Background: While both anti-VEGF(R) and EGFR antibodies have activity in metastatic RAS wild type CRC, the combination of the two appeared to be detrimental when combined with chemotherapy in unselected CRC patients. We undertook this study to determine whether the anti-VEGFR antibody, ramucirumab, improved activity of Irinotecan and Cetuximab as 2nd line therapy in KRASwt CRC patients, who previously received FOLFOX or CAPOX with bevacizumab (bev) first line therapy, and were now progressing. Methods: Patients with advanced and measurable (RECIST 1.1) CRC who had previously been treated with a fluoropyrimidine and oxaliplatin (ox) with bev, and recently showed progression on CT scan were randomized to IC (180 mg/m2 and 500 mg/m2 respectively) or ICR (R = 8 mg/kg) every 2 weeks. After 35 pt were randomized, planned interim analysis showed excess gr 3-5 toxicity for ICR. Therefore a modified ICR (150 mg/m2, 400 mg/m2 and 6 mg/kg) arm was instituted after study hold. Patients were stratified by PS (0 vs 1), progression on ox (Y vs N), and progression within 6 months of last treatment (or longer). 100 patients were then accrued to IC vs mICR, with 85% power to detect improvement in median PFS from 4.5 to 7.65 months (with 15% type I error or p < 0.15) by stratified log-rank test. Results: Results: 102 patients were randomized and evaluable from June, 2014 - July, 2017. Patients were 65% male, 9% black and 8% Hispanic with med age 60 years, PS 0 = 52%, with 24% progressing while on ox and 15% progressing more than 6 months off rx. Gr 3-4 overall toxicity for IC vs mICR was 47% vs 54% with diarrhea = 10 v 15%; rash = 13 vs 8%; neutropenia = 9 vs 10%. Reasons off study were: 60% progression, 18% adverse events and 10% patient choice. Stratified log rank analysis showed a HR = 0.65 for PFS of mICR vs IC (overall med 5.8 months; p = 0.068), which met primary endpoint of p < 0.15. Survival appears to be equal with med = 20.5 months. Conclusion: In KRAS selected, wildtype CRC, 2^nd line therapy (following ox and bev based treatment), an anti-VEGFR antibody, combined with anti-EGFR and irinotecan, prolongs PFS. This effect is similar to the reported improvement in PFS in other 2^nd line anti-VEGF trials and supports the fact that antibodies against these two targets can be combined for additional benefit in the appropriate patient population. This study was coordinated by ECOG-ACRIN & supported by NCI awards: CA180820, CA180794, CA180826, CA180830, CA180888, CA180870, CA189830. Clinical trial information: NCT01079780