Background: Triple chemotherapy with an anti-EGFR reported promising activity with some safety concerns in single arm phase II trials. This trial evaluated activity and safety of mFOLFOXIRI + panitumumab vs FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients. Methods: Prospective 2:1 randomized, multi-center, phase II trial comparing mFOLFOXIRI (Ox 85 mg/m2, Iri 150 mg/m2, 5-FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + Panitumumab 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5-FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Cohort 1: irresectable mCRC; cohort 2: chance of secondary resection of metastatic lesions. Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), DCR, PFS, OS, toxicity, quality of life (QLQ-C30). Financially supported by an unrestricted grant from Amgen. Results: A total of 96 patients were randomized (63 arm A, 33 arm B). ORR was 85.7% in arm A and 54.5% in arm B (p = 0.0013, OR 5.000; 95%-CI 1.870-13.370). DCR was 96.8% in arm A and 78.8% in arm B (p = 0.0071, OR 8.212). ORR in Arm A was 90.6% versus 60.0% (p = 0.0288, OR 6.400) and in Arm B 60.0% versus 50% (p = n.s.) for left and right located CRC, respectively. ORR between arms A and B comparing left and right sided CRC was 90.6% versus 60.0% (p = 0.0039, OR 6.400; 95%-CI 1.889-21.679) and 60.0% versus 50.0% (p = n.s.), respectively. Secondary resections in cohort 2 were 60% (n = 12) and 36.4% (n = 4) in arms A and B, respectively. Treatment related serious adverse advents grade 3-5 occured in 32.8% and 12.1% in arms A and B, respectively (p = 0.0297). Nevertheless, no differences in global health status, functional scales, and symptom scales were reported. Conclusions: mFOLFOXIRI plus Panitumumab results in significantly higher response rates compared to FOLFOXIRI in RAS wild-type mCRC. Strong effectivity was observed also in right sided and BRAF mutated CRC. High secondary resection rates could be achieved. Although toxicity (treatment related SAEs) was increased, QL reporting was similar in both arms. Final PFS, AEs, and dosing data will be presented at the meeting. Clinical trial information: NCT01328171