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.
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。
N Engl J Med. 2016-10-8
J Immunother Cancer. 2025-9-1
J Exp Clin Cancer Res. 2025-8-23
Am J Cancer Res. 2025-7-15
Invest New Drugs. 2025-8-13
Zotero 插件