The study will a be a biologically enriched, prospectively stratified phase II trial in RAS wild type metastatic colorectal cancer patients progressing after first-line treatment with oxaliplatin, fluoropyrimidines and an anti-EGFR monoclonal antibody.

All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.

The study will a be a biologically enriched, prospectively stratified phase II trial in RAS wild type metastatic colorectal cancer patients progressing after first-line treatment with oxaliplatin, fluoropyrimidines and an anti-EGFR monoclonal antibody. Eligible patients will be prospectively allocated to either of two groups according to VEGFR2 levels (ELISA-based technique, pg/ml) at study entry.

Others angiogenetic factors levels concentration before and during treatment. VEGF, PlGF, HGF, VEGFR1, IL8, IL1a, T-cad, VEGFR3, SAP, VDBP, neuropilin1, CRP, endoglin plasma concentrations will be evaluated before each cycle according to an ELISA-based technique All patients will undergo a blood test for retrieving circulating tumor DNA (Liquid Biopsy) at selected time-points before and during treatment for determining whether the status of selected tumor biomarkers evolve during tumor progression by comparing different ctDNA samples.

All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.

Inclusion Criteria:

• • Histological confirmation of colorectal cancer

  • Confirmed RAS wild type patient treated with an oxaliplatin-anti EGFR treatment in 1st line
  • At least one lesion measurable with CT or MRI scan
  • Radiologically documented progression while on or after discontinuation of treatment with FOLFOX in combination with an anti-EGFR monoclonal antibody (either cetuximab or panitumumab)
  • Radiologically documented progressing disease after FOLFOX in combination with an anti-EGFR monoclonal antibody (either cetuximab or panitumumab)
  • Life expectancy plus 3 months
  • Netrophils count ³ 1.5 x 109/L
  • Platelets count ³ 100 x 109/L
  • Hemoglobin ³ 9 g/dL
  • Creatinine £ 1.5 mg/dL, Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour.Bilirubin £ 1.5 x ULN
  • AST and ALT £ 2.5 x ULN (< 5 ULN in case of liver metastases)
  • Informed written consent
  • ECOG Performance Status < 2
  • Age plus18 yrs
  • Regular follow-up feasible.
  • For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior of starting study treatment,
  • Female patients must commit to using reliable and appropriate methods of contraception until at least six months after the end of study treatment

Exclusion Criteria:

• • Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),

  • Treatment with any other investigational medicinal product within 28 days prior to First Study treatment.
  • Other serious and uncontrolled non-malignant disease,
  • History or evidence upon physical examination of CNS metastasis unless adequately treated
  • Gilbert's syndrome
  • Intolerance to atropine sulfate or loperamide
  • Known dihydropyrimidine dehydrogenase deficiency
  • Treatment with CYP3A4 inducers unless discontinued > 7 days prior to First Study treatment.
  • Any of the following in 3 months prior to inclusion: grade 3-4 gastrointestinal bleeding (unless due to resected tumor), treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, or diverticulitis.
  • 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,
  • Major surgery or traumatic injury within the last 28 days or until the surgical wound is fully healed whichever came later
  • Pregnant or breastfeeding women,
  • Patients with known allergy to any excipient to study drugs,
  • Bowel obstruction.
  • Uncontrolled infections
  • Known drugs or alcohol abuse
  • History of severe cardiovascular disease within 6 months prior to First Study treatment Uncontrollable hypertension, when treated with three or more drugs.

All patients will receive aflibercept in combination with FOLFIRI according to the Italian label.