• histologically proven diagnosis of colorectal adenocarcinoma;

• age ≥ 18 years;

• ECOG Performance status ≤ 1;

• BRAFV600E mutated status of primary colorectal cancer and/or related metastasis, by local laboratory assessment according to standard procedures by means of molecular assay on genomic DNA;

• Metastatic disease with at least one measurable lesion according to RECIST 1.1. criteria;

• previous treatment with encorafenib plus cetuximab with or without chemotherapy (i.e., ±FOLFOX/FOLFIRI) in any line, producing a RECIST 1.1 complete/partial response or disease stabilisation, with a PFS of this treatment lasting at least 6 months;

• documentation of RECIST 1.1 disease progression during or after the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy;

• one intervening line of treatment not including any BRAF and EGFR inhibitor, between the end of first exposure to encorafenib plus cetuximab ± chemotherapy and the time of screening;

• at least 4 months elapsed between the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy and the retreatment with encorafenib plus cetuximab;

• previous treatment with immune checkpoint inhibitors (anti-PD-1/PD-L1 alone or in combination with anti-CTLA-4 agent), in the case of MSI-H or dMMR mCRC;

• availability of blood sample for ctDNA analysis within 28 days prior enrolment;

• BRAFV600E mutated status of ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health);

• KRAS, NRAS, MAP2K1 wild-type status and MET not amplified status in ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health);

• Availability of archival tumour tissue (primary tumour and/or metastases) for biomarker analysis;

• neutrophils \>1.5 x 109/L, Platelets \>100 x 109/L, Hgb \>9 g/dl. Transfusions will be permitted provided the patient has not received more than two units red blood cells in the prior 4 weeks to achieve this criterion.

• adequate renal function characterised by 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 characterised by the following at screening: Serum total bilirubin ≤ 1.5 × ULN and \< 2 mg/dL. Note: Patients who have a total bilirubin level \> 1.5 × ULN will be allowed if their indirect bilirubin level is ≤ 1.5 × ULN; Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases. In the presence of documented Gilbert's syndrome, a value of total bilirubin \< 3 × ULN is acceptable.

• adequate electrolytes at baseline, defined as serum potassium and magnesium levels within institutional normal limits (Note: replacement treatment to achieve adequate electrolytes will be allowed).

• INR or aPTT ≤ 1.5 × ULN;

• QT interval corrected for heart rate ≤480 msec at screening;

• ability to take oral medications;

• women of childbearing potential must have a negative blood pregnancy test at the screening. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least twelve continuous months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient;

• subjects and their partners must be willing to avoid pregnancy from the study screening until 1 month after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator. Encorafenib may decrease the efficacy of hormonal contraceptives. Therefore, female patients using hormonal contraception are advised to use an additional or alternative method such as a barrier method (i.e., condom) from the screening phase for at least 1 month following the last dose of study treatment. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;

• written informed consent to study procedures;

• life expectancy of at least twelve weeks;

• will and ability to comply with the protocol.