免疫相关不良反应与免疫检查点抑制剂疗效和获益的关系：系统评价和荟萃分析。
Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors - A systematic review and meta-analysis.
机构信息
Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
出版信息
Cancer Treat Rev. 2021 Jan;92:102134. doi: 10.1016/j.ctrv.2020.102134. Epub 2020 Dec 3.
BACKGROUND
The use of immune checkpoint inhibitors (ICIs) has become standard therapy in many tumor sites. The aim of this study is to systematically review the literature to determine whether the incidence of immune-related adverse events (irAEs) after the use of ICIs is associated with clinical outcomes in all solid malignancies.
METHODS
Embase and PubMed were searched from January 1st, 2000 until March 14, 2020 for relevant studies assessing the relationship between irAEs and treatment efficacy. Outcome measures of interest included: incidence of irAEs, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).
RESULTS
Of 3384 unique citations, 51 studies met inclusion criteria. Studies included melanoma (n = 21), lung (n = 19), renal (n = 4), urothelial (n = 1), head and neck (n = 2) and gastrointestinal cancers (n = 1). In patients with metastatic melanoma (n = 1474), the development of irAEs (irAE + versus irAE-) was associated with better weighted average OS (15.24 months (95% CI 9.95 to 20.5) versus 8.94 months (95% CI 7.76 to 10.1), HR = 0.46 (n = 640, CI 0.35-0.62, p < 0.00001), PFS (17.61 months (95% CI 10.1 to 25.1) versus 2.23 months (95% CI 1.77 to 2.68), HR = 0.51 (n = 1763, CI 0.42-0.63, p < 0.00001), and ORR (37.67% (95% CI 32.8 to 42.5) versus. 23.44% (95% CI 17.8 to 29.1). Similarly, in lung cancer patients, the ORR (irAE + versus. irAE-) was 41.49% (95% CI 36.5 to 46.5) versus 18.01% (95% CI 13.5 to 22.6). The weighted average PFS and OS were 8.97 months (95% CI 7.14 to 10.8) versus 3.06 months (95% CI 2.4 to 3.72) with HR = 0.46 (n = 1575, CI 0.39-0.54, p < 0.00001) and 19.07 months (95% CI 14.3 to 23.8) versus 7.45 months (95% CI 5.34 to 9.56) HR = 0.40 (n = 1085, CI 0.30-0.51, p < 0.00001), respectively. Improved treatment efficacy in patients who developed irAEs was also seen in renal cell carcinoma, urothelial and head and neck cancers. Notably, grade 3 or 4 irAEs were associated with increased ORR but worse OS.
CONCLUSION
A positive association was noted between the development of irAEs and ORR, PFS, and OS in patients treated with ICIs, irrespective of disease site, type of ICI and irAE. Grade 3 or higher toxicities resulted in better ORR, but worse OS.
背景
免疫检查点抑制剂（ICIs）的使用已成为许多肿瘤部位的标准治疗方法。本研究旨在系统地回顾文献，以确定在所有实体恶性肿瘤中，ICI 使用后发生免疫相关不良事件（irAEs）的发生率与临床结局之间是否存在关联。
方法
从 2000 年 1 月 1 日至 2020 年 3 月 14 日，在 Embase 和 PubMed 上搜索评估 irAEs 与治疗疗效之间关系的相关研究。感兴趣的结局指标包括：irAEs 的发生率、客观缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）。
结果
在 3384 篇独特的引文中，有 51 项研究符合纳入标准。研究包括黑色素瘤（n=21）、肺癌（n=19）、肾癌（n=4）、尿路上皮癌（n=1）、头颈部癌症（n=2）和胃肠道癌症（n=1）。在转移性黑色素瘤患者（n=1474）中，irAEs 的发生（irAE+与 irAE-）与加权平均 OS 改善相关（15.24 个月（95%CI 9.95-20.5）与 8.94 个月（95%CI 7.76-10.1），HR=0.46（n=640，CI 0.35-0.62，p<0.00001），PFS（17.61 个月（95%CI 10.1-25.1）与 2.23 个月（95%CI 1.77-2.68），HR=0.51（n=1763，CI 0.42-0.63，p<0.00001），以及 ORR（37.67%（95%CI 32.8-42.5）与 23.44%（95%CI 17.8-29.1）。同样，在肺癌患者中，ORR（irAE+与 irAE-）为 41.49%（95%CI 36.5-46.5）与 18.01%（95%CI 13.5-22.6）。加权平均 PFS 和 OS 分别为 8.97 个月（95%CI 7.14-10.8）与 3.06 个月（95%CI 2.4-3.72），HR=0.46（n=1575，CI 0.39-0.54，p<0.00001）和 19.07 个月（95%CI 14.3-23.8）与 7.45 个月（95%CI 5.34-9.56），HR=0.40（n=1085，CI 0.30-0.51，p<0.00001）。在接受 ICIs 治疗的肾癌、尿路上皮癌和头颈部癌症患者中，irAEs 的发生与治疗效果的改善也存在相关性。值得注意的是，3 级或 4 级 irAEs 与 ORR 增加相关，但 OS 更差。
结论
在接受 ICI 治疗的患者中，irAEs 的发生与 ORR、PFS 和 OS 呈正相关，无论疾病部位、ICI 类型和 irAE 严重程度如何。3 级或更高毒性导致 ORR 更好，但 OS 更差。
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