 Localized cutaneous squamous cell carcinoma CSCC is usually treated by radical surgery with or without radiotherapy. The cure rate is high around 90 of cases 1. Unresectable CSCC represents less than 10 of all CSCC. The prognosis of these advanced forms is poor, without any proven treatment option. The number of studies investigating systemic treatment of advanced or metastatic CSCC is limited, mostly based on phase II trials or case reports. Systemic treatment includes cytotoxic chemotherapy such as cisplatin and 5-Fluoro-uracil 5FU, immunotherapy interferon alpha or retinoic acid 13CRa 1,2. Recently, epidermal growth factor receptor EGFR targeting agents have been explored 1,2. The anti-EGFR monoclonal antibody Cetuximab has shown some clinical efficacy in advanced CSCC alone or concomitant with radiotherapy or chemotherapy 3-5. A recent phase II study aimed at investigating the role of Cetuximab in 36 patients with unresectable CSCC 6. The authors reported a disease control rate at 6 weeks of 69 95 CI, 52 to 84. The best responses were eight partial responses and two complete responses. There were no Cetuximab-related deaths. There were three related serious adverse events: two grade 4 infusion reactions and one grade 3 interstitial pneumopathy. Grade 1 to 2 acne-like rash occurred in 78 of patients and was associated with prolonged Progression Free Survival PFS 6. The authors concluded that regarding the Cetuximab therapeutic index it could be interesting in this particular situation mainly for elderly patient. Unfortunately, the small number of patient included not allowed to draw definitive conclusion. It was interesting to note that the Disease rate control DRC with Cetuximab increased of 15 comparatively of DRC with chemotherapy. Additionally it seems that in case of efficacy the functional improvement of Cetuximab-sensitive patients occurred after very few infusions. 