Efficacy and Safety Study of Afatinib to Treat Lung Cancer Patients (TIMELY)

Inclusion Criteria:

• Any stage not suitable for radical treatment
• Either:

Confirmed activating EGFR mutation (exons 18-21; e.g. L858R, exon 19 deletions, exon 20 insertions, T790M, list is not exhaustive), and WHO PS 0-3 Or No tissue suitable for EGFR genotyping, failed genotype, or EGFR genotyping unavailable, and NSCLC Adenocarcinoma sub-type, and

Eligible smoking history:

Never smoker (<100 cigarettes in lifetime), or Former smoker (stopped >1year ago and ≤10 pack-years) and WHO PS 0-2

• Unsuitable for or patient declining chemotherapy due to significant co-morbidity
• Measurable disease according to RECIST version 1.1
• Adequate haematopoietic, hepatic and renal function defined as follows:

Absolute neutrophil count (ANC) ≤1.5 x 109/L and platelet count ≤100 x 109/L

• Bilirubin ≤1.5 x ULN, ALT (SGPT) ≤3 x ULN (or ≤ 5 x ULN in cases of liver metastases)
• Serum creatinine clearance ≥45 ml/min
• Palliative radiotherapy allowed unless to a solitary target lesion
• Age 18 or over (no upper age limit)
• Written informed consent that is consistent with ICH-GCP guidelines

Exclusion Criteria:

• Previous treatment with afatinib (BIBW 2992), or any EGFR-directed inhibitor
• Any concurrent anticancer systemic therapy
• Prior chemotherapy for relapsed and/or metastatic NSCLC
• Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and registration
• Suitable for radical radiotherapy
• Palliative radiotherapy within 2 weeks prior to registration
• Palliative radiotherapy to a solitary target lesion
• Surgery (other than biopsy) within 4 weeks prior to registration
• Inability to take oral medication, requirement for intravenous feeding, active peptic ulcer, prior surgical procedures affecting absorption, any medical co- morbidity affecting gastrointestinal absorption
• Patients with current or pre-existing interstitial lung disease
• Active or uncontrolled infections or serious illnesses or medical conditions that could interfere with the patient's participation in the trial
• Significant or recent acute gastrointestinal abnormalities with diarrhoea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE version 4.0 Grade ≥3 diarrhoea of any etiology at baseline
• Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants and/or leptomeningeal disease). Steroids will be allowed if administered as a stable (same) dose for at least one month before trial entry.
• Any other current malignancy or malignancy diagnosed within the past five years (other than non-melanomatous skin cancer and in situ cervical cancer)
• History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3 or more, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to registration
• Symptomatic left ventricular failure with NYHA classification of 3 or more
• Active viral hepatitis and/or known HIV positive
• Known or suspected active drug or alcohol abuse
• Use of any investigational drug within 8 weeks of registration.
• Known allergy to BIBW 2992 or other ingredients.
• Patients on steroids must have been on the same dose for at least 4 weeks.
• Inability to understand or to comply with the requirements of the trial, trial protocol or to provide informed consent.
• Women of childbearing potential, or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial
• Women who are pregnant or breast feeding
• Requirement for treatment with any of the prohibited concomitant medications listed in protocol