Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo A Secondary Analysis of a Randomized Clinical Trial
Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo A Secondary Analysis of a Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2019.5570
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发表时间：
2020-04-01
期刊：
影响因子：
28.4
通讯作者：
Suciu, Stefan
中科院分区：
文献类型：
--
作者：
Eggermont, Alexander M. M.;Kicinski, Michal;Suciu, Stefan
免疫相关不良事件（irAE）是否表明接受免疫检查点抑制剂治疗的患者的药物活性仍然未知。目的在比较帕博利珠单抗和安慰剂治疗高危III期黑色素瘤患者的双盲EORTC 1325/KEYNOTE-054临床试验中，研究irAE与无复发生存期（RFS）之间的相关性。设计、设置和参与者：共有1019名患有III期黑色素瘤的成年人以1：1的比例随机分配接受pembrolizumab治疗或安慰剂治疗。合格的患者是18岁及以上的成年人，其具有转移到淋巴结的皮肤黑素瘤的完全切除术，分类为IIIA期（至少1个测量的最大直径> 1mm的微转移）、IIIB期或IIIC期（没有在途转移）癌症。患者于2015年8月26日至2016年11月14日接受随机化。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日锁定。参与者计划每3周接受200 mg pembrolizumab或安慰剂，共18剂，持续约1年或直至疾病复发，不可接受的毒性作用，重大方案违反或撤回同意。主要结局和测量使用校正性别、年龄和AJCC-7分期的考克斯模型估计irAE和RFS之间的关联，时变协变量在irAE发作前的值为0，在irAE发作后的值为1。在1011例开始接受帕博利珠单抗治疗或安慰剂治疗的患者中，622例（61.5%）为男性，389例（38.5%）为女性; 386例（38.2%）患者年龄在50至64岁之间，377例（37.3%）患者年龄小于50岁，248例（24.5%）患者年龄大于或等于65岁。与意向治疗人群中报告的主要分析一致，在开始治疗的患者中，帕博利珠单抗组的RFS长于安慰剂组（风险比[HR]，0. 56; 98. 4% CI，0. 43 - 0. 74）。帕博利珠单抗组（n = 509）和安慰剂组（n = 502）irAE的发生率分别为190例（37.4%）和45例（9.0%）;在每个治疗组中，男性和女性的发生率相似。在男性和女性中，irAE的发生与帕博利珠单抗组的RFS较长相关（HR，0.61; 95% CI，0.39 - 0.95; P = 0.03）。然而，在安慰剂组中，这种关联并不显著。与安慰剂组相比，帕博利珠单抗组在irAE发生后复发或死亡风险的降低幅度大于未发生irAE或irAE发生前（HR，0.37; 95%CI，0.24 - 0.57 vs HR，0.61; 95%CI，0.49 - 0.77; P = 0.03）。结论和相关性在这项研究中，irAE的发生与帕博利珠单抗组的RFS较长相关。
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.