Background: EGFR (ErbB1) is expressed in 90% of HNSCC and associated with poor prognosis. Despite clinical benefit (CB) of EGFR-targeted treatments such as cetuximab treatment resistance will occur resulting in a need for novel targeted treatments to improve prognosis. Afatinib is an ErbB Family Blocker that irreversibly blocks signaling from all relevant ErbB Family dimers and may overcome limitations of current EGFR-targeted treatments in HNSCC. In a randomized, proof-of-concept, Phase II trial, afatinib demonstrated comparable anti-tumor activity to cetuximab in pts with R/M HNSCC progressing after platinum-based therapy (Seiwert TY, et al; THNO, November 2011; Abs 40). Methods: LUX-H&N 1 is a phase III, randomized, open-label trial (NCT01345682) evaluating efficacy and safety of afatinib vs. MTX in pts with R/M HNSCC who have progressed after platinum-based therapy. Key eligibility criteria: confirmed R/M HNSCC not amenable to salvage surgery/radiotherapy; documented PD after cisplatin and/or carboplatin for R/M disease; any other than 1 previous platinum-based regimen for R/M disease; ECOG status 0 or 1; no PD ≤3 months of completion of curatively intended treatment for locoregionally advanced or metastatic HNSCC; and no prior EGFR-targeted small molecules treatment. Eligible pts are stratified into four strata: ECOG performance score (0 vs. 1) and prior use of EGFR-targeted antibody therapy (Yes/No) given in the R/M setting. Pts are randomized 2:1 to: afatinib (40mg/d orally) or MTX (40mg/m² IV weekly). Dose changes are permitted according to absence/presence of drug-related AEs (afatinib: escalation to 50mg/d and/or reduction to 40, 30 then 20mg/d; MTX: escalation to 50mg/m² and/or reduction to 40, 30 then 20mg/m²). Pts receive continuous treatment until PD or AEs requiring withdrawal. Randomized treatment may continue beyond PD in case of CB as judged by the investigator. The primary endpoint is PFS and secondary endpoints include OS, OR, health-related QOL and safety. Target enrolment is 474 pts and completion of pt recruitment and data analyses are awaited.