LUX-Head&Neck 3: Afatinib (BIBW2992) Versus Methotrexate for the Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Cancer After Platinum Based Chemotherapy

Inclusion criteria

• Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, which has recurred/metastasised and is not amenable for salvage surgery or radiotherapy.
• Documented progressive disease based on investigator assessment according to RECIST, following receipt of a cisplatin and/or carboplatin and/or Nedaplatin based regimen administered for recurrent and/or metastatic disease independent of whether patient progressed during or after platinum based therapy.
• Measurable disease according to RECIST (version 1.1).
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at Visit 2.
• Male and female patients age is 18 years or older
• Signed and dated written informed consent that is in compliance with ICH-GCP and local law.

Exclusion criteria

• Progressive disease within three months after completion of curatively intended treatment for locoregionally advanced or for metastatic head and neck squamous cell cancer (HNSCC).
• Primary tumour site nasopharynx (of any histology), sinuses, and/or salivary glands.
• Any other than one previous platinum based systemic regimen given for recurrent and/or metastatic disease, with the exception of immunotherapy used either before or after platinum based treatment. Re-challenge with the platinum based regimen after a temporary break is considered an additional line regimen only in case of progression within the break.
• Prior treatment with EGFR-targeted small molecules.
• Treatment with any investigational drug less than four weeks or anti-cancer therapy less than three weeks prior to randomization (except palliative radiotherapy to bones to alleviate pain).
• Unresolved chronic toxicity, other than hearing loss, tinnitus or dry mouth, CTCAE grade >2 from previous anti-cancer therapy or unresolved skin toxicities CTCAE grade >1 and/or diarrhoea CTCAE grade >1 caused by prior treatment with EGFR targeted antibodies.
• Previous tumour bleeding CTCAE grade =3.
• Requirement for treatment with any of the prohibited concomitant medications.
• Major surgical or planned procedure less than four weeks prior to randomization (isolated biopsies are not considered as major surgical procedures).
• Any other malignancy unless free of disease for at least five years except for:
• Other HNSCC of a location as described in inclusion criterion number 1
• Appropriately treated superficial basal cell skin cancer
• Surgically cured cervical cancer in situ
• For Korea: endoscopically cured superficial esophageal and/or gastric cancer is allowed
• Known lesion or signs of brain metastasis.
• Known pre-existing interstitial lung disease (ILD).
• Clinically relevant cardiovascular abnormalities, as judged by the investigator, such as, but not limited to, uncontrolled hypertension, congestive heart failure NYHA classification =III, unstable angina, myocardial infarction within six months prior to randomization, or poorly controlled arrhythmia.
• Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom in the opinion of the investigator, e.g. Crohn's disease, malabsorption or CTCAE grade >1 diarrhoea of any aetiology at randomization.
• Known HIV, active hepatitis B, active hepatitis C, and/or other known severe infections, including but not limited to tuberculosis, as judged by the investigator.
• Other significant disease that in the investigator's opinion would exclude the subject from the trial.
• Screening laboratory values:
• Absolute neutrophil count (ANC) 1.5 times the upper limit of normal (ULN)
• Aspartate amino transferase (AST) or alanine amino transferase (ALT) >3 times the ULN (if related to liver metastases >5 times the ULN)
• Calculated creatinine clearance <50 ml/min (as evidenced by using the Cockcroft-Gault formula).
• Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or to use adequate contraception during the trial and for