Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma
Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma
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DOI：
10.1001/jama.2016.4059
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发表时间：
2016-04-19
影响因子：
120.7
通讯作者：
Robert, Caroline
中科院分区：
文献类型：
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作者：
Ribas, Antoni;Hamid, Omid;Robert, Caroline
重要性 程序性死亡 1 (PD-1) 通路限制了对黑色素瘤的免疫反应，可以用人源化抗 PD-1 单克隆抗体派姆单抗 (pembrolizumab) 阻断。 目的 表征派姆单抗 (pembrolizumab) 与晚期黑色素瘤患者的肿瘤反应和总体生存率之间的关系。 设计、设置和参与者 开放标签、多队列、1b 期临床试验（入组、 2011 年 12 月至 2013 年 9 月）。中位随访时间为 21 个月。该研究是在澳大利亚、加拿大、法国和美国的学术医疗中心进行的。符合资格的患者年龄在 18 岁及以上，患有晚期或转移性黑色素瘤。数据汇集了 655 名入组患者（其中 135 名患者来自非随机队列 [n = 87 例未接受伊匹单抗治疗；n = 48 例接受过伊匹单抗治疗]，520 名患者来自随机队列 [n = 226 例未接受过伊匹单抗治疗；n = 294 例接受过伊匹单抗治疗]）。安全性分析的截止日期为 2014 年 4 月 18 日，有效性分析的截止日期为 2014 年 10 月 18 日。 暴露 帕博利珠单抗每 2 周 10 mg/kg、每 3 周 10 mg/kg 或每 3 周 2 mg/kg，持续直至疾病进展、不可耐受的毒性或研究者决定。 主要结果和措施 主要终点是确认的客观缓解率（最佳总体缓解率）完整响应或部分响应 根据独立中央审查，基线时患有可测量疾病的患者的反应）。次要终点包括毒性、缓解持续时间、无进展生存期和总生存期。 结果 在 655 名患者（中位年龄 [范围] 61 [18-94] 岁；405 [62%] 男性）中，581 名患者在基线时患有可测量的疾病。 581 名患者中的 194 名（33% [95% CI，30%-37%]）和 133 名初治患者中的 60 名（45% [95% CI，36% 至 54%]）报告了客观缓解。总体而言，在数据截止时，74% (152/205) 的答复仍在进行中； 44% (90/205) 的患者的缓解持续时间至少为 1 年，79% (162/205) 的患者的缓解持续时间至少为 6 个月。总人群的 12 个月无进展生存率为 35%（95% CI，31%-39%），初治患者的 12 个月无进展生存率为 52%（95% CI，43%-60%）。总人群的中位总生存期为 23 个月（95% CI，20-29），12 个月生存率为 66%（95% CI，62%-69%），24 个月生存率为 49%（95% CI，44%-53%）。在初治患者中，中位总生存期为 31 个月（95% CI，24 个月至未达到），12 个月生存率为 73%（95% CI，65%-79%），24 个月生存率为 60%（95% CI，51%-68%）。 655 名患者中的 92 名 (14%) 经历了至少 1 次治疗相关的 3 级或 4 级不良事件 (AE)，655 名患者中的 27 名 (4%) 因治疗相关的 AE 停止了治疗。 59 名患者 (9%) 报告了与治疗相关的严重 AE。没有发生与药物相关的死亡。 结论和相关性 在晚期黑色素瘤患者中，派姆单抗给药与 33% 的总体客观缓解率、35% 的 12 个月无进展生存率以及 23 个月的中位总生存期相关。 14% 发生 3 级或 4 级治疗相关 AE。
IMPORTANCE The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab.OBJECTIVE To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma.DESIGN, SETTINGS, AND PARTICIPANTS Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses.EXPOSURES Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision.MAIN OUTCOMES AND MEASURES The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival.RESULTS Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35%(95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths.CONCLUSIONS AND RELEVANCE Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%.