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Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609
Journal of Clinical Oncology ( IF 45.3 ) Pub Date : 2020-02-20 , DOI: 10.1200/jco.19.01381
Ahmad A Tarhini 1 , Sandra J Lee 2, 3 , F Stephen Hodi 3 , Uma N M Rao 4 , Gary I Cohen 5 , Omid Hamid 6 , Laura F Hutchins 7 , Jeffrey A Sosman 8 , Harriett M Kluger 9 , Zeynep Eroglu 1 , Henry B Koon 10 , Donald P Lawrence 11 , Kari L Kendra 12 , David R Minor 13 , Carrie B Lee 14 , Mark R Albertini 15 , Lawrence E Flaherty 16 , Teresa M Petrella 17 , Howard Streicher 18 , Vernon K Sondak 1 , John M Kirkwood 4
Affiliation  

PURPOSE Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI. PATIENTS AND METHODS E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI. RESULTS Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti-programmed death 1 use in the HDI arm versus ipi3 and ipi10 (P ≤ .001). CONCLUSION Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.

中文翻译:

辅助 Ipilimumab(3 或 10 mg/kg)与高剂量干扰素 Alfa-2b 治疗高危黑色素瘤切除的 III 期研究:北美组间 E1609

目的 III 期辅助试验报告了 10 mg/kg 的高剂量干扰素 α (HDI) 和易普利姆玛 (ipi10) 在无复发生存期 (RFS) 和总生存期 (OS) 方面的显着益处。E1609 评估了 3 mg/kg (ipi3) 和 ipi10 与 HDI 的 ipilimumab 的安全性和有效性。患者和方法 E1609 是一项针对切除皮肤黑色素瘤患者的 III 期试验(美国癌症联合委员会第 7 版 IIIB、IIIC、M1a 或 M1b 期)。它有 2 个共同终点:OS 和 RFS。两步分层方法首先评估了 ipi3 与 HDI,然后是 ipi10 与 HDI。结果 2011 年 5 月至 2014 年 8 月期间,1,670 名成年患者被集中随机分配 (1:1:1) 至 ipi3 (n = 523)、HDI (n = 636) 或 ipi10 (n = 511)。37% 接受 ipi3 的患者发生 ≥ 3 级的治疗相关不良事件,79% 接受 HDI,58% 接受 ipi10,不良事件导致治疗中止的比例分别为 35%、20% 和 54%。ipi3 与 HDI 的比较使用了对同时随机分配的患者病例 (n = 1,051) 的意向治疗分析,并显示有显着的 OS 差异有利于 ipi3(风险比 [HR],0.78;95.6% 重复 CI,0.61 至 0.99 ;P = .044;RFS:HR,0.85;99.4% CI,0.66 至 1.09;P = .065)。在第二步中,对于 ipi10 与 HDI(n = 989),有利于 ipi10 的趋势没有达到统计学意义。黑色素瘤复发后的挽救模式显示,与 ipi3 和 ipi10 相比,HDI 组中易普利姆玛和易普利姆玛/抗程序性死亡 1 的使用率显着高于 ipi3 和 ipi10(P ≤ .001)。结论 与 HDI 相比,ipi3 的辅助治疗有益于生存;据我们所知,在黑色素瘤辅助治疗中,E1609 首次显示出相对于主动控制方案的 OS 显着改善。目前批准的辅助 ipilimumab 剂量 (ipi10) 毒性更大,疗效并不优于 HDI。
更新日期:2020-02-20
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