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Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study
Journal of Clinical Oncology ( IF 45.3 ) Pub Date : 2018-02-01 , DOI: 10.1200/jco.2017.72.2850
Margaret K. Callahan 1 , Harriet Kluger 1 , Michael A. Postow 1 , Neil H. Segal 1 , Alexander Lesokhin 1 , Michael B. Atkins 1 , John M. Kirkwood 1 , Suba Krishnan 1 , Rafia Bhore 1 , Christine Horak 1 , Jedd D. Wolchok 1 , Mario Sznol 1
Affiliation  

Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

中文翻译:

Nivolumab 加 Ipilimumab 用于晚期黑色素瘤患者:更新的 I 期剂量递增研究中的生存、反应和安全性数据

目的 在先前治疗或未治疗的晚期黑色素瘤患者中使用纳武单抗 (NIVO) 和易普利姆玛 (IPI) 进行同步治疗的 I 期剂量递增研究中观察到的临床活性导致了后续的临床开发,包括随机试验。在这里,我们报告了 CA209-004 研究的长期随访数据,包括 3 年总生存率 (OS)。患者和方法 同时队列 1、2、2a 和 3 接受递增剂量的 NIVO 加 IPI 每 3 周一次,共四剂,然后是每 3 周一次 NIVO 一次,共四剂,然后每 12 周一次 NIVO 加 IPI,共八剂. 一个扩展队列(队列 8)同时接受 NIVO 1 mg/kg 加 IPI 3 mg/kg,每 3 周一次,共四剂,然后是每 2 周一次 NIVO 3 mg/kg,这是 II 期和 III 期研究中使用的剂量和时间表,现已批准用于不可切除或转移性黑色素瘤患者。结果 在所有并发队列(N = 94)中,随访 30.3 至 55.0 个月,3 年 OS 率为 63%,中位 OS 尚未达到。根据修订后的 WHO 标准,客观缓解率为 42%,中位缓解持续时间为 22.3 个月。3 级和 4 级治疗相关不良事件的发生率为 59%。最常见的 3 级和 4 级治疗相关不良事件是脂肪酶 (15%)、丙氨酸转氨酶 (12%) 和天冬氨酸转氨酶 (11%) 升高。在最后一剂 NIVO 加 IPI 后 70 天出现多器官衰竭的患者中发生了 1 例治疗相关死亡 (1.1%)。结论 NIVO+IPI联合治疗晚期黑色素瘤患者随访时间最长。63% 的 3 年 OS 率是在该患者群体中观察到的最高值,并为免疫检查点抑制剂在治疗晚期黑色素瘤中的持久临床活性提供了额外的证据。
更新日期:2018-02-01
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