First-line FOLFOXIRI Plus Bevacizumab in BRAF Mutant Metastatic Colorectal Cancer

Inclusion Criteria:

* Histologically confirmed colorectal adenocarcinoma;
* Availability of formalin-fixed paraffin embedded tumor block from primary and/or metastasis;
* BRAF V600E mutant status of primary colorectal cancer and/or related metastasis;
* Unresectable and measurable metastatic disease according to RECIST criteria;
* Male or female, aged \> 18 years and \< 75 years;
* ECOG PS \< 2 if aged \< 71 years;
* ECOG PS = 0 if aged 71-75 years;
* Life expectancy of more than 3 months;
* Adequate haematological function: ANC ≥ 1.5 x 10\^9/L; platelets ≥ 100 x 10\^9/L, Hb ≥ 9 g/dL;
* Adequate liver function: serum bilirubin ≤ 1.5 x ULN; alkaline phosphatase and transaminases ≤ 2.5 x ULN (in case of liver metastases ≤ 5 x ULN);
* Serum creatinine ≤ 1.5 x ULN;
* Previous adjuvant chemotherapy is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse;
* At least 6 weeks from prior extended radiotherapy and 4 weeks from surgery;
* Written informed consent to experimental treatment and molecular analyses.

Exclusion Criteria:

* Presence or history of CNS metastasis;
* Serious, non-healing wound, ulcer, or bone fracture;
* Evidence of bleeding diathesis or coagulopathy;
* Uncontrolled hypertension;
* Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (CVA) (≤6 months before treatment start), myocardial infarction (≤ 6 months before treatment start), unstable angina, NYHA ≥ grade 2 chronic heart failure (CHF), uncontrolled arrhythmia;
* Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes;
* Chronic, daily treatment with high-dose aspirin (\>325 mg/day);
* Symptomatic peripheral neuropathy ≥ 2 grade NCIC-CTG criteria;
* Active uncontrolled infections;
* Treatment with any investigational drug within 30 days prior to enrolment;
* Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of curatively treated basal and squamous cell carcinoma of the skin or in situ cancer of the cervix;
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start;
* Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome;
* Fertile women (\< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception.