Dana-Farber Cancer Institute, Boston, MA 02115, USA.
N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466. Epub 2010 Jun 5.
BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
背景：转移性黑色素瘤患者的总生存改善一直是一个难以实现的目标。在这项 3 期研究中，与单独使用 gp100 肽疫苗相比，阻断细胞毒性 T 淋巴细胞相关抗原 4 以增强抗肿瘤 T 细胞反应的伊匹单抗联合或不联合 gp100 用于治疗先前治疗过的转移性黑色素瘤患者。
方法：共有 676 名 HLA-A*0201 阳性的不可切除 III 期或 IV 期黑色素瘤患者，其疾病在转移性疾病治疗过程中进展，按 3:1:1 的比例随机分配接受伊匹单抗联合 gp100（403 例）、伊匹单抗单药（137 例）或 gp100 单药（136 例）治疗。伊匹单抗剂量为 3mg/kg，每 3 周使用一次，最多进行 4 次治疗（诱导）。符合条件的患者可接受再诱导治疗。主要终点是总生存。
结果：接受伊匹单抗联合 gp100 治疗的患者中位总生存时间为 10.0 个月，而接受 gp100 单药治疗的患者为 6.4 个月（死亡风险比，0.68；P<0.001）。伊匹单抗单药治疗的中位总生存时间为 10.1 个月（与 gp100 单药相比，死亡风险比为 0.66；P=0.003）。伊匹单抗组之间的总生存无差异（伊匹单抗联合 gp100 组的风险比为 1.04；P=0.76）。接受伊匹单抗治疗的患者中有 10%至 15%发生 3 级或 4 级免疫相关不良事件，而单独接受 gp100 治疗的患者中有 3%发生。有 14 例与研究药物相关的死亡（2.1%），其中 7 例与免疫相关不良事件相关。
结论：与单独使用 gp100 肽疫苗相比，伊匹单抗联合或不联合 gp100 可改善先前治疗的转移性黑色素瘤患者的总生存。不良事件可能严重、持久或两者兼而有之，但大多数可通过适当治疗逆转。（由 Medarex 和 Bristol-Myers Squibb 资助；ClinicalTrials.gov 编号，NCT00094653。）
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