Background: The optimal duration and content of first-line therapy in mCRC pts once they have achieved objective response is controversial. In the FIRE-3 trial, ETS was significantly associated with PFS and OS. Based on this evidence it can be hypothesized that once this goal has been achieved, further exposure to combined antineoplastic treatment may not result in improvement or preservation of such result but only in an increase of toxicity. We designed a strategy study to compare FOLFIRI + cetuximab until PD to FOLFIRI + cetuximab for 8 cycles followed by cetuximab alone until PD in first line treatment of RAS/BRAF WT mCRC pts. Methods: This is a multicenter, open-label, randomized phase III trial. Untreated and unresecteble RAS/BRAF WT mCRC pts were randomized 1:1 to receive Cetuximab (400 mg/mq w1 and then 250 mg/mq weekly) + FOLFIRI until PD (standard arm) or Cetuximab (400 mg/mq week 1 and then 250 mg/mq weekly) + FOLFIRI for 8 cycles followed by Cetuximab monotherapy until PD (experimental arm). Tumor assessment is planned every 8 weeks. The objective of the study is to demonstrate a not inferior efficacy and a better toxicity profile for the experimental treatment compared to the standard treatment. The co-primary endpoints are PFS and incidence of G 3-4 AEs. Secondary endpoints are OS, ORR, ETS (8 weeks) and safety. A prospective multiple gene mutation analysis by NGS of both tumor tissue and blood will be performed to find potential predictive factors and surrogate markers of treatment efficacy. The two co-primary endpoints will be compared between the two arms using a fixed-sequence testing procedure to control for the family-wise type I error rate of 0.05 in a strong sense. This sequence considers that a reduction of grade 3-4 AEs is only of relevance, if non-inferiority is shown regarding PFS. 600 evaluable pts will be enrolled and randomized. Study recruitment started on January 2015, currently 139 pts have been randomized. Clinical trial information: NCT02484833