Nivolumab plus ipilimumab in advanced melanoma.
Nivolumab plus ipilimumab in advanced melanoma.
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DOI：
10.1056/nejmoa1302369
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发表时间：
2013-07-11
期刊：
影响因子：
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通讯作者：
Sznol M
中科院分区：
文献类型：
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作者：
Wolchok JD;Kluger H;Callahan MK;Postow MA;Rizvi NA;Lesokhin AM;Segal NH;Ariyan CE;Gordon RA;Reed K;Burke MM;Caldwell A;Kronenberg SA;Agunwamba BU;Zhang X;Lowy I;Inzunza HD;Feely W;Horak CE;Hong Q;Korman AJ;Wigginton JM;Gupta A;Sznol M
在黑色素瘤患者中，ipilimumab（抗CTLA-4）提高了总生存率，nivolumab（抗PD-1）在1期试验中产生了持久的肿瘤消退。基于其独特的免疫学作用机制和支持性临床前数据，我们在晚期黑色素瘤患者中进行了nivolumab联合ipilimumab的I期试验。患者每3周一次接受nivolumab和ipilimumab，共4剂，然后每3周一次单独接受nivolumab，共4剂（并行方案）。随后每12周一次继续联合治疗，最多给药8次。在序贯方案中，先前用伊匹单抗治疗的患者每2周接受纳武单抗。53例患者接受了nivolumab/ipilimumab同时治疗，33例接受了序贯治疗。所有并行治疗方案患者的客观缓解率为40%（修订的WHO标准）。在65%的患者中观察到临床活性证据（常规、未经证实或免疫相关应答或病情稳定≥24周）。在最大耐受剂量（1 mg/kg nivolumab + 3 mg/kg ipilimumab）下，53%的患者实现了客观缓解，所有患者肿瘤缩小≥80%。53%的合并治疗方案患者发生了3-4级相关不良事件，但与历史单药治疗经验在性质上相似，并且通常是可逆的。在序贯治疗方案患者中，18%发生3-4级相关不良事件，客观缓解率为20%。同时使用纳武单抗/伊匹单抗具有可管理的安全性特征，并实现了与已发表的单药治疗数据不同的临床活性，在大量患者中具有快速和深度的肿瘤消退。
In patients with melanoma, ipilimumab (anti-CTLA-4) prolongs overall survival and nivolumab (anti-PD-1) produced durable tumor regressions in a phase 1 trial. Based on their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in advanced melanoma patients. Patients received nivolumab and ipilimumab every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). Combined treatment was subsequently continued every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks. Fifty-three patients received concurrent nivolumab/ipilimumab and 33 received sequenced treatment. The objective response rate, for all concurrent-regimen patients was 40% (modified WHO criteria). Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease ≥24 weeks) was observed in 65% of patients. At the maximum tolerated dose (1 mg/kg nivolumab + 3 mg/kg ipilimumab), 53% of patients achieved an objective response, all with ≥80% tumor reduction. Grade 3–4 related adverse events occurred in 53% of concurrent-regimen patients, but were qualitatively similar to historical monotherapy experience and were generally reversible. Among sequenced-regimen patients, 18% had grade 3–4 related adverse events and the objective response rate was 20%. Concurrent nivolumab/ipilimumab had a manageable safety profile and achieved clinical activity that is distinct from published monotherapy data, with rapid and deep tumor regressions in a substantial number of patients.