Abstract：
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for patients with metastatic melanoma; however, there remains an unmet clinical need for alternative treatment options for those patients who are either intolerant or refractory to immunotherapy. Here we review the role and clinical efficacy of targeted therapies for BRAFV600 wild-type melanoma.
Genomic analyses in BRAFV600 wild-type melanoma have previously identified driver mutations along the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT pathways that can be targeted with small molecule inhibitors. New drugs such as bispecific antibodies and antibody drug conjugates may have significant clinical activity even in rare subtypes of melanoma that are less responsive to ICIs. Historically, molecular-targeted therapies have modest clinical success in treating BRAFV600 wild-type melanoma; nevertheless, they may have a significant clinical role in select, genetically distinct groups of patients. Next-generation immunotherapies or immunomodulators may represent the latest breakthrough in the treatment of melanoma. Additional studies are needed to identify novel drug targets and synergistic drug combinations to expand treatment options and optimize clinical outcomes.
Genomic analyses in BRAFV600 wild-type melanoma have previously identified driver mutations along the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT pathways that can be targeted with small molecule inhibitors. New drugs such as bispecific antibodies and antibody drug conjugates may have significant clinical activity even in rare subtypes of melanoma that are less responsive to ICIs. Historically, molecular-targeted therapies have modest clinical success in treating BRAFV600 wild-type melanoma; nevertheless, they may have a significant clinical role in select, genetically distinct groups of patients. Next-generation immunotherapies or immunomodulators may represent the latest breakthrough in the treatment of melanoma. Additional studies are needed to identify novel drug targets and synergistic drug combinations to expand treatment options and optimize clinical outcomes.
摘要：
免疫检查点抑制剂（ICIs）彻底改变了转移性黑色素瘤患者的治疗模式；然而，对于那些对免疫疗法不耐受或难以治疗的患者,临床上对替代治疗方案的需求仍未得到满足.在这里，我们回顾了靶向治疗BRAFV600野生型黑色素瘤的作用和临床疗效。
在BRAFV600野生型黑色素瘤中进行的基因组分析已经确定了丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3-激酶（PI3K）-AKT途径的驱动突变，这些突变可以被小分子抑制剂靶向。新药如双特异性抗体和抗体药物缀合物甚至在对ICI反应较小的黑色素瘤的罕见亚型中也可能具有显著的临床活性。历史上,分子靶向疗法在治疗BRAFV600野生型黑色素瘤方面取得了适度的临床成功；尽管如此，它们可能在选择中具有重要的临床作用，遗传上不同的患者群体。下一代免疫疗法或免疫调节剂可能代表黑色素瘤治疗的最新突破。需要进一步的研究来确定新的药物靶标和协同药物组合，以扩大治疗选择并优化临床结果。
在BRAFV600野生型黑色素瘤中进行的基因组分析已经确定了丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3-激酶（PI3K）-AKT途径的驱动突变，这些突变可以被小分子抑制剂靶向。新药如双特异性抗体和抗体药物缀合物甚至在对ICI反应较小的黑色素瘤的罕见亚型中也可能具有显著的临床活性。历史上,分子靶向疗法在治疗BRAFV600野生型黑色素瘤方面取得了适度的临床成功；尽管如此，它们可能在选择中具有重要的临床作用，遗传上不同的患者群体。下一代免疫疗法或免疫调节剂可能代表黑色素瘤治疗的最新突破。需要进一步的研究来确定新的药物靶标和协同药物组合，以扩大治疗选择并优化临床结果。
