摘要

Importance:Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown.
Objective:To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma.
Design, Setting, and Participants:A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017.
Interventions:Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent.
Main Outcomes and Measures:The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset.
Results:Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P = .03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P = .03).
Conclusions and Relevance:In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm.
Trial Registrations:ClinicalTrials.gov identifier: NCT02362594; EudraCT identifier: 2014-004944-37.

译文

重要性: 免疫相关不良事件 (irAEs) 是否表明使用免疫检查点抑制剂治疗的患者的药物活性仍然未知。
目的: 探讨 irAEs 与无复发生存期 (RFS) 之间的关系在双盲 EORTC 1325/KEYNOTE-054 临床试验中，比较了 pembrolizumab 疗法和安慰剂治疗高危 ⅲ 期黑素瘤患者。
设计、设置和参与者: 共有 1019 名患有 III 期黑素瘤的成年人被随机分配以 1:1 的比例接受 pembrolizumab 治疗或安慰剂治疗。符合条件的患者是 18 岁及以上的成年人，他们完全切除转移至淋巴结的皮肤黑素瘤，分类为 IIIA 期 (至少 1 个最大直径大于 1毫米的微转移)，IIIB, 或 IIIC (无中转转移) 癌。从 2015年8月26日到 2016年11月14日，患者被随机分配。数据集的临床截止日期为 2017年10月2日。然后对数据库进行分析，该数据库于 2017年11月28日被锁定。
干预: 参与者被安排每三周接受 200 毫克的 pembrolizumab 或安慰剂，总共 18 剂，大约 1 年，或者直到疾病复发，不可接受的毒性作用，严重违反协议, 或者撤回同意。
主要结果和措施: 使用 Cox 模型估计 irAEs 和 RFS 之间的关联，该模型根据性别、年龄和 AJCC-7 阶段进行了调整, 具有时变协变量，irAE 发病前值为 0，irAE 发病后值为 1。
结果: 在 1011 名开始使用 pembrolizumab 疗法或安慰剂治疗的患者中，622 (61.5%) 是男性，389 (38.5%) 是女性; 386 名患者 (38.2%) 年龄在 50 至 64 岁之间, 377 (37.3%) 年龄小于 50 岁，248 (24.5%) 年龄大于 65 岁。与报告的意向治疗人群的主要分析一致，与安慰剂组相比，pembrolizumab 组的 RFS 更长 (风险比 [HR]，0.56; 98.4% CI, 0.43-0.74) 在开始治疗的患者中。在 pembrolizumab 组 (n = 190) 和安慰剂组 (n = 37.4%) 中，irAEs 的发生率为 9.0% (); 在每个治疗组中, 男性和女性的发病率相似。在男性和女性中，irAE 的发生与 pembrolizumab 组较长的 RFS 有关 (HR，0.61; 95% CI，0.39-0.95; p ¼ = ¼.03)。然而，在安慰剂组中，这种关联并不显著。与安慰剂组相比，在 irAE 发病后，pembrolizumab 组的复发或死亡风险降低幅度大于未发病或发病前 (HR，0.37; 95% CI，0.24-0.57 vs HR，0.61; 95% CI，0.49-0.77，分别; p   =  。 03)。
结论和相关性: 在本研究中，aire 的发生与 pembrolizumab 组较长的 RFS 相关。
试验注册: ClinicalTrials.gov 标识符: NCT02362594; EudraCT 标识符: 2014-004944-37。