Background: The ERMES study explored the optimal intensity of anti-EGFR-based first line therapy for RAS/BRAF wt mCRC once achieved disease control. Although the study did not demonstrate non-inferiority of maintenance with Cet alone versus standard treatment, preliminary results suggested that a strategy of de-escalation treatment with only Cet might be effective in selected patients. Conflicting results have been previously reported for the predictive and prognostic role of TP53 variants in mCRC patients receiving anti-EGFR monoclonal antibody therapy. Here we describe the role of TP53 mutations within the ERMES study. Methods: Patients with untreated RAS/BRAF wt mCRC were randomly assigned (1:1) to receive either FOLFIRI/Cet until PD/toxicity (arm A) or FOLFIRI/Cet for 8 cycles followed by Cet alone (arm B). Tumor tissue samples were tested using the Oncomine Solid Tumor DNA kit covering hot spot mutations in 22 genes, including KRAS, NRAS, BRAF and TP53. Variant calling was performed using the Variant Caller Ion Torrent suite 5.16 software. The prognostic value of TP53 variants was assessed in the intention-to-treat (ITT) patients’ population with available sequencing data. Results: Tumor tissue specimens were available for 418/593 (70.5%) patients of the ITT population. Testing failed in 29 cases, whereas KRAS/NRAS/BRAF V600E variants were found in 36/389 (9.2%) patients, who were enrolled on the basis of local testing. Progression free survival (PFS) data were not available for 4 cases. Therefore, the final population in analysis was 349 cases. TP53 variants were detected in 165/349 (47.3%) patients, of which 86/165 (52.1%) in arm A and 79/165 (47.9%) in arm B. The median PFS (mPFS) of TP53 wild type patients in the overall population was 9.4 months versus 10.4 months in the TP53 mutant subgroup (HR 0.8439; 95%CI, 0.673-1.058; p = 0.142). In arm A, the mPFS of TP53 wild type patients was 10.8 months versus 10.7 months in TP53 mutant patients, with an HR 1.053 (95%CI, 0.7582-1.462; p = 0.76). The mPFS of TP53 wild type patients in arm B was 8.3 months versus 10.2 months in the TP53 mutant cohort, with an HR 0.7 (95%CI, 0.5087-0.9657; p = 0.0298). No significant difference was observed for the overall response rate (ORR) in both arms between TP53 mutant and wild type patients. Conclusions: These preliminary data suggest a possible prognostic role of TP53 variants in RAS/BRAF wild type mCRC patients receiving first line FOLFIRI/cetuximab followed by Cet alone. Comprehensive genomic profiling is ongoing to identify genomic signatures associated with sensitivity to Cet.