Abstract

Background

There is limited information about the response to steroids in treatment of immune-mediated hepatitis (IMH) in patients treated with immune checkpoint inhibitors (ICI). We investigated the incidents of IMH in 307 Danish lung cancer patients with advanced non-small cell lung cancer (NSCLC) and reviewed the efficacy of the IMH treatment.

Methods

Data from NSCLC patients medical records were retrospectively registered when treated with ICI between July 2016 and December 2018 at University Hospital Herlev and Rigshospitalet, Copenhagen, Denmark.

Results

In all 307 patients were treated with ICI – 85 patients received nivolumab and 222 pembrolizumab. Age ranged from 21 to 87 years, median 69. IMH was more common with pembrolizumab than with nivolumab (13% vs. 5%). There were 32 patients with grade 1-4 immune-related adverse events (irAEs) IMH (10 %), here off grade 1, 18 (56 %), grade 2, 6 (19 %), grade 3, 7 (22 %) and grade 4, 1 patient (3 %). Onset of raised transaminases ranged from 1-54 weeks, median 8. Time to normalization ranged from 2-464 days, median 24. In 24 patients with grade 1-2 the range was 2-256 days, median 24, until normalization; for grade 3-4 the range was 10-464, median 24. Half of the patients with grade 2 irAEs initiated treatment with steroids and 7 of 8 patients with grade 3-4 irAEs received immediately treatment with steroids. Steroid dose was on average 32 mg/day over a period of 1 year (range 1-32 months). The single patient with grade 4 irAEs also received treatment with mycophenolate mofetil however the transaminases never normalized. One patient with grad 3 irAEs received treatment with ursodeoxycholic acid and tacrolimus due to lack of improvement with steroids. Over a year passed before the transaminases normalized. This patient exclusively underwent liver biopsy which was diagnosed as autoimmune hepatitis. All patients with grade 3-4 had PD-L1 expression above 50% and all permanently discontinued ICI treatment.

Conclusion

Liver toxicity frequency correlates to findings in clinical trials (KEYNOTE-024 and KEYNOTE-042) and are mainly of grade 1. There was no correlation, in this dataset, between dose of steroids and time to normalizing of transaminases in patients treated with immunosuppressants.

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：

---

73P使用PD1抑制剂对丹麦肺癌患者进行免疫介导的肝炎的真实经验

抽象的

背景

有关接受免疫检查点抑制剂（ICI）治疗的患者在免疫介导性肝炎（IMH）治疗中对类固醇反应的信息有限。我们调查了307例患有晚期非小细胞肺癌（NSCLC）的丹麦肺癌患者的IMH事件，并回顾了IMH治疗的疗效。

方法

在2016年7月至2018年12月期间，在丹麦哥本哈根的Herlev大学和Rigshospitalet大学用ICI治疗时，对NSCLC患者病历的数据进行了回顾性注册。

结果

在全部307例接受ICI治疗的患者中，有85例接受了尼古鲁单抗和222种派姆单抗的治疗。年龄介于21岁至87岁之间，中位数为69岁。pembrolizumab的IMH较nivolumab的更为常见（13％比5％）。有32例1-4级免疫相关不良事件（irAEs）IMH（10％），其中1级，18级（56％），2级，6级（19％），3级，7级（22％） ）和4级，1名患者（3％）。转氨酶升高的发作时间为1-54周，中位数为8。恢复正常的时间范围为2-464天，中位数为24。在1-2级的24例患者中，该范围为2-256天，中位数24，直到恢复正常。对于3-4级，其范围为10-464，中位值为24。患有2级irAE的患者中有一半开始使用类固醇治疗，而3-4级irAE的8位患者中有7名立即接受了类固醇治疗。一年内（1-32个月），类固醇的平均剂量为32毫克/天。患有4级irAE的单例患者也接受了霉酚酸酯的治疗，但转氨酶从未正常化。一名患有3级irAE的患者因缺乏类固醇激素而接受了熊去氧胆酸和他克莫司的治疗。在转氨酶正常化之前已经过去了一年多的时间。该患者仅接受了肝活检，被诊断为自身免疫性肝炎。所有3-4级患者的PD-L1表达均超过50％，并且所有患者均永久停止ICI治疗。一名患有3级irAE的患者因缺乏类固醇激素而接受了熊去氧胆酸和他克莫司的治疗。在转氨酶正常化之前已经过去了一年多的时间。该患者仅接受了肝活检，被诊断为自身免疫性肝炎。所有3-4级患者的PD-L1表达均超过50％，并且所有患者均永久停止ICI治疗。一名患有3级irAE的患者因缺乏类固醇激素而接受了熊去氧胆酸和他克莫司的治疗。在转氨酶正常化之前已经过去了一年多的时间。该患者仅接受了肝活检，被诊断为自身免疫性肝炎。所有3-4级患者的PD-L1表达均超过50％，并且所有患者均永久停止ICI治疗。

结论

肝毒性频率与临床试验中的发现相关（KEYNOTE-024和KEYNOTE-042），且主要为1级。在该数据集中，类固醇的剂量与接受免疫抑制剂治疗的患者转氨酶正常化的时间之间没有相关性。

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。