PD-1抑制剂所致免疫相关不良事件的真实世界研究

Real World Study of Immune-Related Adverse Events Caused by PD-1 Inhibitors

摘要: 背景：PD-1抑制剂通过激活自身免疫耐受往往可以发挥意想不到的抗肿瘤效果。然而，PD-1抑制剂引起的过度激活的自身免疫系统可导致免疫相关不良事件(irAEs)的产生。因此，在临床治疗中有必要关注使用PD-1抑制剂患者可能发生的irAEs。方法：本研究回顾性评估了2019.04.01至2021.04.30就诊于浙江省人民医院的288例应用PD-1抑制剂的实体瘤患者。我们就irAEs的发生率、发生时间、发生谱、疗效相关性等进行探究。同时，我们进一步探讨了PD-1抑制剂在肺癌亚组中的治疗疗效。结果：在本研究所涉及的288例患者中，irAEs的总发生率为35.07%，I~II级irAEs和III~V级irAEs的发生率分别为30.38%、4.69%。甲状腺功能减退是最常见的irAEs，其次是肝功能损伤，接下来是皮肤反应、疲乏和免疫相关性肺炎。irAEs的中位发生时间为3.15个月(平均4.09个月，95% CI [3.43, 4.74])。发生irAEs的患者与无irAEs患者相比有更长的OS、PFS (mOS：10.80个月vs 6.32个月，P = 0.01；mPFS：8.95个月vs 4.73个月，P < 0.01)，irAEs发生较晚患者较早发生患者OS、PFS有显著的改善(mOS：13.51个月vs 8.24个月，P < 0.01；mPFS：11.29个月vs 6.74个月，P < 0.01)，但高级别irAEs并不意味着患者可获得更好的预后。各种irAEs在各瘤种发生率的差异均无统计学意义。在小细胞肺癌、肺腺癌和肺鳞癌中，与后线治疗相比，PD-1抑制剂在一线治疗均表现出更好生存获益的趋势。在肺腺癌和肺鳞癌的一线治疗中，与PD-1抑制剂联合化疗相比，PD-1抑制剂加化疗联合抗肿瘤药物显示出更好的联合疗效。结论及意义：在使用PD-1抑制剂治疗前需要进行全面的基线测量，以警惕irAEs的发生。irAEs发生类型与肿瘤类型无关，irAEs是否发生以及发生时间早晚有助于预测PD-1抑制剂的疗效。然而，高级别irAEs的存在并不意味着更好的疗效，这可能与治疗中断有关。对已发生高级别irAEs的患者，应按指南进行规范化管理，及时足量使用糖皮质激素甚至免疫抑制剂。在肺癌患者中，PD-1抑制剂联合抗血管生成药物和化疗可能具有协同效应。我们建议PD-1抑制剂应尽可能应用于肺癌的一线治疗。

Abstract: Background: PD-1 inhibitors can often have unexpected anti-tumor effects by activating autoim-mune tolerance. However, over-activated autoimmune by PD-1 inhibitors responses can lead to immune-related adverse events (irAEs). Therefore, it is necessary to focus on the potential irAEs in patients on PD-1 inhibitors in daily clinical practice. Methods: This study retrospectively studied the case data of 288 patients with solid tumors who applied PD-1 inhibitors attending Zhejiang Pro-vincial People’s Hospital from 2019.04.01 to 2021.04.30. We analyzed the multiple aspects data of irAEs, such as the incidence, time, spectrum and efficacy correlation of it. In parallel, we further ex-plored the efficacy of PD-1 inhibitors for the lung cancer subgroup. Result: For 288 patients in our study, the total incidence of irAEs was 35.07%, and the incidence rate of grade I~II and III~V irAEs were 30.38% and 4.69% respectively. Hypothyroidism is the most common irAEs, followed by liver function injury, followed by skin reaction, weakness and immune-related pneumonia. The median onset time of irAEs was 3.15 months (mean time was 4.09 M, 95% CI [3.43, 4.74]). Compared with patients without irAEs, patients with irAEs had longer OS and PFS (mOS: 10.80 vs 6.32 months, P = 0.01; mPFS: 8.95 vs 4.73 months, P < 0.01). Patients with earlier irAEs had significantly improved OS and PFS (mOS: 13.51 vs 8.24 months, P < 0.01; mPFS: 11.29 vs 6.74 months, P < 0.01) than later irAEs, but high-level irAEs didn’t mean a better prognosis. There was no significant difference in the incidence of irAEs among tumor species. In SCLC, lung adenocarcinoma and lung squamous cell car-cinoma, PD-1 inhibitors showed a trend of better survival benefit in first-line treatment compared with later-line. In the first-line treatment of lung adenocarcinoma and lung squamous cell carcino-ma, compared with PD-1 inhibitor combined with chemotherapy, PD-1 inhibitors combined with chemotherapy and antiangiogenics show a better combined effect. Conclusion: Complete baseline measurements are required before treatment with PD-1 inhibitors to prevent the occurrence of irAEs. The irAEs was not related to the type of tumor. The presence and onset time of irAEs tends to predict the efficacy of PD-1 inhibitors. However, the presence of high-grade irAEs doesn’t indicate better outcomes. This may be related to treatment interruption. For patients with high-level irAEs, they should be standardized treat according to the guidelines and hormones and even immuno-suppressants should be used in sufficient quantities in time. In lung cancer patients, PD-1 inhibitors combined with antiangiogenics and chemotherapy may have a synergistic effect. We suggest that PD-1 inhibitors could be applied in first-line treatment of lung cancer if possible.