编者按：肢端黑色素瘤（acral melanoma，AM）在高加索人中很少见(1-7%)^[1-4]，但却是亚洲人群黑色素瘤的主要亚型（50%-58%）^[5]。近些年，皮肤黑色素瘤的治疗取得了很大进展，但AM患者获益有限。在这里，我们全面回顾了AM的治疗现状。

本期「专家组稿」由吉林大学第一医院吴荻教授担任执行主编，与吉林大学第一医院肿瘤内科张翊群医生共同分享晚期肢端黑色素瘤的治疗现状，为医者和患者提供更多参考。

一、化学治疗

我们对于晚期AM的化疗知之甚少。仅中国一项临床试验表明，白蛋白紫杉醇+卡铂治疗晚期AM患者的客观缓解率（objective response rate，ORR）仅为6.3%，疾病控制率（disease control rate，DCR）为81.3%，中位无进展生存期（progression-free survival，PFS）为6个月，中位总生存期（overall survival，OS）为17个月^[6]。

二、免疫检查点抑制剂(immune checkpoint inhibitors，ICIs)

与ipilimumab相比，PD-1抑制剂在晚期AM患者的治疗中更具优势^[8]。ipilimumab一线治疗晚期AM的ORR为17.8%，中位PFS为6.9个月，中位OS为38.7个月^[9]，而后线治疗的ORR为11.4%，中位PFS为2.5个月，中位OS为7.1-16.7个月^[10,11]。相比之下， PD-1抑制剂一线治疗晚期AM的ORR为34.0%-40.0%，中位PFS为3.1-9.2个月，中位OS为18.6-60.1个月^[9,15],而后线治疗的ORR为14.0%-32.0%，中位PFS为3.2-4.1个月，中位OS为16.9-25.8个月^[7,12-17]。值得注意的是，与手掌和足底AM相比，甲床AM对PD-1抑制剂的反应可能更差^[18]。

三、分子靶向治疗

3.1 BRAF/MEK抑制剂  

AM的BRAF突变频率仅为15%-20%^[19-22]，这限制了BRAF抑制剂在AM患者中的应用。vemurafenib治疗晚期AM患者的ORR为69.2%，中位PFS为5.4个月，中位OS为11.7个月^[23]。此外，BRAF抑制剂与MEK抑制剂的联合在BRAF突变黑色素瘤的治疗中取得了不错的疗效^[24]。dabrafenib联合trametinib治疗无法切除或转移性AM患者的ORR为83.3%，3年OS为35.7%^[25]。

3.2 KIT抑制剂  

10-20%的AM可能发生KIT突变或扩增^[26，27]。一项评估imatinib在KIT突变或扩增的晚期黑色素瘤患者中疗效的II期临床试验共纳入43例晚期黑色素瘤患者（AM患者21例）。DCR为53.5%，中位PFS为3.5个月，中位OS为14个月^[28]。值得注意的是，imatinib对仅存在KIT扩增的患者可能无效^[29]。此外， nilotinib治疗晚期AM患者的ORR为25%-32%，DCR为74%-80%^[30,31]。

四、联合治疗

4.1免疫联合治疗

CTLA-4和PD-1通过不同的的机制抑制抗肿瘤免疫^[32]。据2021年ESMO年会报道，PD-1抑制剂、CTLA-4抑制剂以及二者联合治疗晚期AM的ORR分别为26%、12%、44%，中位PFS分别为7.0个月、4.9个月、7.3个月。联合治疗对比PD-1抑制剂虽然可以提高ORR，但未能显著延长PFS和OS^[33]。值得注意的是，在甲床黑色素瘤患者中，联合治疗能够显著提高ORR，并延长PFS和OS^[34]。

4.2免疫联合化学治疗

替莫唑胺可以通过消耗或抑制肿瘤微环境中的调节性T细胞来增强pembrolizumab的抗肿瘤活性^[35,36]。一项回顾性分析共纳入69例晚期黑色素瘤患者（28例AM）。研究显示，pembrolizumab+替莫唑胺治疗晚期黑色素瘤的ORR和中位PFS明显优于pembrolizumab或替莫唑胺^[37]。

紫杉醇能够通过多种途径来诱导免疫原性细胞死亡和肿瘤细胞表面PD-L1表达^[38-41]。Li JJ等人表明，PD-1抑制剂联合白蛋白紫杉醇治疗的晚期AM患者的ORR为20%，DCR为75%^[42]。

4.3免疫联合抗血管生成治疗

抗血管生成药物可以通过促进抗肿瘤免疫来提高患者对ICIs的反应^[43]。据Wang X等人报道，camrelizumab联合apatinib治疗晚期AM患者的ORR和DCR分别为24.1%和82.8%，中位PFS为7.39，中位OS为13.4个月^[44]。

4.4化疗联合抗血管生成治疗

抗血管生成治疗与化疗联合应用可能产生协同抗肿瘤作用。apatinib联合替莫唑胺治疗免疫治疗失败的晚期AM的中位PFS为4.0个月，中位OS为10.1个月^[45]。

4.5免疫联合化疗联合抗血管生成治疗

随着众多联合用药治疗的数据公布，人们正在考虑通过化疗、免疫及靶向联合治疗晚期AM。据Mao L等人报道，camrelizumab联合替莫唑胺和apatinib治疗晚期AM的ORR和DCR分别为64.6%和88.0%，中位PFS为18.4个月，中位OS未达到^[46]。

总结

AM独特的基因组学特征和肿瘤免疫微环境导致其对当前免疫疗法以及其他系统治疗的反应较差，以ICIs为核心的联合治疗更有可能使患者获益。

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Tags： 吴荻教授组稿｜张翊群：晚期肢端黑色素瘤治疗的现状