Braden J, Conway J W, Wilmott J S, Scolyer R A, Long G V, da Silva I P
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.
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.
ESMO Open. 2025 Jun 20;10(7):105314. doi: 10.1016/j.esmoop.2025.105314.
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.
超过半数的皮肤黑色素瘤存在BRAF突变，这种突变在年轻患者中更为普遍，这些患者通常表现出更具侵袭性的疾病。BRAF靶向治疗和检查点抑制剂免疫治疗已使BRAF突变型黑色素瘤患者的治疗结果有了显著改善。尽管有这些进展，但鉴于超过半数的晚期黑色素瘤患者仍会因黑色素瘤死亡，新的联合策略至关重要。转化医学证据表明BRAF靶向治疗具有潜在的免疫刺激作用，但其与免疫治疗的联合在临床上的成功有限。导致对靶向治疗产生获得性耐药的途径（这可能会使肿瘤对免疫治疗产生耐药）尚未完全明确。本综述将探讨靶向治疗与免疫检查点抑制序贯或同时联合的情况，并研究潜在的交叉耐药机制。此外，还将讨论靶向治疗在免疫治疗时代不断演变的作用。
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