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) \<1.5x10\^9/l
  * Platelet count \<75x10\^9/l
  * Total bilirubin \>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 at least six months after end of treatment. Adequate methods of contraception and definition of child-bearing potential.
* Pregnancy or breast feeding.
* Known or suspected hypersensitivity to any of the study medications or their excipients.
* Patients unable to comply with the protocol, in the opinion of the investigator.