肿瘤患者发生免疫相关不良反应后再次应用免疫检查点抑制剂的评估

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肿瘤患者发生免疫相关不良反应后再次应用免疫检查点抑制剂的评估 | 引经据典[56] · 协和呼吸

阅读量：3837431 2019-10-27

本/期/解/读
肿瘤患者发生免疫相关不良反应后再次应用免疫检查点抑制剂的评估
Evaluation of Readministration of Immune Checkpoint
Inhibitors After Immune-Related Adverse Events
in Patients With Cancer
作者：
Audrey Simonaggio, et al.
翻译：
北京协和医院呼吸与危重症医学科张东明徐燕
文献来源：
JAMA Oncol. 2019;5(9):1310-1317.
DOI:
10.1001/jamaoncol.2019.1022

重要性
尽管免疫检查点抑制剂(ICIs)，如抗PD-1或抗PD-L1免疫治疗已被证明对许多癌症有效，但接受ICIs的患者可能会发生免疫相关的不良事件(irAEs)。目前鲜有证据评估发生irAE后再次应用免疫治疗的安全性。
目的
探讨在发生irAE后再次尝试抗PD-1或抗PD-L1免疫治疗的安全性。
研究设计、入组患者
该队列研究连续纳入2015年8月1日至2017年12月31日期间，提交到法国Villejuif Gustave Roussy癌症中心的免疫毒性评估委员会的93名成年患者，数据分析时间从2018年5月28日至11月25日。
主要结局和计算
患者初次发生2级或以上irAE后，再次使用抗PD-1或抗PD-L1抑制剂，分析第二次irAE的发生率。回顾了患者和irAEs的特点，主要终点是第二次irAEs的发生率。
结果
共纳入93例患者，其中48例(52%)为女性，中位年龄为62.5(33-85)岁。主要癌症类型或肿瘤部位为黑色素瘤(31[33%])、肺(15[16%])、结直肠(8[9%])和淋巴瘤(8[9%])。在初次irAE中，有43例2级事件(46%)，36例3级事件(39%)和14例4级事件(15%)，主要表现为肝炎(17[18%])，皮肤毒性(14[15%])，肺炎(13[14%])，结肠炎(11[12%])，或关节痛(7[7.5%])。其中有40名患者(43%)再次应用相同的抗PD-1或抗PD-L1抗体。在再次使用和不使用免疫治疗组中，患者中位年龄 (范围 (61[34-84]岁vs 63[33-85]岁；P=.0.37)，发生初次irAE时间(5[1-40]个治疗周期vs 3[1-22]个治疗周期；P=0.32)，irAE严重程度(2级：18[47.5%]vs 27[51%]；3-4级：22[52.5%]vs 26[49%]；P=0.70)，激素使用(17[42.5%]vs 32[60%]；P=0.09)方面，两组没有差异。在14个月的中位随访时间里，22例患者(55%)发生了与初次相同或不同的irAE。发生初次irAE时间越短，越容易再次出现irAE (9周vs15周；P=0.04)，但第二次irAE并没有比第一次更严重。
结论和相关性
再次应用抗-PD-1或抗-PD-L1抗体的风险-回报比可以接受，但需要密切监测。仍需通过前瞻性临床试验进一步探索再次应用免疫抑制剂的条件。
原文摘要
Abstract
IMPORTANCE
Although immune checkpoint inhibitors (ICIs), such as anti–PD-1 (programmed cell death 1) or anti–PD-L1 (programmed cell death 1 ligand 1), have proved effective in treating many cancers, patients receiving ICIs may experience immune-related adverse events (irAEs). Little evidence exists on the safety of resuming these treatments after an irAE.
OBJECTIVE
To investigate the safety of a rechallenge with anti–PD-1 or anti–PD-L1 immunotherapies after an irAE.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study of the safety of an ICI rechallenge involved consecutive adult patients (n = 93) who were referred to the ImmunoTOX assessment board at the Gustave Roussy cancer center in Villejuif, France, between August 1, 2015, and December 31, 2017. Data were analyzed from May 28 to November 25, 2018.
MAIN OUTCOMES AND MEASURES
Incidence of a second irAE in patients who had a readministration of an anti–PD-1 or anti–PD-L1 inhibitor after an initial grade 2 or higher irAE. Characteristics of the patients and the irAEs were reviewed, and the primary end point was the rate of occurrence of second irAEs.
RESULTS
A total of 93 patients were included, among whom 48 (52%) were female, and the median (range) age was 62.5 (33-85) years. The main cancer types or tumor sites were melanoma (31 [33%]), lung (15 [16%]), colorectal (8 [9%]), and lymphoma (8 [9%]). For the initial irAE, 43 grade 2 events (46%), 36 grade 3 events (39%), and 14 grade 4 events (15%) were found, presenting primarily as hepatitis (17 [18%]), skin toxic effect (14 [15%]), pneumonitis (13 [14%]), colitis (11 [12%]), or arthralgia (7 [7.5%]). Forty patients (43%) were rechallenged with the same anti–PD-1 or anti–PD-L1 agent. The rechallenged and non-rechallenged groups did not differ in terms of median (range) age (61 [34-84] years vs 63 [33-85] years; P = .37), time to initial irAE (5 [1-40] treatment cycles vs 3 [1-22] treatment cycles; P = .32), irAE severity (grade 2: 18 [47.5%] vs 27 [51%]; grades 3-4:
22 [52.5%] vs 26 [49%]; P = .70), or steroid use (17 [42.5%] vs 32 [60%]; P = .09). With a median follow-up period of 14 months, the same irAE or a different irAE occurred in 22 patients (55%). Shorter time to the initial irAE was linked to the occurrence of a second irAE (9 vs 15 weeks; P = .04). The second irAEs were not found to be more severe than the first.
CONCLUSIONS AND RELEVANCE
The risk-reward ratio for an anti–PD-1 or anti–PD-L1 rechallenge appears to be acceptable, although these patients require close monitoring; further investigation into rechallenge conditions through a prospective clinical trial is needed.

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作者介绍

张东明
呼吸与危重症医学科硕士在读
北京协和医院呼吸与危重症医学科2018级硕士研究生，所在课题组主要从事肺部肿瘤的临床和基础研究。

徐燕
北京协和医院
呼吸与危重症医学科
医学博士副教授
擅长肺部恶性肿瘤的诊断和治疗。熟悉哮喘、慢性阻塞性肺疾病、肺部感染等常见及疑难呼吸系统疾病的诊断和治疗。工作期间发表综述、论著、病例报道以及SCI文章五十余篇，参编专著1部。参与科室所承担的多项国际、国内多中心肺癌相关临床研究。
擅长 : 肺癌的诊断和治疗。
往期经典
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【引经据典第55期】晚期非鳞状NSCLC的维持治疗（ECOG-ACRIN 5508）：培美曲塞、贝伐珠单抗或二者联合？