This is a multicentric, phase II and open label study.75 patients are expected to be randomized in 35 centers. The main objective is to assess the efficacy and safety of Afatinib -cetuximab combo versus cetuximab alone in treatment of patients with refractory wtKRAS metastatic colorectal cancer.

Patients who will sign the inform consent will be enrolled into one of two groups. Group A will receive Afatinib ( 40mg per day) and Cetuximab (500mg/m2)every two weeks until progression. Group B will receive Cetuximab (500mg/m2) alone every two weeks until progression and after progression,patients from group B will receive afatinib (group A treatment) until progression. The criteria for evaluation will be tumor response and progression documented by CT scan and according to RECIST criteria version 1.1.

Patient will also sign a inform consent before participating in biological study. The aim of this translational study is to collect tumor and blood sample in order to determine, the biological factors which are predictive of the response to treatment.

Inclusion Criteria:

1. Metastatic colorectal cancer expressing the wtKRAS status

2. No previous EGFR targeted therapy.

3. Must have failed a prior regimen containing irinotecan for metastatic disease and a prior regimen containing oxaliplatin for metastatic disease

4. Must have previously received a thymidylate synthase inhibitor (eg, fluorouracil, capecitabine, raltitrexed, or fluorouracil-uracil) at any point for treatment of colorectal cancer (CRC)

5. Life expectancy of at least 3 months.

6. Patient with ECOG ≤ 1

7. Patients aged ≥ 18.

8. Patient with measurable lesions according to RECIST criteria (version 1.1) with spiral CT scan and defined as ≥ 10 mm in longest diameter and 2X the slice thickness for extra nodal lesions and/or > 15 mm in short axis diameter for nodal lesions

9. Patient able to receive adequate oral nutrition of ≥ 1500 calories per day and free of significant nausea and vomiting

10. Patient with adequate organ function:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • Haemoglobin ≥ 9 g/dL
    • Platelets (PTL) ≥ 100 x 109/L
    • AST/ALT ≤ 3 x ULN (≤ 5 x ULN in case of liver metastases)
    • GammaGT < 3 x ULN (< 5 x ULN in case of liver involvement)
    • Bilirubin ≤ 1.5 x ULN
    • Creatinine clearance ≥ 50 mL/min (Cockcroft and Gault formula)

11. Adequate contraception if applicable.

12. Ability to take oral medication in the opinion of the investigator

13. Patient able and willing to comply with study procedures as per protocol

14. Patient able to understand and willing to sign and date the written voluntary informed consent form at screening visit prior to any protocol-specific procedures

15. Patient affiliated to a social security regimen

Exclusion Criteria:

1. Previous EGFR targeted therapy.
2. Mutant KRAS status
3. Prior severe reaction to a monoclonal antibody
4. No heart failure or coronary heart disease symptoms Clinically relevant cardiovascular abnormalities, as judged by the investigator, such as, but not limited to, uncontrolled hypertension, congestive heart failure NYHA classification > III, unstable angina, myocardial infarction within six months prior to randomisation, or poorly controlled arrhythmia
5. Cardiac left ventricular dysfunction with resting ejection fraction of less than institutional lower limit of normal (if no lower limit of normal is defined in the institution, the lower limit is 50%)
6. Symptomatic brain metastases requiring treatment
7. Major surgery within 28 days or minor surgery within 14 days of the start of the study treatment
8. Radiotherapy less than two weeks prior to the start of the study treatment
9. Systemic chemotherapy, hormonal therapy, immunotherapy ≤ 21 days before study treatment
10. No major comorbidity that may preclude the delivery of treatment or active infection (HIV or chronic hepatitis B or C) or uncontrolled diabetes.
11. Concomitant occurrence of another cancer, or history of cancer within the past five years except in situ carcinoma of the cervix treated or basal cell carcinoma or squamous cell carcinoma.
12. Known pre-existing interstitial lung disease
13. Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, malabsorption, or CTCAE grade >2 diarrhea of any etiology
14. Pregnant woman or lactating woman.
15. Persons deprived of liberty or under guardianship.
16. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
17. Previous history of keratitis, ulcerative keratitis or severe dry eye.