Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
N Engl J Med. 2013 Jul 11;369(2):122-33. doi: 10.1056/NEJMoa1302369. Epub 2013 Jun 2.
In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.
We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.
A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.
Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).
在黑色素瘤患者中，伊匹单抗（一种针对细胞毒性 T 淋巴细胞相关抗原 4 [CTLA-4] 的抗体）延长了总生存期，纳武单抗（一种针对程序性死亡 1 [PD-1] 受体的抗体）在一项 1 期试验中产生了持久的肿瘤消退。基于其不同的免疫作用机制和支持性临床前数据，我们对晚期黑色素瘤患者进行了纳武单抗联合伊匹单抗的 1 期试验。
我们每 3 周给患者静脉注射纳武单抗和伊匹单抗，共 4 剂，然后单独每 3 周给予纳武单抗，共 4 剂（联合治疗）。联合治疗随后每 12 周进行一次，最多 8 剂。在序贯方案中，先前接受过伊匹单抗治疗的患者每 2 周接受纳武单抗治疗，最多 48 剂。
共有 53 例患者接受了纳武单抗联合伊匹单抗的联合治疗，33 例患者接受了序贯治疗。联合治疗组所有患者的客观缓解率（根据改良的世界卫生组织标准）为 40%。在 65%的患者中观察到临床活性（常规、未经证实或免疫相关反应或稳定疾病≥24 周）。在与可接受的不良事件水平相关的最大剂量（纳武单抗剂量为每公斤体重 1 毫克，伊匹单抗剂量为每公斤体重 3 毫克）下，53%的患者有客观缓解，所有患者的肿瘤缩小≥80%。联合治疗组 53%的患者发生与治疗相关的 3 级或 4 级不良事件，但与单药治疗的既往经验相似，且通常是可逆的。序贯治疗组 18%的患者发生与治疗相关的 3 级或 4 级不良事件，客观缓解率为 20%。
纳武单抗联合伊匹单抗的联合治疗具有可管理的安全性，并提供了与单药治疗发表数据不同的临床活性，在很大一部分患者中迅速而深度地肿瘤消退。（由 Bristol-Myers Squibb 和小野制药公司资助；ClinicalTrials.gov 编号，NCT01024231）。
