Background: Promising results using cetuximab and erlotinib to treat wtKRAS metastatic colorectal cancer (mCRC) were reported by Weickhardt (J Clin Oncol 2012; 30:1505-12). Combining a monoclonal antibody and a tyrosine kinase inhibitor may be a treatment option for mCRC patients (pts). We investigated dual targeting with cetuximab and afatinib in chemotherapy refractory wtKRAS mCRC. Methods: wtKRAS mCRC pts (ECOG ≤ 1) who failed chemotherapy with irinotecan and oxaliplatin were eligible. Due to low accrual and the frequent use of an anti-EGFR antibody in the first- or second-line, the study was amended, after 19 inclusions, to allow pre-treatment with anti-EGFRs. This multicenter, prospective, open phase II trial randomized pts (2:1) to cetuximab (500mg/m²/two weeks) and oral afatinib (40mg/day) (Arm A) or cetuximab alone (500mg/m²/two weeks) (Arm B). Treatment continued until progression (evaluated every six weeks using RECIST 1.1) or limiting toxicity. At progression (Arm B) afatinib could be added to cetuximab. The primary objective was the non-progression rate at six months (Fleming’s one-step design, one-sided a = 5%, b = 10%, H0: 30%; H1: 50%; 75 pts needed, 49 in Arm A). Results: 75 pts were included between November 2012 and May 2015 in 14 French sites. We randomized 51 pts in Arm A and 24 in Arm B. The non-progression rate (CI95%) at six months was 17.0% in Arm A [7.7-30.8] and 20.8% in Arm B [7.1-42.2]. Median PFS (CI95%) and OS (CI95%) were 4.1 months [2.7; 5.4] and 13.6 months [7.7; 19.9] in Arm A; and 2.7 months [1.4; 4.7] and 13.4 months [4.7; 20.4] in Arm B. The objective response was 26.0% in Arm A and 8.3% in Arm B. 38 pts (76%) in Arm A vs 14 (58%) in Arm B had AEs of grade 3 or 4. Conclusions: ORR results are encouraging with cetuximab and afatinib. The median PFS has to be interpreted considering the criterion allowing pre-treatment with anti-EGFRs. Cross-over in Arm A could explain the similar median OS in both arms. Additional data will be presented (NRAS, subgroup of pts not pre-treated with anti-EGFRs, pts treated with cross-over). Clinical trial information: NCT01919879