Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab
Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab
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DOI：
10.1093/annonc/mdw443
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发表时间：
2017-02-01
影响因子：
50.5
通讯作者：
Long, G. V.
中科院分区：
文献类型：
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作者：
Menzies, A. M.;Johnson, D. B.;Long, G. V.
背景：抗PD-1抗体(抗PD-1)在多种恶性肿瘤中具有临床活性。所有临床试验都排除了既往有明显自身免疫性疾病(ADS)的患者，只有一项临床试验包括使用ipilimumab的免疫相关不良事件(IrAEs)患者。我们试图探索抗PD-1在此类患者中的安全性和有效性。患者和方法：对2012年7月1日至2015年9月30日期间接受抗PD-1治疗的晚期黑色素瘤和既往ADS和/或使用ipilimumab(需要全身免疫抑制)的主要免疫相关不良事件(IrAEs)的患者进行回顾性研究。结果：来自13个学术三级转诊中心的119名患者接受了抗PD-1治疗。在既往AD患者(N=52)中，有效率为33%。20例(38%)有AD发作需要免疫抑制，其中7/13为类风湿关节炎，3/3为风湿性多肌痛，2/2为干燥综合征，2/2为免疫性血小板减少性紫癜，3/8为银屑病。胃肠道疾病(N=6)或神经系统疾病(N=5)患者均无起火。只有2例(4%)患者因红斑而停止治疗，但15例(29%)出现其他irAEs，4例(8%)停止治疗。在有ipilimumab irAEs需要免疫抑制的患者(N=67)中，有效率为40%。2例(3%)患者复发相同的ipilimumab irAEs，但23例(34%)出现新的irAEs(14例，21%为3-4级)，8例(12%)停止治疗。没有与治疗相关的死亡。结论：在既往存在ADS或使用ipilimumab的主要irAEs的黑色素瘤患者中，抗PD-1诱导了相对频繁的免疫毒性，但这些毒性通常是温和的，易于处理，不需要停止治疗，并且相当大比例的患者获得了临床反应。结果支持，抗PD-1可以安全地应用于既有ADS或既往使用ipilimumab的主要irAEs的患者，并可获得临床益处。
Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immunerelated adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients.Patients and methods: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified.Results: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths.Conclusions: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.