCL CTC but will not count towards the primary PFS endpoint.
* At least 18 years of age.
* Anticipated life expectancy of at least three months.
* Adequate organ function as defined by the following baseline values:

  * Absolute neutrophil count (ANC) ≥1.5x109/L
  * Platelets ≥100x109/L
  * Serum bilirubin ≤1.5 x upper limit of normal (ULN). In patients with known Gilbert's syndrome, total bilirubin ≤3xULN with direct bilirubin ≤1.5xULN
  * Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤3xULN or ≤5x ULN if liver metastases are present
  * Creatinine clearance must be ≥30mL/min
* Women with child-bearing potential, or men who are able to father a child, must be willing to practice highly effective methods of contraception during the trial and for 1 month after the end of treatment.
* Women of childbearing potential must have a negative pregnancy test within 14 days before the first dose of trial medication.

Exclusion Criteria:

* Currently suitable for radical radiotherapy.
* Requirement for intravenous feeding, active peptic ulcer, prior surgical procedures affecting absorption or any medical comorbidity affecting gastrointestinal absorption.
* Patients with current or pre-existing interstitial lung disease.
* Significant or recent acute gastrointestinal abnormalities with diarrhoea as a major symptom e.g. Crohn's disease, malabsorption, or CTCAE v4.03 Grade ≥3 diarrhoea of any etiology at baseline.
* Known hypersensitivity to afatinib or to any of the excipients.
* Patients with rare hereditary conditions of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
* Women of childbearing potential, or men who are able to father a child, unwilling to use a highly effective method of contraception during the trial.
* Anti-cancer therapy including chemotherapy, immunotherapy, biologic therapy, or major surgery within 14 days prior to start of trial therapy.
* Known human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or syphilis infection. Subjects with evidence of hepatitis B virus clearance may be enrolled.
* History of other malignancy; Exception: (a) Subjects who have been successfully treated and are disease-free for 3 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent prostate cancer requiring no or only anti-hormonal therapy with histologically confirmed tumor lesions that can be clearly differentiated from lung cancer target and non-target lesions are eligible.
* The following cardiac abnormalities:

  * Corrected QT (QTc) interval ≥480 msecs
  * History of acute coronary syndromes (including unstable angina) within the past 24 weeks
  * Coronary angioplasty, or stenting within the past 24 weeks
  * Class III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
  * History of known arrhythmias (except sinus arrhythmia) within the past 24 weeks
  * Myocardial infarction within the last 6 months
* Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension etc), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to comply with the requirements of the trial, trial protocol or to provide informed consent.
* Pregnant, lactating or actively breastfeeding females.