Inclusion Criteria:
* written informed consent to study procedures;
* age ≥ 18 years;
* histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma;
* radiological evidence of metastatic disease;
* evidence of measurable disease according to RECIST 1.1 criteria;
* presence of BRAF V600E mutation in tumor tissue (primary CRC and/or related metastasis) as previously determined by a local assay at any time prior to screening (only PCR and NGS-based local assays results will be acceptable);
* disease progression while on treatment with EC received in 2nd line setting
* EC administered after disease relapse during treatment or within 6 months following adjuvant therapy will be second line;
* maintenance therapy given in the metastatic setting after a first line doublet or triplet chemotherapy will not be considered a separate regimen;
* best response to previous treatment with EC: CR, PR or SD lasting for at least 3 months.
* patient fit for a subsequent treatment line with FOLFIRI. Patients exposed to irinotecan and fluoropyrimidines during previous line for metastatic disease are eligible, provided that the patient has recovered from G3 toxicity;
* life expectancy ≥ 3 months;
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1.
* Adequate bone marrow function at screening:
* Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L;
* Platelets ≥ 100 × 10\^9/L;
* Hemoglobin ≥ 9.0 g/dL;
* Note: Transfusions will be allowed to achieve this. Transfusions will be permitted provided that the patient has not received more than 2 units red blood cells in the prior 4 weeks to achieve this criteria.
* Adequate renal function at screening: serum creatinine ≤ 1.5 × upper limit of normal (ULN), or calculated by Cockroft-Gault formula, or directly measured creatinine clearance ≥ 50 mL/min at screening.
* Adequate hepatic function at screening:
* serum total bilirubin ≤ 1.5 × ULN;
* alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases.
* Adequate cardiac function characterized by the following at screening: QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤480 msec.
* Availability of treatment-naïve, archival FFPE tumor tissue sample.
* Ability to take oral medications.
* Male subjects with female partners of childbearing potential must be willing to use adequate contraception, starting with the first dose of study therapy through 180 days after the last dose of treatment. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
* Women of childbearing potential must have a negative blood or urine pregnancy test at the baseline visit.
* Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study starting with the first dose of study therapy through 180 days after the last dose of treatment. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
* Will and ability to comply with the protocol.
Exclusion Criteria:
* patients experiencing PD as best response to EC;
* patients with specific BRAFi/AntiEGFR contraindications;
* patients with specific irinotecan or fluoropyrimidines contraindications;
* patients with DPYD deficiency;
* life expectancy ≤3 months;
* ECOG PS \>1.
* Any of the following in the 6 months prior to treatment start: myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft \[CABG\], coronary angioplasty or stenting), congestive heart failure (≥ New York Heart Association Classification Class II), serious cardiac arrhythmia (except atrial fibrillation and appropriately controlled paroxysmal supraventricular tachycardia), cerebrovascular accident, symptomatic pulmonary embolism.
* Congenital long QT syndrome.
* Impaired gastrointestinal function or disease that may significantly alter the absorption of encorafenib (uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption).
* Uncontrolled coagulopathy.
* Patients has a known history of Gilbert's syndrome or is known to have any of the following genotypes: UGT1A1\*6/\*6, UGT1A1\*28/\*28, or UGT1A1\*6/\*28.
* Active infection requiring systemic therapy.
* Known history of acute or chronic pancreatitis.
* Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
* Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
* Symptomatic brain metastasis or leptomeningeal disease. Prior hypersensitivity or toxicity that would suggest an inability to tolerate administration of the planned dose of investigational products.
* Residual CTCAE \> Grade 2 toxicity from any prior anticancer therapy, with the exception of alopecia or neuropathy.
* Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies, including current treatment with a non-topical medication known to be a strong inhibitor of cytochrome P450 (CYP) 3A4 ≤ 1 week prior to the start of study treatment.
* Concomitant use of St. John's Wort (hypericum perforatum).
* Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study.
* Concurrent or previous other malignancy within the past 3 years, with the exception of effectively treated squamous cell or basal cell skin cancer, melanoma in situ, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, carcinoma in situ of the colon or rectum, or other noninvasive or indolent malignancy without Sponsor approval.
* Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 180 days after the last trial treatment.
