帕博利珠单抗对比多西他赛用于治疗后 PD-L1 阳性的、晚期非小细胞肺癌（KEYNOTE-010）：一项随机对照试验。
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
机构信息
Yale School of Medicine, Yale Cancer Center, and Smilow Cancer Hospital, New Haven, CT, USA.
The Netherlands Cancer Institute and The Academic Medical Hospital Amsterdam, Amsterdam, Netherlands.
出版信息
Lancet. 2016 Apr 9;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19.
BACKGROUND
Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.
METHODS
We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0.00825 (one-sided) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657.
FINDINGS
Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38-0.77; p=0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36-0.70; p<0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44-0.78; p=0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45-0.78; p<0.0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel).
INTERPRETATION
Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.
FUNDING
Merck & Co.
背景
尽管晚期非小细胞肺癌的治疗方法最近有所进展，但对于进展期疾病仍需要有效的治疗方法。我们评估了帕博利珠单抗治疗先前接受过治疗、PD-L1 阳性、晚期非小细胞肺癌患者的疗效。
方法
我们在 24 个国家的 202 家学术医疗中心进行了这项随机、开放标签、2/3 期研究。至少有 1%肿瘤细胞 PD-L1 表达的先前治疗过的非小细胞肺癌患者，按照每 6 个患者为一组的方式，以交互语音应答系统随机分配接受帕博利珠单抗 2 mg/kg、帕博利珠单抗 10 mg/kg 或多西他赛 75 mg/m2 每 3 周一次。主要终点是总生存期和总人群以及 PD-L1 表达至少为 50%的肿瘤细胞患者的无进展生存期。我们使用了一个显著水平为 p<0.00825（单侧）的阈值来分析总生存期，以及一个显著水平为 p<0.001 的阈值来分析无进展生存期。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01905657。
结果
2013 年 8 月 28 日至 2015 年 2 月 27 日期间，我们共纳入了 1034 名患者：345 名分配至帕博利珠单抗 2 mg/kg 组，346 名分配至帕博利珠单抗 10 mg/kg 组，343 名分配至多西他赛组。截至 2015 年 9 月 30 日，有 521 名患者死亡。在总人群中，帕博利珠单抗 2 mg/kg 组的中位总生存期为 10.4 个月，帕博利珠单抗 10 mg/kg 组为 12.7 个月，多西他赛组为 8.5 个月。帕博利珠单抗 2 mg/kg 组与多西他赛组相比，总生存期显著延长（风险比 [HR] 0.71，95%置信区间 0.58-0.88；p=0.0008），帕博利珠单抗 10 mg/kg 组与多西他赛组相比，总生存期也显著延长（0.61，0.49-0.75；p<0.0001）。帕博利珠单抗 2 mg/kg 组的中位无进展生存期为 3.9 个月，帕博利珠单抗 10 mg/kg 组为 4.0 个月，多西他赛组为 4.0 个月，帕博利珠单抗 2 mg/kg 组与多西他赛组相比，无进展生存期无显著差异（0.88，0.74-1.05；p=0.07），帕博利珠单抗 10 mg/kg 组与多西他赛组相比，无进展生存期也无显著差异（HR 0.79，95%置信区间 0.66-0.94；p=0.004）。在至少有 50%肿瘤细胞表达 PD-L1 的患者中，与多西他赛相比，帕博利珠单抗 2 mg/kg 组的总生存期显著延长（中位 14.9 个月 vs 8.2 个月；HR 0.54，95%置信区间 0.38-0.77；p=0.0002），帕博利珠单抗 10 mg/kg 组也显著延长（17.3 个月 vs 8.2 个月；0.50，0.36-0.70；p<0.0001）。同样，对于这一患者人群，与多西他赛相比，帕博利珠单抗 2 mg/kg 组的无进展生存期也显著延长（中位 5.0 个月 vs 4.1 个月；HR 0.59，95%置信区间 0.44-0.78；p=0.0001），帕博利珠单抗 10 mg/kg 组也显著延长（5.2 个月 vs 4.1 个月；0.59，0.45-0.78；p<0.0001）。与多西他赛相比，帕博利珠单抗治疗的 3-5 级治疗相关不良事件较少（339 名接受 2 mg/kg 治疗的患者中有 43 例[13%]，343 名接受 10 mg/kg 治疗的患者中有 55 例[16%]，309 名接受多西他赛治疗的患者中有 109 例[35%]）。
解释
帕博利珠单抗延长了先前接受过治疗、PD-L1 阳性、晚期非小细胞肺癌患者的总生存期，并具有良好的风险效益比。这些数据确立了帕博利珠单抗作为这一人群的新治疗选择，并验证了 PD-L1 选择的应用。
经费来源
默克公司。
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