Background: Imgatuzumab, a humanized engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, showed promising clinical activity in a phase I trial including KRAS MT mCRC. This multicenter phase II study (NCT01326000) aimed to compare the combination of imgatuzumab with FOLFIRI to cetuximab plus FOLFIRI or FOLFIRI alone as second-line treatment in patients with both KRAS e2WT or e2MT mCRC. Methods: Patients underwent a mandatory fresh tumor biopsy at screening to assess KRAS exon 2 status. KRAS e2WT patients were randomized (1:1) to treatment groups 1 or 2 to receive imgatuzumab (1,400 mg IV on day 1 and 8 then q2-weekly) or cetuximab (400 mg/m² IV on day 1 followed by 250 mg/m² IV q-weekly) respectively plus FOLFIRI (standard IV chemotherapy). KRAS e2MT patients were randomized to groups 3 and 4 to receive imgatuzumab plus FOLFIRI or FOLFIRI alone respectively. Patients were stratified by EGFR expression, time to disease progression on first line treatment and prior treatment with bevacizumab. A run-in phase (n=6/group) was performed to confirm tolerability before recruitment proceeded. Results: 169 patients with an evaluable fresh tumor biopsy were randomized. Median PFS (Investigator reported) was 7.3 months in group 1 versus6.1 in group 2 (HR, 1.13; 95% CI 0.69-1.86) and 5.2 months in group 3 versus 4.3 in group 4 (HR, 0.94; 95% CI 0.57-1.54). Adverse events of ≥ grade 3 included rash (42.5%, 9.8%, 31.8%, 0% in groups 1, 2, 3 and 4 respectively), hypomagnesemia (30.0%, 4.9%, 22.7%, 0% respectively) and neutropenia (20.0%, 29.3%, 25.0%, 21.4% respectively). Conclusions: The outcome was negative with respect to the primary efficacy endpoint (PFS) with no benefit seen for the addition of imgatuzumab to FOLFIRI in second-line in both KRAS e2WT and e2MT populations. We demonstrated that collection of fresh tumor biopsy is feasible in pretreated CRC. Clinical trial information: NCT01326000