Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
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DOI：
10.1056/nejmoa1504030
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发表时间：
2015-07-02
期刊：
影响因子：
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通讯作者：
Wolchok JD
中科院分区：
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作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
1期和2期研究结果表明，纳武利尤单抗（一种程序性死亡受体1[PD - 1]检查点抑制剂）和伊匹木单抗（一种细胞毒性T淋巴细胞相关抗原4[CTLA - 4]检查点抑制剂）在转移性黑色素瘤中具有互补活性。在这项随机、双盲的3期研究中，对转移性黑色素瘤患者分别评估了纳武利尤单抗单药、纳武利尤单抗联合伊匹木单抗以及伊匹木单抗单药的疗效。
我们将945例既往未经治疗的不可切除的Ⅲ期或Ⅳ期黑色素瘤患者按1∶1∶1的比例随机分组，分别接受纳武利尤单抗单药治疗（每2周3毫克/千克体重），或纳武利尤单抗（1毫克/千克剂量）联合伊匹木单抗（3毫克/千克剂量）治疗，每3周给药1次，共4次，之后给予纳武利尤单抗（每2周3毫克/千克），或伊匹木单抗单药治疗（每3周3毫克/千克，共4次）。无进展生存期和总生存期是共同主要终点。患者继续接受总生存期随访。
纳武利尤单抗联合伊匹木单抗组的中位无进展生存期为11.5个月（95%置信区间[CI]，8.9 - 16.7），而伊匹木单抗单药组为2.9个月（95%CI，2.8 - 3.4）（风险比，0.42；95%CI，0.31 - 0.57；P < 0.00001），纳武利尤单抗单药组为6.9个月（95%CI，4.3 - 9.5）（与伊匹木单抗单药组相比的风险比，0.57；95%CI，0.43 - 0.76；P < 0.00001）。在程序性死亡配体1（PD - L1）阳性患者中，纳武利尤单抗联合伊匹木单抗组和纳武利尤单抗单药组的中位无进展生存期均为14.0个月，但在PD - L1阴性患者中，联合用药组的无进展生存期比纳武利尤单抗单药组长（11.2个月[95%CI，8.0 - 未达到]对比5.3个月[95%CI，2.8 - 7.1]）。纳武利尤单抗组、纳武利尤单抗联合伊匹木单抗组和伊匹木单抗单药组中分别有16.3%、55.0%和27.3%的患者发生3 - 4级药物相关不良事件，分别有1例、0例和1例药物相关死亡。
在既往未经治疗的转移性黑色素瘤患者中，与伊匹木单抗相比，纳武利尤单抗单药或联合伊匹木单抗显著改善了无进展生存期。联合用药与单药相比的结果表明，PD - 1和CTLA - 4阻断之间具有互补活性，特别是对于PD - L1阴性肿瘤患者。（由百时美施贵宝资助；CheckMate 067，ClinicalTrials.gov编号，NCT01844505）
The results of phase 1 and phase 2 studies suggest that nivolumab (a PD-1 checkpoint inhibitor) and ipilimumab (a CTLA-4 checkpoint inhibitor) have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab combined with ipilimumab versus ipilimumab alone were evaluated in patients with metastatic melanoma. We randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma, in 1:1:1 ratio, to nivolumab alone (3 mg per kilogram of body weight every 2 weeks), or to nivolumab (at a dose of 1 mg per kilogram) plus ipilimumab (at a dose of 3 mg per kilogram) every 3 weeks for 4 doses followed by nivolumab (3 mg per kilogram every 2 weeks), or to ipilimumab alone (3 mg per kilogram every 3 weeks for 4 doses). Progression-free and overall survival were co-primary end points. Patients continue to be followed for overall survival. Median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) for nivolumab plus ipilimumab as compared with 2.9 months (95% CI, 2.8 to 3.4) for ipilimumab alone (hazard ratio, 0.42; 95% CI, 0.31 to 0.57; P<0.00001), and was 6.9 months (95% CI, 4.3 to 9.5) for nivolumab alone (hazard ratio in the comparison with ipilimumab alone, 0.57; 95% CI, 0.43 to 0.76; P<0.00001). In PD-L1-positive patients, median progression-free survival was 14.0 months in both the nivolumab plus ipilimumab and nivolumab alone groups, but in PD-L1-negative patients, progression-free survival was longer with the combination as compared with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] versus 5.3 months [95% CI, 2.8 to 7.1]). Grade 3–4 drug-related adverse events occurred in 16.3%, 55.0%, and 27.3% of patients in the nivolumab, nivolumab plus ipilimumab, and ipilimumab alone groups, with 1, 0, and 1 drug-related deaths, respectively. Nivolumab alone or combined with ipilimumab significantly improved progression-free survival, as compared with ipilimumab, among previously untreated patients with metastatic melanoma. Results with the combination versus either agent alone suggest complementary activity between PD-1 and CTLA-4 blockade, particularly for patients with PD-L1-negative tumors. (Funded by Bristol-Myers Squibb; CheckMate 067, ClinicalTrials.gov number, NCT01844505.)