KEYNOTE-006：黑色素瘤，派姆单抗优于伊匹单抗

Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)

派姆单抗与伊匹单抗用于晚期黑色素瘤的比较：一项多中心、随机、开放标签的3期研究（KEYNOTE-006）的最终总生存结果山东省肿瘤医院呼吸肿瘤内科张品良

Summary概要

Background背景

Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis.

3期KEYNOTE-006研究的中期分析显示，在晚期黑色素瘤患者中，总体和无进展生存期派姆单抗优于伊匹单抗。我们介绍最终的协议指定的生存分析。

Methods方法

In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralized, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319.

在这项多中心、开放标签、随机3期试验中，招募了来自16个国家（澳大利亚、奥地利、比利时、加拿大、智利、哥伦比亚、法国、德国、以色列、荷兰、新西兰、挪威、西班牙、瑞典、英国和美国）的87个学术机构、医院和癌症中心的患者。使用集中式计算机生成的分配方案将参与者随机分配（1∶1∶1）至派姆单抗两个剂量方案中的一个或伊匹单抗的一个剂量方案。治疗分配使用层内随机分组法。符合条件的患者至少18岁、东部肿瘤协作组（ECOG）功能状态0或1、按照实体瘤疗效评价标准（RECIST 1.1版）至少有一个可测量的病变、不能切除的Ⅲ或Ⅳ期黑色素瘤（不包括眼部黑色素瘤）以及既往最多1个全身治疗（不包括抗CTLA-4、PD-1或PD-L1药物）。次要入选标准稍后描述。排除有活跃的脑转移或需要全身类固醇的活动性自身免疫疾病患者。主要终点为总生存期（定义为从随机化到任何原因死亡的时间）。在第12周时由独立的审查中心按照RECIST 1.1版评价疗效，然后每6周1次直到第48周，之后每12周1次。每12周评估1次生存率，并在所有患者随访至少21个月后进行终期分析。对意向治疗人群（所有随机分配的患者）进行初步分析，并对接受治疗的人群进行安全性分析（所有随机分配至少接受了一次研究治疗的患者）。该分析的数据截止日期是2015年12月3日。本研究已在ClinicalTrials.gov注册，编号NCT01866319。

Findings发现

Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53–0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53–0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group.

在2013年9月18日和2014年3月3日期间，834例晚期黑色素瘤患者入组，随机分配至接受静脉注射派姆单抗每2周1次（n=279）、每3周1次（n=277）或静脉注射伊匹单抗每3周1次（伊匹单抗的4个剂量；n＝278）。派姆单抗2周组的1例患者和伊匹单抗组的22例患者撤回同意，未接受治疗。共有811例患者接受了至少一剂的研究治疗。中位随访时间为22.9个月。383例患者死亡。中位总生存期派姆单抗组均未达到，而伊匹单抗组为16.0个月（与伊匹单抗相比，每2周1次派姆单抗风险比[HR] 0.68，95%CI 0.53-0.87；p=0.0009，每3周1次者HR 0.68，0.53-0.86；p＝0.0008）。24个月的总生存率2周组为55%，3周组为55%，而伊匹单抗组为43%。

Interpretation判读

Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma.

KEYNOTE-006的中期分析结果证实，派姆单抗持续提供优于伊匹单抗的总生存，而派姆单抗的给药方案之间没有区别。这些结论进一步支持使用派姆单抗作为晚期黑色素瘤的标准治疗。