Background: The BRAF-V600E mutation confers poor prognosis in patients with mCRC. E-C+/-B improve clinical outcomes compared with standard of care. Data about subsequent treatment lines and the impact of NGS in the treatment choice after the BRAF targeted treatment are still limited. We have analyzed the global overall survival (OS) and the impact of NGS to guide subsequent treatments (approved targeted therapies (TT) or clinical trials (CT)) after E-C+/-B. Methods: Patients who had received E-C+/-B were included. Clinical data was collected prospectively. Tissue NGS was performed prospectively and retrospectively using an in-house NGS panel (VHIO-300). Subsequent treatments’ clinical outcomes were described. Percentage of patients who received TT or CT based on NGS results is reported. Clinical outcomes were calculated using survival Kaplan-Meier curves. Results: From 2017 to 2021, 59 patients with refractory mCRC received E-C+/-B at our institution. 50 patients have already progressed to the BRAF inhibitor combination and 9 patients remain on BRAF inhibitor treatment. Tumor tissue for NGS testing before BRAF inhibitor treatment was available in 70% of patients (41/59). BRAF-V600E mutation was confirmed in tissue using ddPCR in all patients. The most frequent alterations were: BRAF-V600E 93%, TP53 64%, RNF43 30%, APC 20%, PIK3CA 14%, NOTCH1/2 9%, RANBP2 8%, PTEN 8%, MET amplification 5%. MSI incidence was 10%, 2 out of 6 (33%) received subsequent immunotherapy. After the BRAF inhibitor combination, 23 patients (38%) did not receive subsequent treatment (clinical deterioration or death). The 27 remaining patients (62%) received 41 subsequent treatments (37% of them were TT or CT). Median subsequent lines after the BRAF inhibitor combination were 1 (0-3). NGS led to targeted therapy in 20% of the patients: BRAF inhibitors combos (20%), microtubule inhibitors (13%), antiPD1 (13%), NOTCH inhibitors (6%), and MET inhibitor (6%). ORR among patients who received matched TT or CT was 6% and DCR (CR+PR+SD) was 47%. The median OS after the BRAF inhibitor was 3.8 months; 10.1 months vs 3.0 months (HR 0.43 (95%CI 0.2-0.95), p = 0.04) for those patients who received TT or CT vs patients who did not receive TT or CT. When MSI patients were excluded mOS was 5.2 vs 3.0 months (HR 0.61 (95%CI 0.27-1.37), p = 0.23) respectively. There were no differences in terms of OS regarding the number of previous lines (0-1 vs 2-3, HR 0.75 (95%CI 0.4-1.42), p = 0.37) or with the BRAF inhibitor regimen used (E-C vs E-C-B) (HR 0.84, (95%CI 0.44-1.6), p = 0.61) Conclusions: This study suggests that patients with BRAF-V600E mutant mCRC could have benefit when treated with TT and/or in CT after a BRAF inhibitor-based therapy, including immunotherapy. Genomic analysis might help to guide subsequent treatments. Because of molecular heterogeneity, these patients should be discussed in Molecular Tumor Boards.