Background: dMAPKi with BRAFi and MEKi improves survival in BRAF V600E/K mt MM, but the effects of these inhibitors on nonV600 BRAF mt MM is poorly understood. We sought to characterize nonV600/class II (enhanced kinase activity, dimerization dependent) BRAF mt MM and to investigate their responsiveness to MAPKi. Methods: We analyzed 3 MM datasets (PMH next generation sequencing (NGS) cohort, TCGA, GENIE) for clinicopathologic correlations and outcomes of nonV600 BRAF mt MM pts. Tumors from patients with BRAF WT, V600E (class I), and L597S (class II) MM were used to generate patient-derived xenografts (PDX); both were subjected to NGS analysis with the CANCERPLEX assay. We generated and obtained 8 MM cell lines with class IIa (activation segment) or IIb (p-loop) mt and compared these to BRAF WT and V600E/K MM cells. Cell lines and PDXs were treated with BRAFi (vemurafenib, dabrafenib, encorafenib) and MEKi (cobimetinib, trametinib, binimetinib), or the combination. They were investigated with immunoblots, in vitro, and in vivo growth assays. We identified two patients with BRAF L597S MM who were treated with dMAPKi. Results: NonV600 BRAF mutants comprise 10-35% of all BRAF mts in MM. NonV600 BRAF mts are frequently co-expressed with NRAS mts and associated with poor survival compared to BRAF V600E/K MM (HR 1.49, 95% CI 1.09-2.06). BRAFi impaired Erk phosphorylation and cell growth in class I and IIa BRAF mt cells. dMAPKi was more effective than either single MAPKi at inhibiting cell growth in all class IIa and IIb cell lines tested. PDXs retained high genomic fidelity to the primary tumors from which they were derived. In two independent BRAF L597S (class IIa) PDX models, single MAPKi only slowed the progression of tumor growth whereas dMAPKi resulted in significant tumor shrinkage. Two patients with BRAF L597S mt melanoma obtained objective clinical responses to dual MAPKi. Conclusions: NonV600 BRAF mt MM are associated with poor prognosis. Class II BRAF mt MM are growth inhibited by dMAPKi. Responses to dMAPKi have been observed in two patients with class II BRAF mt MM. Our data provide rationale for clinical investigation of dual MAPKi in patients with class II BRAF mt MM.