Angeles Clinic and Research Institute, Los Angeles, CA, USA.
N Engl J Med. 2013 Jul 11;369(2):134-44. doi: 10.1056/NEJMoa1305133. Epub 2013 Jun 2.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).
背景：程序性死亡受体 1（PD-1）是 T 细胞效应机制的负调节剂，可限制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）。
方法：我们以每公斤体重 10 毫克的剂量静脉内给予 lambrolizumab，每 2 或 3 周一次，或以每公斤体重 2 毫克的剂量每 3 周一次，用于治疗晚期黑色素瘤患者，包括先前接受免疫检查点抑制剂 ipilimumab 治疗和未接受治疗的患者。每 12 周评估一次肿瘤反应。
结果：共有 135 名晚期黑色素瘤患者接受了治疗。归因于治疗的常见不良事件是疲劳、皮疹、瘙痒和腹泻；大多数不良事件为低级别。根据实体瘤反应评价标准（RECIST）1.1 版，通过中央放射学评估，所有剂量组的确认缓解率为 38%（95%置信区间[CI]，25 至 44），其中接受每 2 周 10 毫克/公斤的队列观察到的最高确认缓解率为 52%（95%CI，38 至 66）。在先前接受过 ipilimumab 治疗的患者和未接受过 ipilimumab 治疗的患者之间，缓解率无显著差异（确认缓解率分别为 38%[95%CI，23 至 55]和 37%[95%CI，26 至 49]）。在大多数患者中，应答是持久的（应答患者的中位随访时间为 11 个月）；在 2013 年 3 月分析时，81%的应答患者（42/52）仍在接受治疗。135 名患者的中位无进展生存期均长于 7 个月。
结论：在晚期黑色素瘤患者中，包括那些在接受 ipilimumab 治疗时疾病进展的患者，lambrolizumab 治疗导致肿瘤持续消退，主要为 1 级或 2 级毒性作用。（由默克公司资助；ClinicalTrials.gov 编号，NCT01295827。）
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