Inclusion Criteria:
* Histologically or cytologically confirmed non small cell lung cancer
* Stage IIIB (non amenable to curative-intent multimodal treatment) or IV NSCLC, according to 7th TNM classification.
* Contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals);
* brain MRI or CT within 28 days before the date of enrolment.
* Non-predominant squamous subtype (\<50% squamous cells).
* Previous treatment with a platinum based chemotherapy for advanced disease; or Disease relapse or progression within \<6 months after adjuvant platinum based chemotherapy, or (definitive) platinum-based chemo(radio)therapy for stage I-III NSCLC
* Measurable or evaluable disease (according to RECIST 1.1 criteria). Not eligible: patients with only one measurable or evaluable tumour lesion which was resected or irradiated prior to enrolment.
* Locally documented HER2 mutation
* Age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
* Life expectancy \>3 months.
* Adequate haematological function:
* WBC ≥ 2000/μL
* haemoglobin ≥ 9 g/dL
* neutrophils count ≥1.5×109/L
* platelet count ≥ 100 × 109/L
* Adequate liver function:
* Total bilirubin ≤ 1.5 × ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
* ALT \< 2.5 × ULN
* AST \< 2.5 × ULN
* GGT \< 2.5 × ULN.
* Adequate renal function: Calculated creatinine clearance ≥ 45mL/min (Cockroft-Gault)
* Patient capable of proper therapeutic compliance, and accessible for correct followup.
* Women of childbearing potential (\< 1 year without menstruation or \< 2 years without menstruation following chemotherapy) must have a negative serum or urine pregnancy test within 7 days before beginning trial treatment.
* Sexually active men and women of childbearing potential must use an effective contraceptive method (two barrier methods or a barrier method plus a hormonal method) during the trial treatment and for a period of at least 28 days following the last administration of trial drug.
* Recovered from any previous therapy related toxicity to ≤Grade 1 at date of enrolment (except for recovery to ≤Grade 2 of alopecia, fatigue, creatinine increased, lack of appetite as well as stable sensory neuropathy)
* Written Informed Consent (IC) for trial treatment must be signed and dated by the patient and the investigator prior to any trial-related intervention.
* Tumour block available for central review of HER2 mutation status.
Exclusion Criteria:
* Patient with mixed small-cell and non-small-cell histologic features
* Uncontrolled lepto-meningeal metastatic disease. Radiotherapy-treated or asymptomatic brain metastases are allowed (no systematic screening). Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids or have been on stable dose of corticosteroids for at least 4 weeks before starting trial treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before date of enrolment.
* Previous treatment with HER2 targeted antibody or tyrosine kinase inhibitor including afatinib.
* Major surgery within 4 weeks before starting trial treatment or scheduled for surgery during the projected course of the trial.
* Patient who has had in the past 3 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast.
* History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of III or IV (see Table 2 below), unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to enrolment.
* Patient with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes that could affect the patient's capacity to participate in the trial.
* Known HIV, active Hepatitis B or Hepatitis C infection (screening not required).
* Known or suspected hypersensitivity to afatinib or any of its excipients.
* Interstitial lung disease or pulmonary fibrosis.
* Women who are pregnant or in the period of lactation.
* Patients with any concurrent systemic anticancer therapy.
* Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the trial drug (e.g. Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption.
* Patient who received treatment with an investigational drug agent during the 3 weeks before enrolment in the trial.
