Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced BRAF V600-mutant melanoma.,Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453).,Patients with locally advanced unresectable or metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily.,An updated analysis was conducted 65 months after the last patient was randomly assigned.,Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib.,The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively.,In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively.,The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients.,In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients.,Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib.,Interactive visualization of the data presented in this article is available at COLUMBUS dashboard.,In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600-mutant melanoma.
Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases.,Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies.,In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance.,Thus, combined treatment targeting both pathways is a promising strategy to overcome this.,Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines.,Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis.,Finally, an in vivo treatment experiment was carried out on NOD/SCID mice.,We show that combined therapy was more effective than monotherapy.,Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo.,This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.