Inclusion Criteria:
1. Signed and dated informed consent,
2. Patients willing and able to comply with protocol requirements,
3. Histologically proven colorectal adenocarcinoma,
4. Stage IV disease,
5. Have life expectancy of at least 6 months,
6. Previous chemotherapy regimens with each of the following agents: fluoropyrimidine, oxaliplatin, irinotecan, anti-vascular endothelial growth factor (VEGF) therapy (bevacizumab, aflibercept), and anti-epidermal growth factor receptor (EGFR) therapy (cetuximab or panitumumab for tumors with wild-type RAS and/or BRAF wild type),
7. At least one measurable or evaluable lesion as assessed by computed tomography (CT)-scan or magnetic resonance imaging (MRI) according to RECIST v1.1,
8. Age ≥ 18 years,
9. ECOG PS 0-1,
10. Adequate hematologic function: neutrophils \> 1.5 x 109 /L; platelets \> 100 x 109 /L; hemoglobin ≥ 9 g/dL,
11. Calculated creatinine clearance ≥ 30 mL/min,
12. Adequate liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit normal ULN;
≤ 5 x ULN in case of liver metastasis), total bilirubin ≤ 1.5 x ULN (\< 2 x ULN if hyperbilirubinemia is due to Gilbert's syndrome), albumin ≥ 25 g/L,
13. Baseline evaluations: clinical and blood evaluations no more than 14 days prior to inclusion and start of trifluridine/tipiracil, Tumor assessment (CT-scan or MRI, evaluation of non-measurable lesions) no more than 21 days prior to inclusion and start of trifluridine/tipiracil,
14. Female patients must be surgically sterile, or be postmenopausal, or must commit to using reliable and appropriate methods of contraception during the study (must have a negative pregnancy test within 7 days prior to enrollment) and during at least 6 months after the end of the last dose of study treatment (when applicable). All female patients with reproductive potential must have a negative pregnancy test (β-HCG) within 72 hours prior to starting trifluridine/tipiracil treatment. Breastfeeding is not allowed. Male patients must agree to use effective contraception in addition to having their partner use a contraceptive method as well during the trial and during at least 6 months after the end of the study treatment,
15. Registration with the French National Health Care System or PUMA (Protection Universelle MAladie).
Exclusion Criteria:
1. Medical history or evidence of CNS metastasis upon physical examination, unless adequately treated (e.g. non-irradiated CNS metastasis, seizure not controlled with standard medical therapy, patients are stable without evidence of progression for at least 28 days prior to the first dose of treatment),
2. Local or locally advanced disease (stage I to III),
3. Treatment with warfarin,
4. Uncontrolled hypercalcemia,
5. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),
6. Known complete dihydropyrimidine dehydrogenase (DPD) deficiency,
7. Treatment with any other investigational medicinal product within 28 days prior to study entry,
8. Symptomatic carcinomatosis with occlusive symptoms or ascites requiring paracentesis,
9. Other serious and uncontrolled non-malignant disease (e.g. active infection requiring systemic therapy, coronary stenting or myocardial infarction, or stroke in the past 6 months),
10. HIV-infected patients or otherwise known to be HIV-positive,
11. Untreated hepatitis B or C,
12. Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for \> 5 years,
13. Concomitant administration of prophylactic phenytoin and live attenuated virus vaccine such as yellow fever vaccine 28 days prior to the first dose of treatment.
14. Patient under guardianship, curatorship or under the protection of justice
