帕博利珠单抗联合 CC-486 与安慰剂联合帕博利珠单抗治疗既往治疗的晚期非小细胞肺癌患者的随机 2 期研究。
Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer.
机构信息
Johns Hopkins Sidney Kimmel Cancer Center, Washington, DC, USA.
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
出版信息
Eur J Cancer. 2019 Feb;108:120-128. doi: 10.1016/j.ejca.2018.11.028. Epub 2019 Jan 14.
INTRODUCTION
Preclinical and early clinical studies suggest that combining epigenetic agents with checkpoint inhibitors can potentially improve outcomes in patients with previously treated advanced non-small cell lung cancer (NSCLC). This phase 2 trial examined second-line pembrolizumab + CC-486 (oral azacitidine) in patients with advanced NSCLC.
METHODS
Patients with one prior line of platinum-containing therapy were randomised in a ratio of 1:1 to CC-486 or placebo, on days 1-14, in combination with pembrolizumab on day 1 of a 21-day cycle. The primary end-point was progression-free survival (PFS). Key secondary end-points included overall survival (OS), overall response rate (ORR) and safety.
RESULTS
Among 100 patients randomised (pembrolizumab + CC-486: 51; pembrolizumab + placebo: 49), most were male (57.0%), were white (87.0%) and had Eastern Cooperative Oncology Group performance status 1 (68.0%). No significant difference in PFS was observed between the pembrolizumab + CC-486 and pembrolizumab + placebo arms (median, 2.9 and 4.0 months, respectively; hazard ratio [HR], 1.374; 90% confidence interval [CI], 0.926-2.038; P = 0.1789). Median OS was 11.9 months versus not estimable (HR, 1.375; 90% CI, 0.830-2.276; P = 0.2968); ORR was 20% versus 14%. Median treatment duration was shorter (15.0 versus 24.1 weeks), and the number of cycles was lower (5.0 versus 7.0) with pembrolizumab + CC-486 versus pembrolizumab + placebo. No new safety signals for CC-486 or pembrolizumab were detected. Treatment-emergent adverse events were more common in the pembrolizumab + CC-486 arm, particularly gastrointestinal, potentially impacting treatment feasibility.
CONCLUSIONS
No improvement in PFS was observed with pembrolizumab + CC-486 versus pembrolizumab + placebo. Decreased treatment exposure due to adverse events may have impacted efficacy with pembrolizumab + CC-486.
简介
临床前和早期临床研究表明，将表观遗传学药物与检查点抑制剂联合使用可能会改善先前治疗的晚期非小细胞肺癌（NSCLC）患者的预后。这项 2 期试验研究了二线 pembrolizumab + CC-486（口服阿扎胞苷）在晚期 NSCLC 患者中的应用。
方法
100 例接受过一线含铂化疗的患者按照 1:1 的比例随机分配至 CC-486 或安慰剂组，在第 1-14 天给药，联合第 1 天的 pembrolizumab（每 21 天为一个周期）。主要终点为无进展生存期（PFS）。关键次要终点包括总生存期（OS）、总缓解率（ORR）和安全性。
结果
在 100 例随机分组的患者中（pembrolizumab + CC-486：51 例；pembrolizumab + 安慰剂：49 例），大多数患者为男性（57.0%），为白人（87.0%），东部肿瘤协作组体能状态为 1 级（68.0%）。与 pembrolizumab + 安慰剂组相比，pembrolizumab + CC-486 组的 PFS 无显著差异（中位 PFS：2.9 个月和 4.0 个月，风险比[HR]：1.374；90%置信区间[CI]：0.926-2.038；P = 0.1789）。中位 OS 分别为 11.9 个月和不可估计（HR：1.375；90%CI：0.830-2.276；P = 0.2968）；ORR 分别为 20%和 14%。与 pembrolizumab + 安慰剂组相比，pembrolizumab + CC-486 组的中位治疗持续时间更短（15.0 周 vs 24.1 周），用药周期更少（5.0 周期 vs 7.0 周期）。未发现 CC-486 或 pembrolizumab 的新安全性信号。与 pembrolizumab + 安慰剂组相比，pembrolizumab + CC-486 组治疗相关不良事件更为常见，特别是胃肠道相关不良事件，可能会影响治疗可行性。
结论
与 pembrolizumab + 安慰剂相比，pembrolizumab + CC-486 并未改善 PFS。由于不良事件导致治疗暴露减少可能会影响 pembrolizumab + CC-486 的疗效。
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