Larkin James, Chmielowski Bartosz, Lao Christopher D, Hodi F Stephen, Sharfman William, Weber Jeffrey, Suijkerbuijk Karijn P M, Azevedo Sergio, Li Hewei, Reshef Daniel, Avila Alexandre, Reardon David A
The Royal Marsden, London, United Kingdom
University of California Los Angeles Medical Center, Santa Monica, California, USA.
Oncologist. 2017 Jun;22(6):709-718. doi: 10.1634/theoncologist.2016-0487. Epub 2017 May 11.
Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management.
We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned.
In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy ( = 22), noninfective meningitis ( = 5), encephalitis ( = 6), neuromuscular disorders ( = 3), and nonspecific adverse events ( = 7). Study drug was discontinued ( = 20), interrupted ( = 8), or unchanged ( = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1-170) and to resolution was 32 days (2-809+). Median time to onset of encephalitis was 55.5 days (range 18-297); four cases resolved and one was fatal.
Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs.
With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.
尽管免疫检查点抑制剂疗法在多种肿瘤类型中展现出了前所未有的疗效，但它与一系列独特且广泛的免疫相关不良事件（irAEs）相关，包括从轻度头痛到可能危及生命的脑炎等神经系统事件。在此，我们总结了与纳武单抗和伊匹单抗治疗黑色素瘤相关的神经系统irAEs，呈现了治疗相关脑炎的病例，并提供了诊断和管理的实用指导。
我们在一个全球药物警戒和流行病学数据库中搜索了在12项由百时美施贵宝赞助的研究中，接受纳武单抗联合或不联合伊匹单抗治疗的晚期黑色素瘤患者在8年期间报告的神经系统irAEs。对严重神经系统irAEs进行了审查，并确定了其与纳武单抗或伊匹单抗的关系。
在对3763例患者的搜索中，35例患者（0.93%）出现了43例严重神经系统irAEs，包括神经病变（n = 22）、非感染性脑膜炎（n = 5）、脑炎（n = 6）、神经肌肉疾病（n = 3）和非特异性不良事件（n = 7）。研究药物停用（n = 20）、中断（n = 8）或未改变（n = 7）。大多数神经系统irAEs得到缓解（26/35例患者；75%）。总体而言，发病的中位时间为45天（范围1 - 170天），缓解的中位时间为32天（2 - 809 +天）。脑炎发病的中位时间为55.5天（范围18 - 297天）；4例缓解，1例死亡。
肿瘤学家和神经科医生都需要了解与检查点抑制剂相关的严重但不常见的神经系统irAEs的体征和症状。使用既定算法进行及时诊断和管理对于将这些神经系统irAEs的严重并发症降至最低至关重要。
随着检查点抑制剂在癌症治疗中的使用增加，执业肿瘤学家需要意识到神经系统免疫相关不良事件的潜在风险，并能够对这类不常见但可能严重的不良事件进行及时治疗。我们总结了12项研究中晚期黑色素瘤患者单独使用纳武单抗或与伊匹单抗联合使用时相关的神经系统不良事件，并深入研究了6例脑炎病例。我们还为现有的纳武单抗和伊匹单抗神经系统不良事件管理算法提供了意见和指导。
