STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer

Inclusion Criteria: 1. Written informed consent to study procedures and to correlative studies. 2. Either sex aged ≥ 18. 3. Histologically proven of colorectal adenocarcinoma. 4. Diagnosis of metastatic disease. 5. RAS mutant at initial diagnosis assessed at local centers according with a validated method defined by EMA and known MMR/MSI status. 6. Achieved a PFS in first line \> 6 months with chemotherapy in combination to antiangiogenic treatment OR with one metastatic site at study entry 7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry. 8. Imaging-documented measurable disease, according to RECIST 1.1 criteria. 9. Estimated life expectancy of more than 12 weeks 10. 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. 11. 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. 12. 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). 13. Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range. 14. Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory. Additional analysis of polymorphisms uridine diphosphate-glycosyltransferase 1 (UGT1A1) enzyme is recommended but not mandatory. Exclusion Criteria: 1. Prior malignancy within five years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 2. Any contraindication to regorafenib. 3. Not received immunotherapy if dMMR or MSI-H. 4. Major surgical intervention within 4 weeks prior to enrollment. 5. Pregnancy and breast-feeding. 6. Any brain metastasis. 7. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study. 8. History of poor co-operation, non-compliance with medical treatment, unreliability or any condition that may impair the patient's understanding of the Informed consent form. 9. Participation in any interventional drug or medical device study within 30 days prior to treatment start. 10. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment. 11. Complete deficiency of activity of dihydropyrimidine dehydrogenase (DPYD)