Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
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DOI：
10.1056/nejmoa1305133
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发表时间：
2013-07-11
期刊：
影响因子：
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通讯作者：
Ribas A
中科院分区：
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作者：
Hamid O;Robert C;Daud A;Hodi FS;Hwu WJ;Kefford R;Wolchok JD;Hersey P;Joseph RW;Weber JS;Dronca R;Gangadhar TC;Patnaik A;Zarour H;Joshua AM;Gergich K;Elassaiss-Schaap J;Algazi A;Mateus C;Boasberg P;Tumeh PC;Chmielowski B;Ebbinghaus SW;Li XN;Kang SP;Ribas A
程序性死亡1（PD-1）受体是T细胞效应机制的负调节因子，限制了针对癌症的免疫反应。我们在晚期黑色素瘤患者中测试了抗PD-1抗体lambrolizumab（以前称为MK-3475）。我们在晚期黑色素瘤患者中静脉注射lambrolizumab，剂量为每公斤体重10 mg，每2或3周一次，或每公斤体重2 mg，每3周一次，这些患者既往接受过免疫检查点抑制剂ipilimumab治疗，而那些没有接受过治疗。每12周评估一次肿瘤缓解。共治疗了135例晚期黑色素瘤患者。治疗引起的常见不良事件为疲乏、皮疹、瘙痒和腹泻;大多数不良事件为低度。根据实体瘤疗效评价标准（RECIST）第1.1版，通过中心放射学审查评价，所有剂量队列的确认缓解率为38%（95%置信区间[CI]，25 - 44），在每2周一次接受10 mg/kg剂量的队列中观察到最高的确认应答率（52%; 95% CI，38 - 66）。既往接受过ipilimumab治疗的患者和未接受过ipilimumab治疗的患者之间的缓解率无显著差异（确认缓解率分别为38% [95%CI，23 - 55]和37% [95%CI，26 - 49]）。大多数患者的缓解是持久的（中位随访时间，缓解患者为11个月）;在2013年3月分析时，81%的缓解患者（52例中的42例）仍在接受治疗。135例患者的总体中位无进展生存期超过7个月。在晚期黑色素瘤患者中，包括那些在接受伊匹单抗治疗时疾病进展的患者，lambrolizumab治疗导致持续肿瘤消退率高，主要是1级或2级毒性作用。（由Merck Sharp和Dohme资助; ClinicalTrials.gov编号，NCT 01295827。）
The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti–PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma. We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks. A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.)