Stroud Chipman Rg, Hegde Aparna, Cherry Cynthia, Naqash Abdul R, Sharma Nitika, Addepalli Srikala, Cherukuri Sulochana, Parent Teresa, Hardin Jessica, Walker Paul
Department of Hematology Oncology, Leo Jenkins Cancer Center at East Carolina University, Greenville, USA.
J Oncol Pharm Pract. 2019 Apr;25(3):551-557. doi: 10.1177/1078155217745144. Epub 2017 Dec 5.
Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid refractory irAEs.
The character and clinical course of irAEs were abstracted from the medical record and analyzed. The dose of tocilizumab was 4 mg/kg given IV over one hour. C-reactive protein was drawn at first nivolumab infusion and at q two weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital discharge within seven days.
Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All patients were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, serum sickness/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). There was a statistically significant increase in C-reactive protein from a median of 23 mg/L (range 0.1-238.5) at baseline to 109.3 mg/L (21.5-350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25-149) after tocilizumab ( p < 0.00001). Clinical improvement was noted in 27/34 patients (79.4%). Some patients (52.9%) required a single dose, while 38.2% required two, 8.8% required three and 1 patient required four doses. Twenty-seven doses were given in the inpatient setting (49.1%). Median time to discharge was four days (range 1-27). Seventy-four percent of patients were discharged home. For the 53 doses of tocilizumab that were delivered when infliximab was an option, there was a cost savings of $141,048.72 (WAC) during the 18 month study period.
Tocilizumab may be a therapeutic option for the management of steroid refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.
免疫检查点抑制剂有望彻底改变越来越多恶性肿瘤的治疗方式。不幸的是，对于类固醇难治性免疫介导的不良事件的管理，基于缺乏随机数据，且仅限于单中心经验。我们使用白细胞介素-6受体拮抗剂托珠单抗的初步经验显示，在多种免疫相关不良事件（irAEs）中临床症状有所改善。因此，我们采用托珠单抗来治疗类固醇难治性irAEs。
从病历中提取irAEs的特征和临床过程并进行分析。托珠单抗的剂量为4mg/kg，静脉输注1小时。在首次输注纳武单抗时以及此后每两周（出现irAEs时）检测C反应蛋白。临床改善定义为以下两种情况之一：症状缓解的记录或在7天内出院。
在最初接受纳武单抗治疗的87例患者中，34例需要使用托珠单抗（39.1%）。所有患者均在使用皮质类固醇。大多数（88.2%）为肺癌患者。初始的3/4级irAE中，肺炎占35.3%，血清病/全身炎症反应综合征占35.3%，脑炎占14.7%，垂体炎、结肠炎、胰腺炎、肝炎和免疫介导的凝血病各1例。从首次使用纳武单抗到开始使用托珠单抗的中位时间为76天（范围1 - 429天）。C反应蛋白从基线时中位数23mg/L（范围0.1 - 238.5）在出现irAE时显著升高至109.3mg/L（21.5 - 350.4），随后在使用托珠单抗后降至19.2mg/L（0.25 - 149）（p < 0.00001）。27/34例患者（79.4%）出现临床改善。一些患者（52.9%）只需一剂，而38.2%需要两剂，8.8%需要三剂，1例患者需要四剂。27剂在住院环境中使用（49.1%）。中位出院时间为4天（范围1 - 27天）。74%的患者出院回家。在英夫利昔单抗可用的情况下，使用的53剂托珠单抗在18个月的研究期间节省了成本141,048.72美元（批发收购成本）。
托珠单抗可能是治疗免疫检查点阻断继发的类固醇难治性irAEs的一种治疗选择。然而，需要进行随机试验以更好地阐明这些药物的相对疗效和安全性。
