Pembrolizumab versus Ipilimumab in Advanced Melanoma
Pembrolizumab versus Ipilimumab in Advanced Melanoma
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DOI：
10.1056/nejmoa1503093
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发表时间：
2015-06-25
影响因子：
158.5
通讯作者：
Ribas, Antoni
中科院分区：
文献类型：
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作者：
Robert, Caroline;Schachter, Jacob;Ribas, Antoni
免疫检查点抑制剂ipilimumab是晚期黑色素瘤患者的标准治疗。Pembrolizumab抑制程序性细胞死亡1（PD-1）免疫检查点，在晚期黑素瘤患者中具有抗肿瘤活性。1例患者接受帕博利珠单抗治疗每2周或每3周施用一次伊匹单抗（剂量为10 mg/kg体重）或每3周施用四次伊匹单抗（剂量为3 mg/kg）。Pembrolizumab每2周一次治疗的6个月无进展生存率估计为47.3%，Pembrolizumab每3周一次治疗的6个月无进展生存率估计为46.4%，ipilimumab每3周一次治疗的6个月无进展生存率估计为26.5（疾病进展的风险比，0.58;两种帕博利珠单抗方案与伊匹单抗相比P< 0.001; 95%置信区间[CI]，分别为0.46 - 0.72和0.47 - 0.72）。估计的12个月生存率分别为74.1%、68.4%和58.2%（帕博利珠单抗每2周一次组的死亡风险比为0.63; 95% CI为0.47至0.83; P = 0.0005;帕博利珠单抗每3周一次组的风险比为0.69; 95% CI为0.52至0.90; P = 0.0036）。与ipilimumab（11.9%）相比，每2周（33.7%）和每3周（32.9%）给药一次的pembrolizumab的缓解率有所改善（两种比较均为P< 0.001）。中位随访7.9个月后，分别有89.4%、96.7%和87.9%的患者的缓解仍在持续。两个Pembrolizumab组的疗效相似。与ipilimumab组相比，pembrolizumab组治疗相关的3 - 5级不良事件发生率分别为13.3%和10.1%（P <0.01），而ipilimumab组为19.9%（P <0.01）。
BACKGROUNDThe immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma.METHODSIn this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1: 1: 1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival.RESULTSThe estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P< 0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P = 0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P = 0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P< 0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).CONCLUSIONSThe anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma.