Continuation of Cetuximab Beyond First-Line Progression in Metastatic Colorectal Cancer

Inclusion Criteria: 1. Histologically proven diagnosis of colorectal adenocarcinoma. 2. Diagnosis of metastatic disease. 3. Efficacy of a first line therapy containing anti-EGFR drug with a major response achieved (i.e. complete or partial response according to RECIST criteria v1.1) or a prolonged (at least 6 months) stable disease. 4. Progression to first line therapy. 5. RAS and BRAF wild-type status of FFPE analysis of primary colorectal cancer and/or related metastasis. 6. RAS (NRAS and KRAS exon 2,3 and 4), BRAFV600E, PIK3CA, EGFR ECD wild-type and HER2 not amplified in liquid biopsy at the time of screening (according to NGS, Foundation/Roche). 7. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST criteria, vers.1.1). 8. Male or female patients ≥ 18 years of age. 9. ECOG Performance Status 0-1. 10. Adequate bone marrow, liver and renal function assessed within 14 days before starting study treatment as defined by the following parameters: Bone marrow: * Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L * Hemoglobin (Hgb) ≥ 9 g/dL * Platelets ≥ 100 x 109/L Liver function: • Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and ALT (SGPT) ≤ 2.5 x ULN, except in patients with tumor involvement of the liver who must have AST and ALT ≤ 5 x ULN Renal function: • Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min 11. If female and of childbearing potential\*, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment. \*A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 12. If female and of childbearing potential, or if male, agreement to use adequate contraception (e.g., abstinence, intrauterine device, oral contraceptive, or double-barrier method), during the study and until at least 6 months after last dose of study treatment administration, based on the judgment of the Investigator or a designated associate. 13. Signed informed consent obtained before screening. Exclusion Criteria: 1. Any contraindication to the use of cetuximab, bevacizumab, Irinotecan, 5-FU, oxaliplatin, folic acid. 2. Active uncontrolled infections, active disseminated intravascular coagulation or history of interstitial lung disease. 3. Past or current history of malignancies other than colorectal carcinoma, except for curatively treated basal and squamous cell carcinoma of the skin cancer or in situ carcinoma of the cervix. 4. Pregnancy (exclusion to be ascertained by a beta hCG test). 5. Breastfeeding. 6. Fertile women (\<2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception. 7. Myocardial infarction, unstable angina pectoris, balloon angioplasty (PTCA) with or without stenting within the past 12 months before inclusion in the study, Grade III or IV heart failure (NYHA classification). 8. Cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin. 9. Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study. 10. Participation in a clinical study or experimental drug treatment within 30 days prior to study inclusion or during participation in the study. 11. Known or clinically suspected brain metastases. 12. History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhea. 13. Severe, non-healing wounds, ulcers or bone fractures. 14. Marked proteinuria (nephrotic syndrome). 15. Known DPD deficiency (specific screening not required). 16. Known history of alcohol or drug abuse. 17. A significant concomitant disease which, in the investigating physician's opinion, rules out the patient's participation in the study. 18. Absent or restricted legal capacity. 19. Patients with known dMMR or MSI-H tumors who are eligible for approved immune checkpoint inhibitor therapy will be excluded from the trial, unless ICI therapy is contraindicated or declined by the patient. This ensures alignment with current standard of care.