Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma.
Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma.
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DOI：
10.1111/cas.13226
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发表时间：
2017-05
期刊：
影响因子：
5.7
通讯作者：
Tahara H
中科院分区：
文献类型：
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作者：
Yamazaki N;Kiyohara Y;Uhara H;Iizuka H;Uehara J;Otsuka F;Fujisawa Y;Takenouchi T;Isei T;Iwatsuki K;Uchi H;Ihn H;Minami H;Tahara H
在先前的I期研究中提出了nivolumab（一种针对程序性死亡-1蛋白的完全人源化IgG 4抑制剂抗体）有希望的抗肿瘤活性。目前的II期单组研究（JAPIC-CTI #111681）在日本11个研究中心的晚期黑色素瘤患者中评价了nivolumab的抗肿瘤活性，并探索了其预测相关性。从2011年12月至2012年5月入组的37例患者中，35例患者以3周间隔重复静脉注射纳武单抗2 mg/kg，直至出现不可接受的毒性、疾病进展或完全缓解。主要终点为客观缓解率。在多个时间点评估免疫调节剂的血清水平。截至2014年10月21日，中位缓解持续时间、中位无进展生存期和中位总生存期分别为463天、169天和18.0个月。总缓解率和1年、2年生存率分别为28.6%、54.3%和42.9%。13例患者在观察期结束时仍存活，无死亡与药物相关。在31.4%的患者中观察到3-4级药物相关不良事件。客观肿瘤缓解患者的治疗前血清干扰素-γ、白细胞介素-6和-10水平显著高于肿瘤进展患者。总之，在晚期黑色素瘤患者中，重复静脉内给予nivolumab具有有效和持久的抗肿瘤作用以及可管理的安全性特征，这强烈表明nivolumab对晚期黑色素瘤的有用性以及预处理血清细胞因子特征作为预测治疗疗效的相关性的有用性。
Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death‐1 protein, were suggested in previous phase 1 studies. The present phase 2, single‐arm study (JAPIC‐CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3‐week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression‐free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1‐ and 2‐year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3–4 drug‐related adverse events were observed in 31.4% of patients. Pretreatment serum interferon‐γ, and interleukin‐6 and ‐10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy.