Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Lawrenceville, New Jersey.
Global Medical Affairs, Oncology, Bristol-Myers Squibb, Lawrenceville, New Jersey.
Clin Cancer Res. 2017 Sep 15;23(18):5394-5405. doi: 10.1158/1078-0432.CCR-16-2842.
Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients with previously treated, advanced non-small cell lung cancer (NSCLC). Exposure-response (E-R) analyses for efficacy and safety were conducted to inform the benefit-risk assessment of nivolumab in this patient population. The analyses used clinical trial data from patients with squamous ( = 293) or nonsquamous ( = 354) NSCLC from four clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E-R efficacy analyses were performed by investigating the relationship between time-averaged nivolumab concentration after the first dose () and the probability of overall survival by histology. E-R safety analyses examined relationships between nivolumab and hazards of adverse events leading to discontinuation or death (AEs-DC/D). Nivolumab exposure was not associated with overall survival [the 95% confidence interval (CI) of effect included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555-1.16) or nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683-1.29). Similarly, nivolumab exposure was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI, 0.644-1.31). The risk of AEs-DC/D was similar among patients with squamous or nonsquamous histology. Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E-R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC. .
纳武利尤单抗是一种完全人源 IgG4 单克隆抗程序性死亡-1 抗体，在先前接受治疗的晚期非小细胞肺癌（NSCLC）患者中显示出疗效，包括持久的反应和延长的生存。进行了疗效和安全性的暴露-反应（E-R）分析，以告知纳武利尤单抗在该患者人群中的获益风险评估。这些分析使用了来自四项临床试验中鳞状（=293）或非鳞状（=354）NSCLC 患者的临床试验数据，这些患者每 2 周接受 1 至 10 mg/kg 的纳武利尤单抗剂量。E-R 疗效分析通过研究首次剂量后时间平均纳武利尤单抗浓度（）与组织学总生存概率之间的关系进行。E-R 安全性分析检查了纳武利尤单抗与导致停药或死亡的不良事件（AE-DC/D）风险之间的关系。在鳞状（HR，0.802；95%CI，0.555-1.16）或非鳞状 NSCLC（HR，0.94；95%CI，0.683-1.29）患者中，纳武利尤单抗暴露与总生存无关（效应的 95%置信区间包括 1）。同样，在总体人群中，纳武利尤单抗暴露与 AE-DC/D 无关（HR，0.917；95%CI，0.644-1.31）。鳞状或非鳞状组织学患者的 AE-DC/D 风险相似。纳武利尤单抗单药治疗显示出广泛的治疗范围，这从每 2 周 1 至 10 mg/kg 剂量产生的暴露范围内相对平坦的 E-R 关系得到证明，支持在 NSCLC 患者中使用最初批准的 3 mg/kg Q2W 剂量。
