Metastatic uveal melanoma showing durable response to anti-CTLA-4 and anti-PD-1 combination therapy after experiencing progression on anti-PD-1 therapy alone
Metastatic uveal melanoma showing durable response to anti-CTLA-4 and anti-PD-1 combination therapy after experiencing progression on anti-PD-1 therapy alone
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DOI：
10.1186/s40425-018-0322-1
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发表时间：
2018-02-12
影响因子：
10.9
通讯作者：
Shirai, Keisuke
中科院分区：
文献类型：
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作者：
Afzal, Muhammad Zubair;Mabaera, Rodwell;Shirai, Keisuke
背景：葡萄膜黑色素瘤占眼部黑色素瘤的85%，并增加了血源性扩散的风险，最常见的是肝脏。经过手术和放疗等治疗意向治疗后，50%的患者存在远处转移。转移性葡萄膜黑色素瘤(MUM)不像皮肤黑色素瘤那样具有典型的靶向性突变，例如BRAF。因此，对于妈妈来说，还没有得到证实的治疗方法。已经尝试了各种化疗和免疫治疗方案，在大多数病例中，只有部分缓解(PR)是最好的。在此，我们提出了一例MUM的病例，在单药nivolumab的进展之后，用联合免疫检查点疗法(ipilimumab和nivolumab)治疗，并显示出持久的反应，从最后一次治疗到22个月没有复发。病例介绍：一位72岁的高加索男子，患有左眼睫状体黑色素瘤，接受了治疗性眼球摘除，但6个月后发展为弥漫性肝转移瘤。最初，他每两周服用尼伏卢单抗3 mg/kg，共4个周期，但再次扫描显示，随着LDH的增加，疾病有明显的进展。在FDA批准尼伏单抗1 mg/kg和伊匹单抗3 mg/kg联合治疗转移性黑色素瘤后，该联合治疗持续4个周期，LDH持续上升至993U/L(110-220U/L)，直到完成第四周期治疗。3周后开始维持尼伏单抗3 mg/kg，但2周后出现4级肝毒性，ALT 1565单位/L(0~55单位/L)。推定为自身免疫性肝炎，停用尼伏卢单抗，开始口服泼尼松1 mg/kg，转氨酶升高迅速消退。在第一次和最后一次服药后1个月，腹部MRI显示转移灶PR和持续缩小，即使在PET/CT上也没有高代谢活动。经过22个月的治疗，他的病情一直很好，没有任何活动性疾病的迹象。结论：虽然单剂免疫检查点抑制剂和化疗的反应有限，但我们的患者在MUM中使用抗CTLA-4和抗PD-1联合治疗显示出持久的疗效。
Background: Uveal melanoma accounts for 85% of the ocular melanomas and has an increased risk of hematogenous spread, most commonly to the liver. After curative intent therapy like surgery and radiation, fifty percent of patients present with distant metastasis. Metastatic uveal melanoma (MUM) does not harbor typically targetable mutations, e.g., BRAF as in cutaneous melanoma. As a result, there is no proven therapy for MUM. Various chemotherapy and immunotherapy regimens have been tried and only partial response (PR) is the best that has been achieved in most of the cases. Here, we present a case of MUM treated with combination immune checkpoint therapy (ipilimumab and nivolumab) following the progression with single-agent nivolumab and demonstrating a durable response without recurrence more than 22 months from the last treatment.Case Presentation: A 72-year-old Caucasian man presented with ciliary body melanoma of the left eye and underwent curative-intent enucleation but six months later developed diffuse hepatic metastases. He initially was treated with nivolumab 3 mg/kg every two weeks for four cycles but restaging scan showed a significant progression of the disease with increasing LDH. With the FDA approval for the combination of nivolumab 1mg/kg with Ipilimumab 3 mg/kg every three weeks for metastatic melanoma, this combination was given for four cycles with continuous rise in LDH to 993 unit/L (110-220 unit/L) until finishing cycle four of the treatment. Three weeks later, maintainence nivolumab 3mg/kg was initiated but two weeks later, he developed grade 4 liver toxicity with ALT 1565 unit/L (0-55 unit/L). A presumptive diagnosis of autoimmune hepatitis was made, nivolumab was stopped and oral prednisone 1mg/kg was started with quick resolution of elevated transaminases. Restaging abdominal MRI one month after the first and last dose of maintenance nivolumab showed PR and continuous shrinkage of the metastatic lesions with no hypermetabolic activity even on PET/CT. He is 22 months' post-treatment and continues to do well without any evidence of active disease.Conclusion: Although, limited response has been shown to single agent immune checkpoint inhibitors and chemotherapy, our patient showed durable response with anti-CTLA-4 and anti-PD-1 combination therapy in MUM.