Background: A previous study assessing erlotinib-cetuximab combo in chemo- refractory wt KRAS mCRC (Weickhardt AJ, et al J Clin Oncol 201;30:1505-12) has shown encouraging data (ORR=41 %, PFS=5.6 months). Afatinib is an Erb-B family blocker that irreversibly blocks signaling from all relevant Erb-B family homo and heterodimers. Methods: We conduct a randomized phase II study to determine the benefit of afatinib plus cetuximab versus cetuximab alone in patients with wtRAS metastatic CRC after oxaliplatin and irinotecan failure.Key eligibility criteria: pts with mCRC expressing wt KRAS/NRAS status; ECOG status 0 or 1; no disease progression with previous anti-EGFR targeted therapy; failure with a prior regimen containing irinotecan or oxaliplatin for metastatic disease; pts must have previously received a thymidylate inhibitor at any point for treatment of CRC; Pts are randomized 2:1 to receive oral afatinib (40 mg/qd) in combo with i.v. cetuximab (500mg/m² q 2 weeks) or cetuximab alone (500mg/m² q2 weeks). Dose adjustments are permitted according to the occurrence of drug related Adverse Events (AE). Pts receive treatment until PD or unacceptable AE. Pts randomized in the cetuximab arm have the opportunity to crossover to the combo arm after disease progression. The primary endpoint is the 6-month PFS rate. Secondary endpoints include ORR, median PFS, OS, safety and tolerability. Target enrolment is 75 pts. Completion of pt recruitment and data analyses are awaited. this study is promoted by UNICANCER GI. Clinical trial information: NCT01919879.