Abstract only 3591 Background: Translational research identified numerous putative markers for a “beyond-k-RAS” selection of colorectal cancer patients receiving cetuximab, but none of these entered clinical practice mainly because prospective validation is lacking. The aim of our study was to evaluate whether a panel of biomarkers, prospectively analysed may be able to predict patients’ clinical outcome more accurately than k-RAS status alone. Methods: Metastatic, K-RAS wild type colorectal cancer patients, candidate to receive second/third-line cetuximab with chemotherapy have been prospectively allocated, after informed consent, into 2 groups on the basis of their genetic profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN ≥ 2.6, HER-3 Rajkumar score ≤ 8, IGF-1 immunostaining < 2) and unfavourable (any of the previous markers altered or mutated). All patients received cetuximab treatment as planned by treating physician who was unaware of biomarkers results. To detect a difference in terms of response rate (RR) among patients with an unfavourable profile (estimated around 25%) and patients with a favourable profile (estimated around 60%), assuming a probability alpha of 0.05 and beta of 0.05, required sample size will be 46 patients. Results: 31 patients have been enrolled, most patients (27, 86%) received cetuximab as third-line. Eleven patients (35%) were allocated to the favourable profile and 20 patients (75%) to the unfavourable profile. Patients with the unfavourable profile showed 1 BRAF mutation, 2 PIK3CA exon 20 mutations, 12 cases of EGFR GCN < 2.6, 13 cases of HER-3 and 11 cases of IGF-1 overexpression respectively. RR in the favourable and unfavourable group was 7/11 (64%) and 1/20 (5%) (p= 0.008) respectively. The favourable group also showed an improved median TTP (8 months vs. 2.6 months, p = 0.0007) and OS (16 months vs. 6 months, p = 0.0002). Conclusions: Our results suggest that prospective selection of candidates for cetuximab may be able to improve clinical outcome in patients with a favourable profile. This approach, if confirmed, may also allow an early switch to alternative treatment in patients with an unfavourable profile.