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Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy ( LUX-Head & Neck 1 ) : an open-label , randomised phase 3 trial . BACKGROUND Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck ( HNSCC ) progressing after first-line platinum regimens have a poor prognosis and few treatment options . Afatinib , an irreversible ERBB family blocker , has shown efficacy in a phase 2 study in this setting . We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy . METHODS In this open-label , phase 3 , randomised controlled trial conducted in 101 centres in 19 countries , we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent , metastatic , or both who had progressed on or after first-line platinum-based therapy , were not amenable for salvage surgery or radiotherapy , and who had an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 or 1 . Previous treatment with more than one systemic regimen in this setting was not allowed ; previous treatment with EGFR-targeted antibody therapy ( but not EGFR-targeted tyrosine-kinase inhibitors ) was allowed . We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib ( 40 mg/day ) or intravenous methotrexate ( 40 mg/m ( 2 ) per week ) , stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease . Randomisation was done centrally with an interactive voice or web-based response system . Clinicians and patients were not masked to treatment allocation ; independent review of tumour response was done in a blinded manner . The primary endpoint was progression-free survival as assessed by an independent , central imaging review committee . Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug . This ongoing study is registered with ClinicalTrials.gov , number NCT01345682 . FINDINGS Between Jan 10 , 2012 , and Dec 12 , 2013 , we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate . After a median follow-up of 6·7 months ( IQR 3·1-9·0 ) , progression-free survival was longer in the afatinib group than in the methotrexate group ( median 2·6 months [ 95 % CI 2·0-2·7 ] for the afatinib group vs 1·7 months [ 1·5-2·4 ] for the methotrexate group ; hazard ratio [ HR ] 0·80 [ 95 % CI 0·65-0·98 ] , p=0·030 ) . The most frequent grade 3 or 4 drug-related adverse events were rash or acne ( 31 [ 10 % ] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group ) , diarrhoea ( 30 [ 9 % ] vs three [ 2 % ] ) , stomatitis ( 20 [ 6 % ] vs 13 [ 8 % ] ) , fatigue ( 18 [ 6 % ] vs five [ 3 % ] ) , and neutropenia ( 1 [ < 1 % ] vs 11 [ 7 % ] ) ; serious adverse events occurred in 44 ( 14 % ) of afatinib-treated patients and 18 ( 11 % ) of methotrexate-treated patients . INTERPRETATION Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile . These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC . FUNDING Boehringer Ingelheim .
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Intervention_Pharmacological
Afatinib
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Intervention_Pharmacological
methotrexate
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Intervention_Pharmacological
Afatinib
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Intervention_Pharmacological
afatinib
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Intervention_Pharmacological
methotrexate
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Intervention_Pharmacological
EGFR-targeted antibody therapy ( but not EGFR-targeted tyrosine-kinase inhibitors
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Intervention_Pharmacological
oral afatinib ( 40 mg/day )
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Intervention_Pharmacological
intravenous methotrexate
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Intervention_Pharmacological
afatinib
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Intervention_Pharmacological
methotrexate .
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Outcome_Mortality
progression-free survival
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Outcome_Other
Efficacy analyses
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Outcome_Other
safety analyses