Evaluation of Readministration of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer
Evaluation of Readministration of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer
复制标题
DOI：
10.1001/jamaoncol.2019.1022
复制
发表时间：
2019-09-01
期刊：
影响因子：
28.4
通讯作者：
Lambotte, Olivier
中科院分区：
文献类型：
--
作者：
Simonaggio, Audrey;Michot, Jean Marie;Lambotte, Olivier
在发生2级或以上免疫相关不良事件后，抗pd -1或抗pd - l1抑制剂再挑战安全吗？在这项队列研究中，93名法国成年人经历了2级或更高级别的免疫相关不良事件，并有抗pd -1或抗pd - l1再挑战，55%的人经历了第二次不良事件。早期的初始毒性作用与更频繁的复发有关，第二次事件不如第一次严重。意义抗pd -1或抗pd - l1再挑战的风险-回报比似乎是可以接受的，尽管这些患者需要密切监测；再挑战条件需要在前瞻性临床试验中进一步调查。尽管免疫检查点抑制剂（ICIs），如抗pd -1（程序性细胞死亡1）或抗pd - l1（程序性细胞死亡1配体1），已被证明对治疗许多癌症有效，但接受ICIs的患者可能会经历免疫相关不良事件（irAEs）。几乎没有证据表明在rae后恢复这些治疗的安全性。目的探讨抗pd -1或抗pd - l1免疫治疗再攻的安全性。设计、环境和参与者：在2015年8月1日至2017年12月31日期间，这项ICI再挑战安全性的队列研究纳入了连续的成年患者（n=93），他们被转至法国Villejuif Gustave Roussy癌症中心的ImmunoTOX评估委员会。数据分析时间为2018年5月28日至11月25日。在最初的2级或更高级别的irAE后再给抗pd -1或抗pd - l1抑制剂的患者第二次irAE的发生率。回顾患者和irAEs的特征，主要终点为第二次irAEs的发生率。结果共纳入93例患者，其中女性48例（52%），年龄中位数（范围）为62.5（33-85）岁。主要癌症类型或肿瘤部位为黑色素瘤（31例[33%]）、肺癌（15例[16%]）、结直肠癌（8例[9%]）和淋巴瘤（8例[9%]）。对于初始irAE，发现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例[18%]），皮肤毒性作用（14例[15%]），肺炎（13例[14%]），结肠炎（11例[12%]）或关节痛（7例[7.5%]）。40名患者（43%）再次使用相同的抗pd -1或抗pd - l1药物。再挑战组和非再挑战组在中位（范围）年龄（61[34-84]岁vs 63[33-85]岁，P= 0.37）、开始irAE的时间（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）或类固醇使用（17 [42.5%]vs 32 [60%]， P= 0.09）方面没有差异。中位随访期为14个月，22例（55%）患者发生相同或不同的irAE。较短的初始irAE时间与第二次irAE的发生有关（9周vs 15周；P=.04）。研究发现，第二次急性呼吸道感染并不比第一次更严重。结论和相关性抗pd -1或抗pd - l1再挑战的风险回报比似乎是可以接受的，尽管这些患者需要密切监测；需要通过前瞻性临床试验进一步调查再挑战条件。本队列研究评估了在经历严重免疫相关不良事件的癌症患者中恢复免疫检查点抑制剂治疗的可行性、风险和优势。
Key PointsQuestionAfter a grade 2 or higher immune-related adverse event, is an anti-PD-1 or anti-PD-L1 inhibitor rechallenge safe? FindingsIn this cohort study of 93 French adults who experienced a grade 2 or higher immune-related adverse event and had an anti-PD-1 or anti-PD-L1 rechallenge, 55% experienced a second adverse event. Earlier initial toxic effect was associated with more frequent recurrence, and the second event was not as severe as the first. MeaningThe risk-reward ratio for anti-PD-1 or anti-PD-L1 rechallenge appears to be acceptable, although these patients require close monitoring; rechallenge conditions warrant further investigation in a prospective clinical trial.ImportanceAlthough 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. ObjectiveTo investigate the safety of a rechallenge with anti-PD-1 or anti-PD-L1 immunotherapies after an irAE. Design, Setting, and ParticipantsThis 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 MeasuresIncidence 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. ResultsA 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 RelevanceThe 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.This cohort study evaluates the feasibility, risks, and advantages of resuming immune checkpoint inhibitor therapy in patients with cancer who experienced severe immune-related adverse events.