Background: RAS mutant metastatic colorectal cancer (mCRC) patients (pts) are excluded from treatment with anti-EGFR monoclonal antibodies. Nevertheless, retrospective data from large phase III trials led to hypothesize a potential benefit from cetuximab in KRAS G13D mutant pts both in first and advanced lines of treatment (De Roock JAMA 2010, Tejpar JCO 2012). In the refractory setting, KRAS G13D mutant pts achieved a superior progression free survival (PFS) (4.0 vs. 1.9 months, HR=0.51, p=0.004) and overall survival (OS) (7.6 vs. 5.7 months, HR=0.50, p=0.005) compared to pts with other KRAS mutations. We conducted the present trial in order to prospectively confirm those findings and to evaluate the clinical relevance of single agent cetuximab in KRAS G13D mutant mCRC pts. Methods: According to previously reported results, using a phase 2 Fleming single-stage design, with 90% power and alpha 0.05, setting p0=10% and p1=50%, the study required the inclusion of 12 pts. The alternative hypothesis would have been rejected if 3 or less pts would have been progression-free at four months after treatment start. We prospectively enrolled mCRC patients to receive treatment with cetuximab monotherapy (500 mg/mq bi-weekly). Main eligibility criteria were the following: KRAS G13D mutant, measurable metastatic disease, progression after treatment with fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab or no other valid therapeutic option. Pts were re-evaluated according to RECIST 1.1 criteria. Results: Twelve consecutive KRAS G13D mutant eligible pts were enrolled. Main pts’ characteristics were the following: Male/Female, 6/6; median age, 74 years (range 26-79); Eastern Cooperative Oncology Group performance status 0/1-2, 6/6; synchronous/metachronous disease, 8/4; median number of previous CT lines, 2 (range 0-5). Three patients (25%) showed disease stabilization at four months after treatment start and no RECIST responses were observed. Disease control rate at six months was 0%. Median PFS and OS were 1.9 and 7.2 months, respectively. Grade 3 rash was observed in two (17%) patients and no unexpected toxicities occurred. Conclusions: The hypothesis of a clinically relevant benefit with cetuximab monotherapy in KRAS G13D mutant mCRC pts was rejected. KRAS G13D mutant mCRC pts should not be treated with cetuximab and alternative strategies should be adopted.