Background: Second-line treatment with chemotherapy plus bevacizumab (Bev) or cetuximab (Cet) is now recognized as a standard treatment in mCRC. The main objective of this French multicenter, prospective open randomized trial was to evaluate the Progression Free Survival (PFS) rate at 4 months in patients receiving chemotherapy plus Bev or Cet after failure with Bev plus chemotherapy. Methods: The main eligibility criteria were disease progression after first-line chemotherapy: 5-FU with irinotecan or oxaliplatin associated with bevacizumab in wtKRAS mCRC. Patients were treated with cross over chemotherapy (FOLFIRI or mFOLFOX6) with bevacizumab (Arm A) or cetuximab (Arm B) until progression or limiting toxicity. The tumor response was evaluated every 6 weeks until progression using RECIST 1.1. Results: 133 patients, 86 male(64.7%), PS 0 (n = 74, 57.8%), 1 (n = 54, 42.2%), in 25 sites in France, were included between October 2010 and May 2015. Most frequent chemotherapy regimens delivered were mFOLFOX6 + Bev (n = 41) or Cet (n = 42); FOLFIRI + Bev (n = 25) or Cet (n = 25). The PFS rate at 4 months was 79% in Arm A and 66.7% in Arm B (p = 0.09). Secondary objectives included median PFS: 7.1 months (Arm A) vs 5.6 months (Arm B) (HR = 1.43; 95%CI [0.99-2.06] p = 0.06), and median OS: 15.9 months (Arm A) vs 10.6 months (Arm B) (HR = 1.44; 95%CI [0.95-2.18] p = 0.08). Conclusions: In wtKRAS mCRC patients progressing after bevacizumab plus chemotherapy, continuation beyond progression with bevacizumab and crossover chemotherapy is associated with a numerically higher but not statistically significant median PFS and OS compared to cetuximab plus chemotherapy. Final data with KRAS and NRAS analysis will be presented at the meeting. Clinical trial information: NCT01442649