Background: Panitumumab alone in third-line chemotherapy increased objective response rate (ORR) from 0 to 17% (95% CI 11%-25%) and prolonged progression-free survival (PFS) versus best supportive care in patients (pts) with chemorefractory KRAS wild-type (WT) MCRC (Amado et al, J Clin Oncol 2008). This trial (NCT00655499) was evaluating the combination of panitumumab and irinotecan in the same population. Methods: Main inclusion criteria were: pts with KRAS WT MCRC refractory to standard FOLFOX or XELOX ± bevacizumab and irinotecan alone or FOLFIRI or CAPIRI ± bevacizumab, PS 0-2, age 18-80 years, bilirubin level ≤1.5xULN, no prior therapy with EGFR inhibitors. KRAS status was assessed in each center for inclusion and a central assessment was done for confirmation after inclusion (allelic discrimination on tumor DNA). BRAF, NRAS and PTEN expression were evaluated. Pts received panitumumab (day 1: 6 mg/kg) and irinotecan (day 1: 180 mg/m²) Q2W until disease progression or unacceptable toxicity. Tumor evaluation was performed every 2 months (RECIST 1.0). The primary endpoint was ORR, with an anticipated rate of 30% and an expected CI between 18.2%-41.8%. Results: Sixty-nine pts were included in 12 centers. Seven pts were not eligible (3 with KRAS mutation at central assessment, 1 did not receive irinotecan, 2 received EGFR inhibitor, and 1 for other reason). The ORR was 32.3% (95%CI 20.7-43.9) (CR: N=3, 4.8%, PR: N=17, 27.4%); 22 (35.5%) pts had stable disease, 19 (30.6%) pts had a progressive disease, and 1 (1.6%) was not evaluable (unacceptable skin toxicity). Median PFS was 5.5 months (95%CI: 4.1-8.7). Three (4.8%) pts stopped treatment for limiting toxicity without toxic death. Most frequent grade 3/4 toxicities were: acneiform rash 19.0%, diarrhea 14.3%, and neutropenia 12.7%. There were no infusion reactions. Conclusions: This trial reached its primary endpoint with an ORR of 32.3%. These results suggest that the combination of panitumumab and irinotecan in third-line chemotherapy should be preferred to panitumumab monotherapy in pts with KRAS WT MCRC refractory to standard chemotherapy.