Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma
Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma
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DOI：
10.1001/jamaoncol.2021.0051
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发表时间：
2021-03-25
期刊：
影响因子：
28.4
通讯作者：
Johnson, Douglas B.
中科院分区：
文献类型：
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作者：
Patrinely, J. Randall, Jr.;Johnson, Rebecca;Johnson, Douglas B.
靶向程序性细胞死亡1（PD-1）/PD配体1（PD-L1）的药物可改善许多晚期癌症的长期生存率，目前被用作切除的III期和IV期黑色素瘤的辅助治疗。慢性免疫相关不良事件（irAE）的发病率和谱尚未得到很好的defined.Objective确定的发病率，时间过程，谱，和协会的慢性irAE所产生的辅助抗PD-1 therapeutic.DESIGN，SETTING，AND PARTICIPANTS这一回顾性多中心队列研究进行了2015年和2020年之间在美国和澳大利亚的8个学术医疗中心。III期至IV期黑色素瘤患者接受抗PD-1辅助治疗包括在内。主要结果和指标慢性irAE（定义为治疗停止后持续至少12周的irAE）的发病率、类型和时程。结果在387例患者中，中位（范围）年龄为63（17-88）岁，235（60.7%）例为男性。在这些患者中，267例（69.0%）发生任何急性irAE，定义为抗PD-1治疗期间发生的事件，包括52例（19.5%）发生3 - 5级事件;各有1例患者发生致死性心肌炎和神经毒性。167例（43.2%）患者发生了慢性irAE（定义为持续超过抗PD-1停药12周的事件），其中大多数（n = 161; 96.4%）为轻度（1级或2级），大多数持续至末次随访（n = 143; 85.6%）。内分泌疾病（73/88; 83.0%）、关节炎（22/45; 48.9%）、口干症（9/17; 52.9%）、神经毒性（11/15; 73.3%）和眼部事件（5/8; 62.5%）特别可能变为慢性。相比之下，影响内脏器官（肝脏、结肠、肺、肾脏）的irAE变为慢性irAE的比率要低得多;例如，44例病例中有6例（13.6%）结肠炎变为慢性，其中6例病例中有4例（66.7%）在长期随访后消退。年龄，性别，发病时间，需要类固醇与慢性irAEs.CONCLUSION和RELEVANCE的可能性无关在这个多中心队列研究中，慢性irAEs与抗PD-1治疗似乎是更常见的比以前认识到，并经常坚持，即使长期随访，虽然大多数是低级别。应将慢性irAE的风险纳入治疗决策。
IMPORTANCE Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined.OBJECTIVE To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy.DESIGN, SETTING, AND PARTICIPANTS This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included.MAIN OUTCOMES AND MEASURES Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation).RESULTS Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs.CONCLUSION AND RELEVANCE In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.