Department of Pulmonary Medicine, Sendai Kousei Hospital, Aoba-ku, Sendai, Miyagi, Japan.
JAMA Oncol. 2019 Mar 1;5(3):376-383. doi: 10.1001/jamaoncol.2018.5860.
Administration of anti-programmed cell death protein 1 (anti-PD-1) is now standard therapy in advanced non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors, including anti-PD-1, have not been assessed in patients with subclinical disease with advanced NSCLC, and no useful clinical biomarkers have been associated with immune-related adverse events (irAEs) among these patients treated with anti-PD-1.
To assess the safety and efficacy of anti-PD-1 treatment in patients with subclinical disease with advanced NSCLC and with or without preexisting autoimmune markers, including rheumatoid factor, antinuclear antibody, antithyroglobulin, and antithyroid peroxidase; and to assess potential clinical biomarkers that may be meaningfully and conveniently associated with clinical benefit or with irAEs following anti-PD-1 treatment.
DESIGN, SETTING, AND PARTICIPANTS: This medical records analysis retrospectively evaluated 137 patients who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital in Japan between January 2016 and January 2018. Treatment efficacy and irAEs were evaluated along with candidate factors that may be associated with irAEs.
Absence or presence of specific autoimmune markers and antibodies before treatment.
Preexisting antibodies and autoimmune markers, progression-free survival (PFS), and irAEs.
Of 137 patients with advanced NSCLC, 105 were men, the median age was 68 (range, 36-88) years, 99 underwent nivolumab monotherapy, 38 underwent pembrolizumab monotherapy, and 134 had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median PFS was 6.5 (95% CI, 4.4-12.9) months among patients with examined preexisting antibodies and 3.5 (95% CI, 2.4-4.1) months among patients without, suggesting significantly better prognosis in the former. The hazard ratio for disease progression or death in the presence of the examined preexisting antibodies was 0.53 (95% CI, 0.36-0.79; P = .002). The PFS was significantly longer among patients with any preexisting antibodies than among those without. The examined preexisting antibodies (48 patients [73%]) and rheumatoid factor (26 patients [39%]) were more common among patients who developed irAEs. Multivariate analysis indicated that the presence of the examined preexisting antibodies was independently associated with irAEs (odds ratio, 3.25; 95% CI, 1.59-6.65; P = .001). Skin reactions were more frequent among patients with preexisting rheumatoid factor (47% vs 24%, P = .02), whereas thyroid dysfunction was more frequent among patients with preexisting antithyroid antibodies (20% vs 1%, P < .001).
The presence of the examined preexisting antibodies was associated with clinical benefit and with the development of irAEs in patients with NSCLC treated with nivolumab or pembrolizumab. Thus, the presence of these autoimmune markers may help determine the risk-benefit ratio for individual patients with NSCLC, maximizing therapeutic benefits while minimizing irAEs.
抗程序性细胞死亡蛋白 1（抗 PD-1）的给药现在是晚期非小细胞肺癌（NSCLC）的标准治疗方法。然而，免疫检查点抑制剂，包括抗 PD-1，尚未在患有亚临床疾病的晚期 NSCLC 患者中进行评估，并且在接受抗 PD-1 治疗的这些患者中，没有与免疫相关的不良反应（irAE）相关的有用临床生物标志物。
评估抗 PD-1 治疗在亚临床疾病的晚期 NSCLC 患者中的安全性和有效性，无论是否存在预先存在的自身免疫标志物，包括类风湿因子、抗核抗体、抗甲状腺球蛋白和抗甲状腺过氧化物酶；并评估可能与临床获益或抗 PD-1 治疗后 irAE 有意义且方便相关的潜在临床生物标志物。
设计、地点和参与者：这项病历分析回顾性评估了 2016 年 1 月至 2018 年 1 月期间在日本仙台厚生病院接受纳武单抗或帕博利珠单抗单药治疗的 137 名患者。评估了治疗效果和 irAE，以及可能与 irAE 相关的候选因素。
治疗前是否存在特定的自身免疫标志物和抗体。
预先存在的抗体和自身免疫标志物、无进展生存期（PFS）和 irAE。
在 137 名患有晚期 NSCLC 的患者中，105 名为男性，中位年龄为 68 岁（范围，36-88 岁），99 名接受纳武单抗单药治疗，38 名接受帕博利珠单抗单药治疗，134 名患者的东部肿瘤协作组体能状态为 0 或 1。在检查到预先存在的抗体的患者中，中位 PFS 为 6.5 个月（95%CI，4.4-12.9），而在没有预先存在抗体的患者中为 3.5 个月（95%CI，2.4-4.1），前者的预后明显更好。存在检查到的预先存在的抗体时疾病进展或死亡的风险比为 0.53（95%CI，0.36-0.79；P = .002）。在存在任何预先存在的抗体的患者中，PFS 明显更长。预先存在的抗体（48 例[73%]）和类风湿因子（26 例[39%]）在发生 irAE 的患者中更为常见。多变量分析表明，存在检查到的预先存在的抗体与 irAE 独立相关（优势比，3.25；95%CI，1.59-6.65；P = .001）。类风湿因子阳性患者的皮肤反应更常见（47%比 24%，P = .02），而甲状腺功能障碍在预先存在抗甲状腺抗体的患者中更为常见（20%比 1%，P < .001）。
预先存在的抗体与 nivolumab 或 pembrolizumab 治疗的 NSCLC 患者的临床获益和 irAE 的发生相关。因此，这些自身免疫标志物的存在可能有助于确定 NSCLC 患者的风险-获益比，最大限度地提高治疗效益，同时最大限度地减少 irAE。
