Until recently, the first line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) was a platine-based chemotherapy. It has been changed by the discovery of EGFR (Epidermal Growth Factor Receptor) mutations and associated treatment with Tyrosine Kinase Inhibitor (TKI) of EGFR. The superiority of EGFR TKI over chemotherapy for EGFR mutated patients has been proved in several phase III trials with gefitinib, erlotinib or afatinib.

Nevertheless, all patients will progress after 9 to 12 months of treatment due to the appearance of a treatment resistance.

Afatinib is an irreversible EGFR TKI. It binds to its receptor permanently.Contrary to erlotinib and gefitinb which inhibits only EGFR, afatinib inhibits the kinase activity of all HER family (Human Epidermal growth factor Receptor). Nevertheless, there is no proof that afatinib delay the appearance of resistance.

Cetuximab is a monoclonal antibody which binds specifically with EGFR. The double inhibition of EGFR by afatinib and cetuximab has demonstrated its efficacy in pre-clinical models. The hypothesis of this study is that the combination between cetuximab and afatinib will permit to delay or decrease the appearance of resistances.

Principal Inclusion Criteria:

• Stage III or IV NSCLC, non irradiable non operable
• Non squamous NSCLC histologically or cytologically confirmed
• No previous treatment of NSCLC
• EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion)
• Presence of at least one lesion that can be measured
• PS 0 or 1

Principal Exclusion Criteria:

• Symptomatic brain metastasis or requiring immediate radiotherapy
• T790M mutation or exon 20 insertion
• Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy
• Interstitial pneumopathy