Targeting the untargeted: Emerging targeted therapies in metastatic melanoma beyond BRAF/MEK inhibitors

The therapeutic landscape of advanced melanoma has been transformed by immune checkpoint inhibitors and BRAF/MEK inhibitors, resulting in substantial improvements in response rates and overall survival. However, both primary and acquired resistance remain frequent, commonly driven by MAPK pathway reactivation and activation of compensatory signaling pathways. A persistent, unmet clinical need is particularly evident in certain molecular subgroups, including NRAS-mutant melanoma and tumors harboring non-V600 BRAF alterations. Better understanding of melanoma's molecular heterogeneity has led to the development of investigational targeted strategies beyond BRAF/MEK inhibition. These include next-generation MAPK pathway inhibitors, such as pan-RAF and ERK inhibitors, agents that target cell-cycle dysregulation, particularly in tumors with CDKN2A loss or CDK4/6 pathway activation. Epigenetic regulators, including PRMT5 inhibitors, are also being evaluated based on emerging preclinical evidence. Furthermore, alternative modalities such as targeted protein degradation platforms and antibody-drug conjugates directed against melanoma-associated antigens represent mechanistically distinct strategies. This review outlines the biological rationale for these approaches and summarizes available preclinical and early-phase clinical data.