Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.
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DOI：
10.1056/nejmoa1414428
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发表时间：
2015-05-21
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影响因子：
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通讯作者：
Hodi FS
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作者：
Postow MA;Chesney J;Pavlick AC;Robert C;Grossmann K;McDermott D;Linette GP;Meyer N;Giguere JK;Agarwala SS;Shaheen M;Ernstoff MS;Minor D;Salama AK;Taylor M;Ott PA;Rollin LM;Horak C;Gagnier P;Wolchok JD;Hodi FS
在一项 1 期剂量递增研究中，nivolumab 和 ipilimumab 对 T 细胞检查点通路的联合抑制显示出较高的客观缓解率，包括晚期黑色素瘤患者的完全缓解。在这项双盲研究中，142 名未接受治疗的转移性黑色素瘤患者按照 2:1 的比例随机分配，每 3 周接受 3 mg/kg 伊匹单抗联合 1 mg/kg 纳武单抗或安慰剂，共 4 剂，随后每 2 周接受 3 mg/kg 纳武单抗或安慰剂，直至疾病进展。主要终点是研究者评估的 BRAF 野生型患者的客观反应。在BRAF野生型患者中，纳武单抗和伊匹单抗联合治疗组的客观缓解率为61.1%（44/72），而伊匹单抗单药治疗组为10.8%（4/37）（P<0.001），联合组中有16名患者（22.2%）报告完全缓解； ipilimumab 组中没有。两种治疗均未达到中位缓解持续时间。联合用药未达到中位无进展生存期，而伊匹单抗单药治疗则为 4.4 个月（风险比 0.40，95% CI 0.23 至 0.68；P<0.001）。在 33 名 BRAF 突变阳性患者中也观察到类似的缓解和无进展生存结果。接受联合治疗的患者中有 54.3% 报告了 3-4 级药物相关不良事件，而接受伊匹单抗单药治疗的患者中这一比例为 23.9%。免疫学病因学的部分不良事件与 1 期报告一致，并且大多数通过免疫调节药物得到解决。与伊匹单抗单药治疗相比，纳武单抗联合伊匹单抗显着改善了初治晚期黑色素瘤患者的客观缓解率和无进展生存期，并且具有可控的安全性。 （ClinicalTrials.gov 编号，NCT01927419）
In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab demonstrated a high objective response rate, including complete responses in patients with advanced melanoma. In this double-blind study, 142 treatment-naïve patients with metastatic melanoma were randomized 2:1 to receive ipilimumab 3 mg/kg combined with either nivolumab 1 mg/kg or placebo every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg or placebo every 2 weeks until disease progression. The primary endpoint was investigator-assessed objective response in BRAF wild-type patients. Among BRAF wild-type patients, the confirmed objective response rate was 61.1% (44/72) in the nivolumab and ipilimumab combination group versus 10.8% (4/37) in the ipilimumab monotherapy group (P<0.001), with complete responses reported in 16 (22.2%) patients in the combination group; none in the ipilimumab group. Median duration of response was not reached with either treatment. Median progression-free survival was not reached for the combination versus 4.4 months for ipilimumab monotherapy (hazard ratio 0.40, 95% CI 0.23 to 0.68; P<0.001). Similar results for response and progression-free survival were also observed in 33 BRAF mutation-positive patients. Grade 3–4 drug-related adverse events were reported in 54.3% of patients receiving the combination compared with 23.9% with ipilimumab monotherapy. Select adverse events of immunological etiology were consistent with phase 1 reports, and most resolved with immune-modulating medication. Nivolumab combined with ipilimumab significantly improved objective response rate and progression-free survival compared with ipilimumab monotherapy in treatment-naïve patients with advanced melanoma, and had a manageable safety profile. (ClinicalTrials.gov number, NCT01927419)