This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m, and capecitabine 2000 mg/m repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3-4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n = 34; 55%), as well as those with left colon primary tumors (n = 66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations.ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010.