編者按：肢端黑色素瘤（acral melanoma，AM）在高加索人中很少見(1-7%)[1-4]，但卻是亞洲人群黑色素瘤的主要亞型（50%-58%）[5]。近些年，皮膚黑色素瘤的治療取得了很大進展，但AM患者獲益有限。在這裡，我們全面回顧了AM的治療現狀。
本期「專家組稿」由吉林大學第一醫院吳荻教授擔任執行主編，與吉林大學第一醫院惡性良性腫瘤内科張翊群醫生共同分享晚期肢端黑色素瘤的治療現狀，為醫者和患者提供更多參考。
專家介紹
吳荻
吉林大學第一醫院惡性良性腫瘤中心
博士研究所學生導師、主任醫師、教授
吉林大學第一醫院惡性良性腫瘤綜合治療區主任
中國臨床惡性良性腫瘤學會（CSCO）理事
CSCO黑色素瘤專家委員會副主任委員
CSCO小細胞肺癌專家委員會委員
CSCO骨與軟組織肉瘤專家委員會委員
中國抗癌協會惡性良性腫瘤轉移專業委員會委員
CSCO惡性良性腫瘤心髒病學專家委員會常務委員
張翊群
吉林大學第一醫院惡性良性腫瘤内科博士研究所學生在讀
主要研究方向：黑色素瘤的靶向、免疫、化療等綜合治療。
題目：晚期肢端黑色素瘤治療的現狀
◾ 作者：吳荻 張翊群
一、化學治療
我們對于晚期AM的化療知之甚少。僅中國一項臨床試驗表明，白蛋白紫杉醇+卡鉑治療晚期AM患者的客觀緩解率（objective response rate，ORR）僅為6.3%，疾病控制率（disease control rate，DCR）為81.3%，中位無進展生存期（progression-free survival，PFS）為6個月，中位總生存期（overall survival，OS）為17個月[6]。
二、免疫檢查點抑制劑(immune checkpoint inhibitors，ICIs)
與ipilimumab相比，PD-1抑制劑在晚期AM患者的治療中更具優勢[8]。ipilimumab一線治療晚期AM的ORR為17.8%，中位PFS為6.9個月，中位OS為38.7個月[9]，而後線治療的ORR為11.4%，中位PFS為2.5個月，中位OS為7.1-16.7個月[10,11]。相比之下， PD-1抑制劑一線治療晚期AM的ORR為34.0%-40.0%，中位PFS為3.1-9.2個月，中位OS為18.6-60.1個月[9,15],而後線治療的ORR為14.0%-32.0%，中位PFS為3.2-4.1個月，中位OS為16.9-25.8個月[7,12-17]。值得注意的是，與手掌和足底AM相比，甲床AM對PD-1抑制劑的反應可能更差[18]。
三、分子靶向治療
3.1 BRAF/MEK抑制劑
AM的BRAF突變頻率僅為15%-20%[19-22]，這限制了BRAF抑制劑在AM患者中的應用。vemurafenib治療晚期AM患者的ORR為69.2%，中位PFS為5.4個月，中位OS為11.7個月[23]。此外，BRAF抑制劑與MEK抑制劑的聯合在BRAF突變黑色素瘤的治療中取得了不錯的療效[24]。dabrafenib聯合trametinib治療無法切除或轉移性AM患者的ORR為83.3%，3年OS為35.7%[25]。
3.2 KIT抑制劑
10-20%的AM可能發生KIT突變或擴增[26，27]。一項評估imatinib在KIT突變或擴增的晚期黑色素瘤患者中療效的II期臨床試驗共納入43例晚期黑色素瘤患者（AM患者21例）。DCR為53.5%，中位PFS為3.5個月，中位OS為14個月[28]。值得注意的是，imatinib對僅存在KIT擴增的患者可能無效[29]。此外， nilotinib治療晚期AM患者的ORR為25%-32%，DCR為74%-80%[30,31]。
四、聯合治療
4.1免疫聯合治療
CTLA-4和PD-1通過不同的的機制抑制抗惡性良性腫瘤免疫[32]。據2021年ESMO年會報道，PD-1抑制劑、CTLA-4抑制劑以及二者聯合治療晚期AM的ORR分别為26%、12%、44%，中位PFS分别為7.0個月、4.9個月、7.3個月。聯合治療對比PD-1抑制劑雖然可以提高ORR，但未能顯著延長PFS和OS[33]。值得注意的是，在甲床黑色素瘤患者中，聯合治療能夠顯著提高ORR，并延長PFS和OS[34]。
4.2免疫聯合化學治療
替莫唑胺可以通過消耗或抑制惡性良性腫瘤微環境中的調節性T細胞來增強pembrolizumab的抗惡性良性腫瘤活性[35,36]。一項回顧性分析共納入69例晚期黑色素瘤患者（28例AM）。研究顯示，pembrolizumab+替莫唑胺治療晚期黑色素瘤的ORR和中位PFS明顯優于pembrolizumab或替莫唑胺[37]。
紫杉醇能夠通過多種途徑來誘導免疫原性細胞死亡和惡性良性腫瘤細胞表面PD-L1表達[38-41]。Li JJ等人表明，PD-1抑制劑聯合白蛋白紫杉醇治療的晚期AM患者的ORR為20%，DCR為75%[42]。
4.3免疫聯合抗血管生成治療
抗血管生成藥物可以通過促進抗惡性良性腫瘤免疫來提高患者對ICIs的反應[43]。據Wang X等人報道，camrelizumab聯合apatinib治療晚期AM患者的ORR和DCR分别為24.1%和82.8%，中位PFS為7.39，中位OS為13.4個月[44]。
4.4化療聯合抗血管生成治療
抗血管生成治療與化療聯合應用可能産生協同抗惡性良性腫瘤作用。apatinib聯合替莫唑胺治療免疫治療失敗的晚期AM的中位PFS為4.0個月，中位OS為10.1個月[45]。
4.5免疫聯合化療聯合抗血管生成治療
随着衆多聯合用藥治療的資料公布，人們正在考慮通過化療、免疫及靶向聯合治療晚期AM。據Mao L等人報道，camrelizumab聯合替莫唑胺和apatinib治療晚期AM的ORR和DCR分别為64.6%和88.0%，中位PFS為18.4個月，中位OS未達到[46]。
總結
AM獨特的基因組學特征和惡性良性腫瘤免疫微環境導緻其對目前免疫療法以及其他系統治療的反應較差，以ICIs為核心的聯合治療更有可能使患者獲益。
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