• Written informed consent to study procedures and to correlative studies.

• Either sex aged ≥ 18.

• Histologically proven of colorectal adenocarcinoma.

• Diagnosis of metastatic disease.

• RAS/BRAF wild-type status at initial diagnosis assessed at local centers according with a validated method defined by EMA and known MMR/MSI status

• RAS (NRAS and KRAS exon 2,3 and 4) and BRAF wild-type in liquid biopsy at study entry (according to central testing).

• Patient candidate to anti-EGFR rechallenge therapy with panitumumab and irinotecan as clinical practice; Efficacy of anti-EGFR drug in any line of treatment with a major response achieved (i.e. complete or partial response according to RECIST criteria v1.1) or stable disease ≥ 6 months and received a subsequent line of therapy upon progression.

• a. Note. Patients must have received at least 2 lines of treatment. Previous treatment with regorafenib, trifluridine/tipiracile, trifluridine/tipiracile + bevacizumab or fruquintinib is allowed. Previous rechallenge with anti-EGFR MoAb is NOT allowed. Adjuvant treatment will be considered as one line of therapy in case of progression within 6 months from the last dose of treatment.

• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry.

• Imaging-documented measurable disease, according to RECIST 1.1 criteria.

⁃ Estimated life expectancy of more than 12 weeks

⁃ Adequate bone marrow hematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL.

⁃ Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 2 (in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5 X ULN.

⁃ Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula).

⁃ Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range.