Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma
Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma
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DOI：
10.1038/s41591-018-0198-0
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发表时间：
2018-11-01
期刊：
影响因子：
82.9
通讯作者：
Schumacher, Ton N.
中科院分区：
文献类型：
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作者：
Blank, Christian U.;Rozeman, Elisa A.;Schumacher, Ton N.
辅助剂ipilimumab(抗CTLA-4)和nivolumab(抗PD-1)均可提高III期黑色素瘤患者(1，2)的无复发存活率。在IV期疾病中，ipilimumab+nivolumab联合治疗优于ipilimumab单独治疗，也似乎比nivolumab单独治疗更有效(3)。临床前研究表明，检查点抑制剂的新辅助应用可能优于辅助治疗(4)。为了解决这个问题并测试可行性，20例可触及的III期黑色素瘤患者被1：1随机分为两组，分别接受ipilimumab 3 mg kg(-1)和nivolumab 1 mg kg(-1)，作为术后4个疗程(辅助组)或手术前2个疗程和术后2个疗程(新佐剂组)。新辅助治疗是可行的，所有患者都在预先计划的时间点接受手术。然而，在两组患者中，9/10的患者经历了一个或多个3/4级的不良事件。在接受新辅助治疗的9例患者中，有7例(78%)取得了病理反应。到目前为止，这些患者都没有复发(中位随访时间为25.6个月)。我们发现，新佐剂ipilimumab+nivolumab比佐剂应用能扩增更多的肿瘤常驻T细胞克隆。新辅助治疗虽然前景看好，但在目前的方案下，其毒副作用很高，因此，在保持疗效的同时降低毒性还需要进一步的研究。
Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (antiPD-1) both improve relapse-free survival of stage III melanoma patients(1,2). In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy(3). Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy(4). To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg(-1) and nivolumab 1 mg kg(-1), as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm). Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity.