Surgery, Yale School of Medicine, New Haven, Connecticut, USA.
Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
J Immunother Cancer. 2020 Mar;8(1). doi: 10.1136/jitc-2019-000341.
Checkpoint inhibitors (CPIs) are thought to be effective against cutaneous melanoma in part because of the large burden of somatic mutations (neoantigens) generated from exposure to ultraviolet radiation. However, rare melanoma subtypes arising from acral skin, mucosal surfaces, and the uveal tract are largely sun-shielded. Genomic studies show these sun-shielded melanomas have a paucity of neoantigens and unique biology; they are thought to be largely resistant to immunotherapy. It has not been definitively shown that CPI improves survival in metastatic sun-shielded melanoma.
We reviewed a single institutional experience using antibodies against CTLA-4, PD-1 and/or PD-L1 to treat patients with metastatic melanoma. Primary tumor histology was categorized as cutaneous, unknown, acral, mucosal, or uveal. We studied demographic data, treatment characteristics, and overall survival (OS) after CPI.
We treated 428 patients with metastatic melanoma from 2007 to 2019. Primary tumors were cutaneous in 283 (66%), unknown in 55 (13%), acral in 22 (5%), mucosal in 38 (9%), and uveal in 30 (7%). Patients with metastatic disease from cutaneous primary tumors had median OS after CPI of 45 months compared with 17 months for acral (p=0.047), 18 months for mucosal (p=0.003), and 12 months for uveal (p<0.001). For all patients with sun-shielded melanoma (n=90), first treatment with anti-PD-1 or anti-PD-L1 was followed by a median OS of 9 months compared with 18 months after anti-CTLA-4 (p=0.010) and 20 months after combination therapy (p=0.003). There were 21 patients who achieved actual 3-year survival; 20 received both anti-CTLA-4 and anti-PD-1, either sequentially or in combination. Over 80% of 3-year survivors with progressive disease were treated with local therapy after CPI.
Long survival in patients with metastatic melanoma from acral, mucosal, and uveal primary tumors was associated with receipt of both anti-CTLA-4 and anti-PD-1 antibodies. Complete responses were rare, and local therapy was frequently employed to control disease progression. While sun-shielded melanomas exhibit worse outcomes after CPI than cutaneous melanomas, with an aggressive multidisciplinary approach, 5-year survival is still possible for 25%-32% of these patients.
检查点抑制剂（CPIs）被认为对皮肤黑色素瘤有效，部分原因是暴露于紫外线辐射产生了大量的体细胞突变（新抗原）。然而，起源于肢端皮肤、黏膜表面和葡萄膜的罕见黑色素瘤亚型主要受到阳光的保护。基因组研究表明，这些受阳光保护的黑色素瘤新抗原数量较少，具有独特的生物学特性；它们被认为对免疫疗法有很大的抵抗力。尚未明确 CPIs 是否能提高转移性受阳光保护的黑色素瘤的生存率。
我们回顾了单机构使用抗 CTLA-4、PD-1 和/或 PD-L1 抗体治疗转移性黑色素瘤患者的经验。原发肿瘤的组织学分类为皮肤、未知、肢端、黏膜或葡萄膜。我们研究了人口统计学数据、治疗特征和 CPI 后的总生存期（OS）。
我们从 2007 年至 2019 年治疗了 428 例转移性黑色素瘤患者。283 例（66%）为皮肤原发肿瘤，55 例（13%）为未知原发肿瘤，22 例（5%）为肢端原发肿瘤，38 例（9%）为黏膜原发肿瘤，30 例（7%）为葡萄膜原发肿瘤。接受 CPI 治疗后，有皮肤原发肿瘤的转移性疾病患者的中位 OS 为 45 个月，而肢端（p=0.047）、黏膜（p=0.003）和葡萄膜（p<0.001）的中位 OS 分别为 17、18 和 12 个月。对于所有有阳光保护的黑色素瘤（n=90）患者，首次接受抗 PD-1 或抗 PD-L1 治疗后，中位 OS 为 9 个月，而抗 CTLA-4 后为 18 个月（p=0.010），联合治疗后为 20 个月（p=0.003）。有 21 例患者实际存活 3 年；20 例患者同时接受了抗 CTLA-4 和抗 PD-1 治疗，或序贯或联合治疗。在接受 CPI 治疗后，超过 80%的疾病进展的 3 年幸存者接受了局部治疗。
肢端、黏膜和葡萄膜原发肿瘤的转移性黑色素瘤患者接受抗 CTLA-4 和抗 PD-1 抗体治疗后，存活时间较长。完全缓解罕见，经常采用局部治疗来控制疾病进展。虽然阳光保护的黑色素瘤在接受 CPI 治疗后的结局比皮肤黑色素瘤差，但通过积极的多学科治疗，仍有 25%-32%的患者 5 年生存率仍有可能。
