Inclusion Criteria:
* Written informed consent to study procedures.
* Histologically proven diagnosis of colorectal cancer.
* Metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease.
* At least one measurable lesion according to RECIST1.1.
* Age ≥ 18 years.
* ECOG PS ≤ 1.
* Life expectancy of at least 12 weeks.
* Previous adjuvant fluoropyrimidine-based chemotherapy allowed only if more than 12 months elapsed between the end of adjuvant and first relapse.
* Availability of archival tumour tissue (primary tumour and metastases or at least one of the two) for biomarker analysis.
* Availability of blood sample for biomarker analysis.
* Previously not eligible for a chemotherapy doublet or triplet (oxaliplatin and/or irinotecan-based combination).
* Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hemoglobin ≥ 9 g/dl.
* Total bilirubin ≤1.5 fold the upper-normal limits (UNL), AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x UNL (or \<5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or \<5 x UNL in case of liver metastases).
* Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL.
* Male subjects with female partners of childbearing potential must be willing to use adequate contraception as approved by the investigator (barrier contraceptive measure or oral contraception).
* Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive.
* Subjects and their partners must be willing to avoid pregnancy during the trial and until 6 months after the last trial treatment.
* Will and ability to comply with the protocol.
Exclusion Criteria:
* Radiotherapy to any site within 4 weeks before the study.
* Previous treatment with trifluridine/tipiracil, bevacizumab and capecitabine (previous treatment with capecitabine was permitted only in the adjuvant setting and if more than 12 months elapsed between the end of adjuvant and first relapse).
* Untreated brain metastases or spinal cord compression or primary brain tumors.
* History or evidence upon physical examination of CNS disease unless adequately treated.
* Clinical signs of malnutrition.
* Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.
* Evidence of bleeding diathesis or coagulopathy.
* Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.
* Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication.
* Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
* Any previous venous thromboembolism ≥ NCI CTCAE Grade 4.
* History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment.
* Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer).
* Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ.
* Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
* Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
* Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
* Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. 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.
