Abstract

Background

Immune checkpoint inhibitors (ICIs) are key in the treatment of advanced non-small cell lung cancer (NSCLC). However, there is a paucity of large real-world case series on timing and severity of immune-related adverse events (irAEs) that could inform treatment service provision.

Methods

A retrospective study of patients with advanced NSCLC treated with ICIs at The Clatterbridge Cancer Centre between 2016 and 2018 was conducted to review irAEs in the context of therapeutic efficacy. Kaplan Meier analysis, Mann-Whitney and chi-squared tests were used.

Results

303 patients were identified. Median age was 68 years; 83 patients (27%) had a performance status (PS) of 0; 85 (28%) had an ACE-27 comorbidity score ≥2. 277 (91%) had pembrolizumab (107 (35%) first line), 21 (7%) nivolumab and 5 (2%) atezolizumab. Median number of cycles was 6 (range 1-29). Median progression-free and overall survival (PFS/OS) were 5.0 and 10.0 months. IrAEs were reported in 40% of patients and 13% experienced multiple irAEs; 11% were ≥G3. The most common irAEs were dermatitis (12%), dysthyroidism (9%), colitis (6%), hepatitis (5%), arthralgia (5%), pneumonitis (5%); the most common ≥G3 irAEs were pneumonitis (3%), hepatitis (2%) and colitis (2%). Treatment was discontinued due to irAEs in 12% of patients. Median time to irAEs onset by system involved varied between 46 days (hyperthyroidism) and 122 days (arthralgia). There was no association between irAEs and age (p = 0.16), PS (p = 0.46), or ACE-27 score (p = 0.68). 83% of irAEs occurred within 6 months of initiating ICIs; no clear correlation between irAEs incidence and time on treatment was found. Patients with irAEs within 6 months of treatment had longer PFS (7.1 vs. 3.9 months, HR 0.70, p = 0.014) and OS (15.6 vs. 7.7 months, HR 0.48, p < 0.001) than those without irAEs. Notably, patients experiencing irAEs ≥G2 within the first 21 days of treatment had poorer clinical outcomes than those with later irAEs (median PFS 2.9 vs 10.3 months, p < 0.001; median OS 5.9 vs. 20.3 months, p = 0.001).

Conclusion

In our large real-world retrospective cohort study the incidence of irAEs reflected that seen in clinical trials. There appears to be a toxicity-efficacy relationship with irAEs; however, larger studies are required to validate this.

Legal entity responsible for the study

The Clatterbridge Cancer Centre NHS Foundation Trust.

Funding

Has not received any funding.

Disclosure

A.C. Olsson-Brown: Honoraria (self): MSD; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (self): Eli Lily; Research grant / Funding (self): Novartis. C. Escriu: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Boeringher Ingelheim; Speaker Bureau / Expert testimony: Pfizer. All other authors have declared no conflicts of interest.

中文翻译：

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NSCLC中的75P免疫相关毒性：三级癌症中心的真实经验

抽象的

背景

免疫检查点抑制剂（ICIs）是晚期非小细胞肺癌（NSCLC）治疗的关键。但是，关于免疫相关不良事件（irAEs）的时间和严重程度的大型现实案例系列很少，可能会为治疗服务的提供提供信息。

方法

于2016年至2018年间，在The Clatterbridge Cancer Center进行了一项针对ICI治疗的晚期NSCLC患者的回顾性研究，以从治疗效果的角度审查irAEs。使用Kaplan Meier分析，Mann-Whitney和卡方检验。

结果

确定了303例患者。中位年龄为68岁。83名患者（27％）的表现状态（PS）为0；85（28％）的ACE-27合并症评分≥2。277（91％）的患者接受pembrolizumab（107（35％）的第一线），21（7％）的nivolumab和5（2％）的atezolizumab。周期中位数为6（范围为1-29）。中位无进展生存期和总生存期（PFS / OS）分别为5.0和10.0个月。据报道，有40％的患者患有IrAEs，有13％的患者患有多种irAEs。≥G3为11％。最常见的irAE是皮炎（12％），甲状腺功能减退（9％），结肠炎（6％），肝炎（5％），关节痛（5％），肺炎（5％）；最常见的≥G3irAE是肺炎（3％），肝炎（2％）和结肠炎（2％）。12％的患者由于irAE终止治疗。由系统引起的irAE发作的中位时间在46天（甲状腺功能亢进）和122天（关节痛）之间变化。irAEs与年龄（p = 0.16），PS（p = 0.46）或ACE-27评分（p = 0.68）之间没有关联。83％的irAE在启动ICI后的6个月内发生；没有发现irAEs发生率与治疗时间之间有明确的相关性。与不使用irAE的患者相比，在治疗后6个月内患有irAE的患者的PFS（7.1比3.9个月，HR 0.70，p = 0.014）和OS（15.6对7.7个月，HR 0.48，p <0.001）更长。值得注意的是，在治疗的前21天内出现irAE≥G2的患者的临床结局要比后来的irAE差（中位PFS 2.9比10.3个月，p <0.001；中位OS 5.9比20.3个月，p = 0.001）。没有发现irAEs发生率与治疗时间之间有明确的相关性。与不使用irAE的患者相比，在治疗后6个月内患有irAE的患者的PFS（7.1比3.9个月，HR 0.70，p = 0.014）和OS（15.6对7.7个月，HR 0.48，p <0.001）更长。值得注意的是，在治疗的前21天内出现irAE≥G2的患者的临床结局要比后来的irAE差（中位PFS 2.9比10.3个月，p <0.001；中位OS 5.9比20.3个月，p = 0.001）。没有发现irAEs发生率与治疗时间之间有明确的相关性。与没有irAEs的患者相比，在治疗6个月内患有irAEs的患者的PFS（7.1 vs. 3.9个月，HR 0.70，p = 0.014）和OS（15.6 vs. 7.7个月，HR 0.48，p <0.001）更长。值得注意的是，在治疗的前21天内出现irAE≥G2的患者的临床结局要比后来的irAE差（中位PFS 2.9比10.3个月，p <0.001；中位OS 5.9比20.3个月，p = 0.001）。001; 中位操作系统5.9和20.3个月，p = 0.001）。001; 中位操作系统5.9和20.3个月，p = 0.001）。

结论

在我们的大型真实世界回顾性队列研究中，irAEs的发生率反映了在临床试验中看到的情况。irAEs似乎具有毒性-功效关系；但是，需要更大的研究来验证这一点。

负责研究的法人实体

克拉特布里奇癌症中心NHS基金会信托基金。

资金

尚未收到任何资金。

揭露

AC Olsson-Brown：Honoraria（个体）：MSD；酬金（个体经营），研究资助/资助（个体经营）：罗氏；Honoraria（个体经营），咨询/顾问：Bristol-Myers Squibb；研究补助金/资金（个体经营）：Eli Lily；研究资助/资助（个体）：诺华。C. Escriu：咨询/顾问，发言人局/专家证词，研究补助金/资金（自己）：阿斯利康；咨询/顾问：MSD；发言人办公室/专家证词：百时美施贵宝（Bristol-Myers Squibb）；咨询/顾问，研究资助/资助（自己）：Boeringher Ingelheim；发言人办公室/专家证词：辉瑞公司。所有其他作者都声明没有利益冲突。