Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.
Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.
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DOI：
10.1200/jco.2013.53.0105
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发表时间：
2014-04-01
期刊：
影响因子：
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通讯作者：
Hodi FS
中科院分区：
文献类型：
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作者：
Topalian SL;Sznol M;McDermott DF;Kluger HM;Carvajal RD;Sharfman WH;Brahmer JR;Lawrence DP;Atkins MB;Powderly JD;Leming PD;Lipson EJ;Puzanov I;Smith DC;Taube JM;Wigginton JM;Kollia GD;Gupta A;Pardoll DM;Sosman JA;Hodi FS
程序性细胞死亡1(PD-1)是一种由活化的T细胞表达的抑制性受体，它下调效应器功能，限制免疫记忆的产生。PD-1阻断可以在相当大比例的黑色素瘤患者中介导肿瘤消退，但尚不清楚这是否与延长生存期或在停止治疗后维持反应有关。2008年至2012年间登记的晚期黑色素瘤患者(N=107)在门诊环境中每隔2周静脉注射nivolumab，持续时间长达96周，并在停止治疗后观察总体存活率、长期安全性和反应持续时间。接受nivolumab治疗的患者的中位总存活率为16.8个月，1年和2年存活率分别为62%和43%。在33名目标肿瘤消退的患者中(31%)，Kaplan-Meier估计的中位缓解期为2年。17名患者因疾病进展以外的原因停止治疗，17名患者中有12名(71%)在停止治疗至少16周(范围从16周到56周以上)保持反应。客观反应和毒副作用与以前报道的相似；在对本试验中所有306名患者(包括其他癌症类型的患者)进行的扩展分析中，暴露调整后的毒副作用没有累积。在晚期难治性黑色素瘤患者中，nivolumab治疗后的总存活率与类似患者群体的文献研究中的结果相比是有利的。反应是持久的，在停药后持续存在。长期安全性是可以接受的。正在进行的随机临床试验将进一步评估nivolumab治疗对转移性黑色素瘤患者总存活率的影响。
Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31 %), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71 %) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.