Safety, Efficacy, and Biomarkers of Nivolumab With Vaccine in Ipilimumab-Refractory or -Naive Melanoma
Safety, Efficacy, and Biomarkers of Nivolumab With Vaccine in Ipilimumab-Refractory or -Naive Melanoma
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DOI：
10.1200/jco.2013.51.4802
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发表时间：
2013-12-01
影响因子：
45.3
通讯作者：
Chen, Y. Ann
中科院分区：
文献类型：
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作者：
Weber, Jeffrey S.;Kudchadkar, Ragini Reiney;Chen, Y. Ann
Nivolumab是一种针对t细胞程序性死亡-1检查点蛋白的人免疫球蛋白G(4)阻断抗体，具有抗转移性黑色素瘤的活性。在伊匹单抗难治性和初发性黑色素瘤中，使用或不使用肽疫苗对其安全性、临床疗效和相关生物标志物进行了评估。患者和方法在这项I期研究中，90例不可切除的III期或IV期黑色素瘤患者首次接受伊匹单抗治疗，在至少一次既往治疗后出现进展（队列1至3,34例患者），或在既往伊匹单抗治疗后出现进展（队列4至6,56例患者），每2周接受1、3或10 mg/kg的纳武单抗治疗，持续24周，然后每12周接受一次，接受或不接受多肽疫苗治疗，持续2年。结果Nivolumab与疫苗在所有剂量下均具有良好的耐受性和安全性。伊匹单抗难治性和初治性患者的RECIST 1.1缓解率均为25%。中位缓解持续时间未达到中位随访8.1个月。高预处理NY-ESO-1和mart -1特异性CD8(+) T细胞与疾病进展相关。在第12周，外周血T调节性细胞增加和抗原特异性T细胞减少与进展相关。PD-L1肿瘤染色与对纳武单抗的反应相关，但阴性染色不排除有反应。在纳武单抗后出现进展的患者可能对伊匹单抗有反应。结论：在伊匹单抗难治性或初发性黑色素瘤患者中，nivolumab 3mg /kg的耐受性良好，诱导反应持续时间长达140周。伊匹单抗难治性患者对纳武单抗的反应或伊匹单抗难治性患者对伊匹单抗的反应支持纳武单抗和伊匹单抗的联合或测序。(C)美国临床肿瘤学会2013
Purpose Nivolumab, a human immunoglobulin G(4)-blocking antibody against the T-cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma.Patients and Methods In this phase I study, 90 patients with unresectable stage III or IV melanoma who were ipilimumab naive and had experienced progression after at least one prior therapy (cohorts 1 to 3, 34 patients) or experienced progression after prior ipilimumab (cohorts 4 to 6, 56 patients) received nivolumab at 1, 3, or 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine.Results Nivolumab with vaccine was well tolerated and safe at all doses. The RECIST 1.1 response rate for both ipilimumab-refractory and -naive patients was 25%. Median duration of response was not reached at a median of 8.1 months of follow-up. High pretreatment NY-ESO-1 and MART-1-specific CD8(+) T cells were associated with progression of disease. At week 12, increased peripheral-blood T regulatory cells and decreased antigen-specific T cells were associated with progression. PD-L1 tumor staining was associated with responses to nivolumab, but negative staining did not rule out a response. Patients who experienced progression after nivolumab could respond to ipilimumab.Conclusion In patients with ipilimumab-refractory or -naive melanoma, nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks. Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab. (C) 2013 by American Society of Clinical Oncology