編者按：在亞洲人群中，黏膜黑色素瘤（mucosal melanoma，MM）占所有黑色素瘤的9.5%-22.6%[1-4]，僅次于肢端黑色素瘤。随着靶向治療和免疫治療的出現，皮膚黑色素瘤治療取得了進展，但是MM患者獲益有限。本文回顧了MM的治療現狀，并提出了針對MM的潛在的治療政策。
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黏膜黑色素瘤的治療現狀及展望，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：晚期黏膜黑色素瘤的治療現狀及展望
◾ 作者：吳荻 張翊群
治療現狀
1.化學治療
對于晚期黑色素瘤，達卡巴嗪一直是最常用的化療藥物之一。以達卡巴嗪為基礎的化療治療晚期MM的客觀緩解率（objective response rate，ORR）為36%-47%，中位PFS為3-10個月，中位OS為9.6-22個月[5-8]。在MM占比更高的亞洲，以達卡巴嗪為基礎的化療仍然可以作為一線治療選擇。
2.免疫治療
Ipilimumab作為第一個被證明可以延長黑色素瘤患者生存的免疫檢查點抑制劑，對轉移性MM的療效并不理想。其作為晚期MM一線治療的ORR為8.2%，中位PFS為3個月，中位OS為12個月，而後線治療的ORR為6.7%-12.0%，中位PFS為4.3個月，中位OS為6.4個月[9-12]。
與ipilimumab相比，PD-1抑制劑在晚期MM患者中獲得了更好的療效，但依舊不盡如人意。PD-1抑制劑一線治療晚期MM的ORR為20.0%-26.0%，中位PFS為5.9-6.2個月，中位OS為15.9-20.4個月[13-15],而後線治療晚期MM的ORR為13.3%-19.0%，中位PFS為2.6-2.8個月，中位OS為7.4-11.5個月[16-19]。
3.分子靶向治療
3.1 BRAF抑制劑 MM的BRAF突變頻率僅為6%-17%[20-24]，這限制了BRAF抑制劑在MM患者中的應用。僅一項回顧性研究顯示，BRAF抑制劑治療的BRAF突變的轉移性/不可切除的MM患者的ORR為20%，中位 PFS為4.4個月，中位 OS為8.2個月[25]。
3.2 KIT抑制劑 KIT突變和擴增在MM中的頻率為15%-39%[22,26]。目前常見的KIT抑制劑中，僅有imatinib和nilotinib在晚期MM中顯現出一定療效。Hodi等人發現，imatinib治療KIT突變的晚期MM患者的ORR為64%，而對僅具有KIT擴增的患者療效欠佳[27]。
對于imatinib治療後進展的KIT突變的晚期MM，我們可以嘗試nilotinib治療。nilotinib治療其他KIT抑制劑治療後進展的晚期黑色素瘤患者的ORR為25%[28]。
4.聯合治療
4.1免疫聯合治療 CTLA-4和PD-1通過不同的機制抑制抗惡性良性腫瘤免疫反應[29]。遺憾的是，CheckMate067研究顯示，對于晚期MM患者，盡管nivolumab聯合ipilimumab治療的療效優于ipilimumab，但對比nivolumab并無優勢。
4.2免疫聯合化學治療 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[30-33]。Li JJ等人稱，PD-1抑制劑聯合白蛋白紫杉醇治療晚期MM的ORR為33.3%，DCR為63.3%，中位PFS為4.9個月[34]。
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[35]。一項Ib期臨床試驗表明，在toripalimab聯合axitinib治療未經化療的轉移性MM患者的ORR為48.3%，中位PFS為7.5個月，中位OS為20.7個月[36]。另一項II期臨床研究表明，atezolizumab聯合bevacizumab治療既往未經免疫治療的不可切除/晚期MM的的ORR為45.0%，中位PFS為8.2個月，中位OS未達到[37]。目前尚未有研究結果表明PD-1和PD-L1抑制劑在與抗血管生成藥物聯合治療晚期MM方面存在療效上的差異。
4.4化療聯合免疫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MM。據2023年ASCO會議報道，一項camrelizumab聯合anlotinib和nab-paclitaxel一線治療晚期MM的單臂、多中心探索性研究正在進行（NCT04979585），期待其結果的釋出。
未來展望
1.免疫治療
1.1.新型瘤内免疫治療 BO-112是Poly I：C（雙鍊病毒RNA的類似物）與聚乙烯亞胺絡合而成的納米複合制劑，在惡性良性腫瘤内釋放時可增加T細胞介導的免疫反應，引起惡性良性腫瘤細胞凋亡[38,39]。據2022年AACR年會報道，BO-112聯合pembrolizumab治療晚期MM患者的ORR為66%[40]。
1.2.新型細胞因子 Nemvaleukin alfa是一種新的工程細胞因子，可以激活CD8+ T細胞和自然殺傷細胞，減少調節性T細胞的增殖[41]。Nemvaleukin已被美國FDA準許為治療MM的孤兒藥。ARTISTRY-1研究(NCT02799095)表明，nemvaleukin alfa治療ICIs治療失敗的晚期MM的ORR為33.3%。
1.3.TIL細胞療法 Lifileucel作為一種自體惡性良性腫瘤浸潤淋巴細胞(tumor-infiltrating lymphocytes，TIL)療法細胞療法，使用集中制造技術，利用從患者惡性良性腫瘤組織中回收的TIL來制備多克隆的患者特異性TIL[42]。C-144-01研究表明，部分接受過免疫檢查點抑制劑和BRAF/MEK抑制劑治療的晚期MM患者在Lifileucel治療後獲得了持續臨床緩解[43]。
2.免疫治療失敗後的DNA損傷修複
惡性良性腫瘤細胞通常在DNA損傷反應 (DNA damage response,DDR)方面存在缺陷。DDR基因的改變可以促進PD-L1表達，提高惡性良性腫瘤浸潤淋巴細胞數量[44]，增加惡性良性腫瘤突變負荷，并通過增加新抗原負荷增強免疫原性[45]，這些都是ICIs治療反應的潛在決定因素。
RAD3相關蛋白激酶(Rad3-related protein kinase，ATR)是DDR通路的關鍵[46]，其抑制劑有望用于MM治療。一項II期臨床試驗表明，durvalumab聯合ATR抑制劑ceralasertib治療PD-1抑制劑治療失敗後的晚期MM患者的ORR為40%[47]。另一項I期研究表明，ceralasertib聯合紫杉醇治療抗PD-1治療耐藥的晚期MM患者的ORR為45.5%[48]。
MDM2可通過抑制p53功能進而抑制DDR[49]，且MDM2擴增可能導緻晚期MM對ICIs的反應更差[50]。Zhou R等人在50%的MM樣本中觀察到MDM2擴增[51]。這些使得MDM2成為MM的潛在治療靶點。Alrizomadlin作為一種新型小分子MDM2抑制劑，可以恢複PD-1/PD-L1阻斷失敗的惡性良性腫瘤患者的抗惡性良性腫瘤活性[52]。據2021年ASCO年會報道，alrizomadlin與pembrolizumab聯合治療免疫治療失敗的晚期MM患者的ORR為40%（NCT03611868）。
總結
MM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。随着對MM的基因組學特征和惡性良性腫瘤免疫微環境的深入了解，開發新的藥物以及聯合治療方案以改善晚期MM患者生存将成為可能。
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