This study is a phase II, open-label, multicenter clinical trial designed to evaluate two different treatment options for patients with metastatic colorectal cancer whose disease has progressed after standard therapies. The study compares a rechallenge treatment using irinotecan plus cetuximab with the current standard of care, trifluridine/tipiracil plus bevacizumab, as third-line therapy. Patients enrolled in the study are selected based on specific molecular characteristics of their cancer, identified through circulating tumor DNA analysis from a blood sample. The main purpose of the study is to determine whether the rechallenge with irinotecan and cetuximab leads to a higher tumor response rate compared with trifluridine/tipiracil plus bevacizumab. Secondary objectives include evaluating progression-free survival, overall survival, safety, and quality of life. Patients will be randomly assigned to one of the two treatment groups and will receive treatment until disease progression, unacceptable side effects, or withdrawal of consent. Tumor response will be assessed using standard imaging techniques according to RECIST criteria.

This is a phase II, open-label, randomized, multicenter clinical trial designed to evaluate the efficacy and safety of an anti-EGFR rechallenge strategy compared with the current standard of care in patients with molecularly selected metastatic colorectal cancer (mCRC). Eligible patients have metastatic colorectal cancer that has progressed after standard first- and second-line therapies and have previously achieved clinical benefit from an anti-EGFR-based regimen. Patient selection is based on molecular profiling performed on circulating tumor DNA obtained from a baseline blood sample, identifying tumors that are wild-type for RAS, BRAF, EGFR, PIK3CA exon 20, MAP2K1, and MET, and without HER2 amplification. A total of 150 patients will be randomized in a 1:1 ratio to one of two treatment arms. In the experimental arm, patients will receive cetuximab in combination with irinotecan administered every two weeks. In the control arm, patients will receive trifluridine/tipiracil administered orally according to standard dosing schedules in combination with bevacizumab administered every two weeks. Treatment in both arms will continue until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria. Tumor assessments will be performed at regular intervals using computed tomography or magnetic resonance imaging and evaluated according to RECIST version 1.1 criteria. The primary endpoint of the study is the objective response rate. Secondary endpoints include progression-free survival, overall survival, safety and tolerability, and quality of life assessed using validated questionnaires. Adverse events will be monitored throughout the study and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Following disease progression, crossover to the alternative treatment arm may be considered at the investigator's discretion. Long-term follow-up will be conducted to assess survival outcomes.

Inclusion Criteria:

1. Male or female aged ≥18 years

2. Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤1

3. Diagnosis of histologically or cytologically confirmed colorectal cancer.

4. At least one measurable lesion according to RECIST1.1

5. KRAS/NRAS/BRAFV600E wt status of primary CRC or related metastasis (local laboratory assessment).

6. Progression to previous first-line anti-EGFR-containing therapy producing at least a partial response ≥ 6 months.

7. Received and progressed to an anti-EGFR and irinotecan free second-line treatment.

8. Have an anti-EGFR free interval of at least 4 months.

9. Refractory to previous 5-fluorouracil/capecitabine, irinotecan, oxaliplatin, bevacizumab.

10. RAS/BRAF/EGFR/PIK3CAex20/MAP2K1/MET WT and HER2 not amplified ctDNA at FoundationOne CDx test at baseline.

11. Life expectancy of at least 3 months.

12. Adequate hematological function defined by white blood cell (WBC) count ≥ 2.5 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused).

13. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and alanine aminotransferase (ALT) levels ≤ 2.5 × ULN for all subjects or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver).

14. Adequate renal function defined by an estimated creatinine clearance > 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).

15. No contraindication to the study drugs.

16. No prior treatment with trifluridine/tipiracil.

17. Women of childbearing potential* must have a negative blood pregnancy test at thescreening visit. Subjects and their partners must be willing to avoid pregnancy during the trial.

    *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.

18. Women of childbearing potential, or male, must agree 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.

19. Will and ability to comply with the protocol.

20. Signed informed consent obtained before screening.

Exclusion Criteria:

1. ECOG PS ≥2
2. Received more than 2 lines of treatment for metastatic disease.
3. Previous treatment with trifluridine/tipiracil
4. RAS/BRAF/EGFR/PIK3CAex20/MAP2K1/MET WT HER2 not amplified status at liquid biopsy analysis during screening.
5. Previous history of malignancy within the last 2 years will be excluded with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ
6. Evidence of bleeding diathesis or coagulopathy.
7. Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.
8. Known severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v 5 Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
9. Clinically significant cardiovascular disease, active inflammatory bowel disease, active autoimmune disease.
10. Diagnosis of interstitial pneumonitis or pulmonary fibrosis.
11. History of abdominal fistula, GI perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to the first study treatment.
12. Pregnant or lactating women.
13. Psychiatric or addictive disorders would preclude study participation.
14. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating study treatments.
15. Withdrawal of the consent to take part to the study.