Abstract

Background

Immunotherapy has become a standard of care for an increasing number of tumors. Patients have a chance of developing immune-related adverse events (irAEs). In general, irAEs occur quite early, mostly within weeks to 3 months after initiation of treatment. Being drugs relatively innovative, “late” irAEs are still unknown.

Methods

We conducted a multicenter retrospective study of advanced cancer patients (any histology, regardless of treatment line) treated with anti-PD-1/PD-L1 (mono)immunotherapy, with a minimum time to treatment failure (TTF) of 12 months. IrAEs were categorized into “early” (<12 months of treatment) and “late”. An explorative analysis of clinical outcomes (TTF and Overall Survival – OS) was performed.

Results

We evaluated 318 consecutive patients treated with immunotherapy from September 2013 to August 2018. Median age was 68.6 years (32-90). 175 patients (55.5%) experienced any grade early-irAEs, while 110 (34.6%) experienced any grade late-irAEs (p = 0.0013); 13 patients (4.1%) experienced G3/G4 early-irAEs, while 12 (3.8%) G3/G4 late-irAEs (p = 0.8446). There was a significant association between the occurrence of any grade early-irAEs and late-irAEs (p = 0.0452), as well as between G3/G4 early-irAEs and late-irAEs (p = 0.0251). Among patients who experienced early-irAEs, 63 (36%) experienced “multiple-site” irAEs (multiple sites/organs), while 17 patients (15.4%) experienced multiple-site late-irAEs (p = 0.0040). The median period of follow-up was 22.2 months. The median time to irAEs onset were 3.1 and 16.1 months for early- and late-irAEs, respectively. Late irAEs were not significantly related to TTF; on the other hand, were significantly related to a prolonged OS. When adjusted for primary tumor, late-irAEs were confirmed to be significantly related to a prolonged OS (HR = 0.25 [95%CI:0.11-0.55]; p = 0.0006).

Conclusion

Late-irAEs among long responders seem to have a mild/moderate incidence. They are mostly non-serious and clinical manageable, with a low rate of treatment discontinuation. In this positive-selected population, the occurrence of any grade late-irAEs seems to be furtherly related to a prolonged OS.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

中文翻译：

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多中心研究：PD-1 / PD-L1检查点抑制剂的长期应答者中55P晚期免疫相关不良事件的发生率和临床意义

抽象的

背景

免疫疗法已成为治疗越来越多的肿瘤的标准治疗方法。患者有机会发展免疫相关的不良事件（irAE）。通常，irAE发生的时间很早，通常在治疗开始后的数周至3个月内。作为药物的相对创新，“晚期” irAEs仍然未知。

方法

我们对接受抗PD-1 / PD-L1（单次）免疫疗法治疗的晚期癌症患者（任何组织学，无论治疗路线如何）进行了多中心回顾性研究，其治疗失败的最短时间（TTF）为12个月。IrAEs分为“早期”（<12个月治疗）和“晚期”。对临床结果（TTF和总生存期– OS）进行了探索性分析。

结果

我们评估了2013年9月至2018年8月连续318例接受免疫治疗的患者。中位年龄为68.6岁（32-90）。175名患者（55.5％）经历了任何等级的早期irAE，而110名患者（34.6％）经历了任何等级的早期irAE（p = 0.0013）；13例患者（4.1％）经历了G3 / G4早期irAEs，而12例（3.8％）了G3 / G4晚期irAEs（p = 0.8446）。在任何级别的早期irAEs和晚期irAEs的发生之间存在显着关联（p = 0.0452），以及在G3 / G4早期irAEs和晚期irAEs之间存在显着关联（p = 0.0251）。在经历早期irAE的患者中，有63名（36％）经历了“多部位” irAE（多部位/器官），而17名患者（15.4％）经历了多部位irAE（p = 0.0040）。随访的中位时间为22.2个月。早期和晚期irAE发生irAE的中位时间分别为3.1和16.1个月，分别。晚期irAE与TTF无关。另一方面，与长时间的OS显着相关。调整原发性肿瘤后，可确认晚期irAE与OS延长密切相关（HR = 0.25 [95％CI：0.11-0.55]； p = 0.0006）。

结论

长反应者中的晚期irAEs似乎具有轻度/中度的发病率。它们大多是非严重的，临床上可控的，治疗中断率低。在这一积极选择的人群中，任何等级的晚期irAE的发生似乎都与OS延长有关。

负责研究的法人实体

作者。

资金

尚未收到任何资金。

揭露

所有作者均声明没有利益冲突。