Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France.
J Clin Oncol. 2017 Mar;35(7):785-792. doi: 10.1200/JCO.2015.66.1389. Epub 2016 Nov 14.
Purpose We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines. Patients and Methods Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy. Results Among 576 patients, 71% (95% CI, 67% to 75%) experienced any-grade treatment-related AEs (most commonly fatigue [25%], pruritus [17%], diarrhea [13%], and rash [13%]), and 10% (95% CI, 8% to 13%) experienced grade 3 to 4 treatment-related AEs. No drug-related deaths were reported. Select AEs (occurring in 49% of patients) were most frequently skin related, GI, endocrine, and hepatic; grade 3 to 4 select AEs occurred in 4% of patients. Median time to onset of select AEs ranged from 5 weeks for skin to 15 weeks for renal AEs. Approximately 24% of patients received systemic IMs to manage select AEs, which in most cases resolved. Adjusting for number of doses, objective response rate (ORR) was significantly higher in patients who experienced treatment-related select AEs of any grade compared with those who did not. ORRs were similar in patients who did and patients who did not receive systemic IMs. Conclusion Treatment-related AEs with nivolumab monotherapy were primarily low grade, and most resolved with established safety guidelines. Use of IMs did not affect ORR, although treatment-related select AEs of any grade were associated with higher ORR, but no progression-free survival benefit.
我们进行了一项回顾性分析，以评估纳武利尤单抗单药治疗晚期黑色素瘤患者的安全性概况，并根据既定的安全性指南描述不良反应（AE）的管理情况。
安全性数据来自四项研究的汇总，包括两项 III 期试验，纳入接受纳武利尤单抗 3mg/kg 每 2 周一次治疗的患者。我们评估了治疗相关 AE 的发生率、特定 AE（具有潜在免疫病因的 AE）的发生时间和缓解时间，以及特定 AE 和抑制性免疫调节药物（IMs）对抗肿瘤疗效的影响。
在 576 例患者中，71%（95%CI，67%至 75%）发生任何级别治疗相关 AE（最常见的是疲劳[25%]、瘙痒[17%]、腹泻[13%]和皮疹[13%]），10%（95%CI，8%至 13%）发生 3 至 4 级治疗相关 AE。未报告药物相关死亡。特定 AE（49%的患者发生）最常发生于皮肤、胃肠道、内分泌和肝脏；4%的患者发生 3 至 4 级特定 AE。特定 AE 的中位发生时间从皮肤的 5 周到肾脏 AE 的 15 周不等。约 24%的患者接受全身 IMs 治疗特定 AE，大多数情况下 AE 缓解。在调整了剂量数后，发生任何级别治疗相关特定 AE 的患者的客观缓解率（ORR）显著高于未发生 AE 的患者。发生和未发生全身 IMs 的患者的 ORR 相似。
纳武利尤单抗单药治疗的治疗相关 AE 主要为低级别，且大多数采用既定安全性指南可缓解。IMs 的使用并未影响 ORR，尽管任何级别治疗相关特定 AE 与更高的 ORR 相关，但无无进展生存期获益。
