This clinical program aims to evaluate the activity and efficacy of cetuximab continuation of treatment for three lines of therapy with rotation of chemotherapy (FOLFIRI, FOLFOX, irinotecan) in mCRC patients, whose tumors remain RAS/BRAF WT. The study will also evaluate the activity and efficacy of cetuximab re-introduction in combination with irinotecan as third line therapy in the concept of re-challenge for those patients that will be treated in second line with chemotherapy plus anti-angiogenic drugs (FOLFOX plus bevacizumab), having a RAS or BRAF mutant disease at the time of progression after FOLFIRI plus cetuximab first line treatment. A novel characteristic of this program is that the therapeutic algorithm will be defined at each treatment decision (first line, second line and third line) in a prospective fashion in each patient by liquid biopsy assessment of RAS/BRAF status.

Based on dynamic and longitudinal liquid biopsy assessment of RAS/BRAF status, that will be prospectively performed before each line of treatment, mCRC patients will be treated with cetuximab in combination with chemotherapy throughout three lines of therapy, as follows: FOLFIRI plus cetuximab (first line); FOLFOX plus cetuximab (second line); irinotecan plus cetuximab (third line) in case of RAS/BRAF WT at each time point of progression. If at progression after the first line, the liquid biopsy assessment indicates RAS and or BRAF mutant status, patients will be treated with FOLFOX plus bevacizumab as the second line of therapy. If at progression after the second line, the liquid biopsy assessment indicates RAS and or BRAF mutant status, patients will be treated with regorafenib or trifluridine-tipiracil (investigator's choice), as third line of therapy. Each treatment will be administered using standard doses and schedules until progression of disease or unacceptable toxicity.

This study will also evaluate the activity and efficacy of cetuximab re-introduction in combination with irinotecan as third line therapy in the concept of re-challenge for those patients that will be treated in second line with FOLFOX plus bevacizumab, having a RAS or BRAF mutant disease at the time of progression after FOLFIRI plus cetuximab first line treatment. A novel characteristic of this program is that the therapeutic algorithm will be defined at each treatment decision (first line, second line and third line) in a prospective fashion in each patient by liquid biopsy assessment of RAS/BRAF status

Inclusion Criteria:

1. Histologically proven diagnosis of colorectal adenocarcinoma

2. Diagnosis of metastatic disease

3. RAS and BRAF wild-type status of FFPE analysis of primary colorectal cancer and/or related metastasis

4. Measurable disease according to Response Evaluation Criteria in Solid Tumors RECIST criteria, vers.1.1)

5. Male or female patients ≥ 18 years of age

6. ECOG Performance Status 0,1

7. 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

8. 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

9. 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 3 months after last dose of study treatment administration, based on the judgment of the Investigator or a designated associate

10. Signed informed consent obtained before screening.

Exclusion Criteria:

1. Any contraindication to the use of cetuximab, Irinotecan, 5-FU, oxaliplatin, folinic acid,bevacizumab, trifluridine-tipiracil, regorafenib
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. Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study
11. Participation in a clinical study or experimental drug treatment within 30 days prior to study inclusion or during participation in the study
12. Known or clinically suspected brain metastases
13. History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea
14. Severe, non-healing wounds, ulcers or bone fractures
15. Uncontrolled hypertension
16. Marked proteinuria (nephrotic syndrome)
17. Known DPD deficiency (specific screening not required)
18. Known history of alcohol or drug abuse
19. A significant concomitant disease which, in the investigating physician's opinion, rules out the patient's participation in the study
20. Absent or restricted legal capacity