Do BRAF-targeted therapies have a role in the era of immunotherapy?

J Braden; J W Conway; J S Wilmott; R A Scolyer; G V Long; I P da Silva

doi:10.1016/j.esmoop.2025.105314

Do BRAF-targeted therapies have a role in the era of immunotherapy?

ESMO Open. 2025 Jun 20;10(7):105314. doi: 10.1016/j.esmoop.2025.105314. Online ahead of print.

Authors

J Braden¹, J W Conway², J S Wilmott², R A Scolyer³, G V Long⁴, I P da Silva⁵

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. Electronic address: https://twitter.com/JorjaBraden.
² Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Charles Perkins Centre, The University of Sydney, Sydney, Australia.
³ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Charles Perkins Centre, The University of Sydney, Sydney, Australia; NSW Health Pathology, Sydney, Australia.
⁴ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Charles Perkins Centre, The University of Sydney, Sydney, Australia; Royal North Shore Hospital, Sydney, Australia; Mater Hospital, Sydney, Australia. Electronic address: https://twitter.com/ProfGLongMIA.
⁵ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Charles Perkins Centre, The University of Sydney, Sydney, Australia. Electronic address: ines.silva@melanoma.org.au.

PMID: 40543211
DOI: 10.1016/j.esmoop.2025.105314

Abstract

Over half of cutaneous melanomas have BRAF mutations, with this mutation being more prevalent in younger patients who often present with more aggressive disease. BRAF-targeted therapy and checkpoint inhibitor immunotherapy have led to marked improvements in outcomes for patients with BRAF-mutant melanoma. Despite these advances, novel combinatorial strategies are vital given that more than half of advanced melanoma patients will still die due to melanoma. Translational evidence has suggested potential immunostimulatory effects of BRAF-targeted therapies, yet their combination with immunotherapy has shown limited clinical success. The pathways that lead to acquired resistance to targeted therapy, which may confer resistance to immunotherapy, are not yet fully understood. This review will explore the combination of targeted therapy with immune checkpoint inhibition, either sequentially or concurrently, and examine potential cross-resistance mechanisms. Additionally, it will discuss the evolving role of targeted therapy in the era of immunotherapy.

Keywords: BRAF-mutant melanoma; BRAF-targeted therapy; anti-PD-1 therapy; cutaneous melanoma; immunotherapy; metastatic melanoma.

Publication types

Review