PD-1联合化疗治疗晚期非小细胞肺癌 | 引经据典[2]·协和呼吸
本期解读
派姆单抗联合化疗
治疗晚期非小细胞肺癌
Pembrolizumab plus Chemotherapy in
Metastatic Non–Small-Cell
Lung Cancer
抗PD-1单抗在晚期肺癌中发威
关键词
派姆单抗，联合化疗，晚期非小细胞肺癌
作者：
Leena Gandhi, et al.
翻译：
北京协和医院呼吸内科 刘潇衍 黄慧
文献来源：
N Engl J Med 2018; 378:2078-2092
DOI: 10.1056/NEJMoa1801005
临床试验编号：
NCT02578680
背景及目的
无驱动基因突变的晚期非小细胞肺癌（NSCLC）的一线治疗是以铂类为基础的化疗。对于肿瘤细胞中PD-L1染色阳性的细胞比例（tumor proportion score，TPS）≥50%的NSCLC患者，派姆单抗（pembrolizumab）已取代化疗成为新的一线治疗选择。在II期临床试验KEYNOTE-021G中，派姆单抗联合化疗较单纯化疗提高了客观缓解率（objective response rate, ORR）和无进展生存期（progression free survival, PFS）。该III期研究拟探索派姆单抗或安慰剂联合化疗在晚期NSCLC中的疗效和安全性，并进一步探索不同PD-L1 TPS对疗效的影响。
方 法
该研究是一项随机、对照、双盲设计的III期临床试验，共纳入616名初治的晚期非鳞NSCLC患者，均无EGFR突变或ALK融合基因。患者按2:1比例随机分配到培美曲塞+铂类联合派姆单抗组或联合安慰剂组（派姆单抗，200mg/次，每3周给药1次，连续4个周期），后续予派姆单抗或安慰剂联合培美曲塞维持治疗，直至35个周期结束。如果安慰剂组患者出现疾病进展，可交叉至派姆单抗单药治疗。主要研究终点是意向治疗（intent to treat, ITT）人群的总生存率（overall survival, OS）和PFS。
结 果
中位随访时间10.5个月，派姆单抗联合化疗组12个月生存率为69.2% (95% CI, 64.1-73.8)，安慰剂联合化疗组为49.4% (95% CI, 42.1-56.2)；HR为0.49（95% CI, 0.38-0.64）（ P<0.001）。不同PD-L1 TPS亚组中均观察到OS的改善。两组的中位PFS分别为：派姆单抗联合化疗组位8.8个月(95% CI, 7.6-9.2)，安慰剂联合化疗组为4.9个月 (95% CI, 4.7-5.5)；HR为0.52（95% CI, 0.43-0.64）（P<0.001）。安全性方面，两组患者最常见的不良反应是恶心，贫血和乏力。派姆单抗组、安慰剂组3级以上AE的发生率分别为67.2% vs. 65.8%；AE导致的所有治疗终止的发生率分别为13.8％和7.9％；AE导致的死亡率分别为6.7％和5.9％。值得注意的是，与安慰剂组相比，派姆单抗组急性肾损伤的发生率更高（5.2% vs.0.5%）。
结 论
对于初治的无EGFR/ALK驱动基因突变的晚期非鳞NSCLC患者，在标准化疗培美曲塞+铂类的基础上加用派姆单抗较联合安慰剂，能显著改善这类患者的OS和PFS（注：但仍然是PD-L1 TPS≥50%的患者获益最大）；具有较好的安全性。
原文摘要
BACKGROUND
First-line therapy for advanced non–small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.
METHODS
In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.
RESULTS
After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.
CONCLUSIONS
In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.
作者介绍
刘潇衍
医学博士 北京协和医院内科临床博士后
博士期间主要从事呼吸系统恶性肿瘤内科治疗方面的临床和基础研究，在国内外期刊已发表论文10余篇。积极参与多个呼吸系统恶性肿瘤的国内外临床研究。
往期经典
文字来源：刘潇衍 黄慧
栏目负责：黄慧
版面编辑：陈珂琪
图片来源：部分来源于网络，如有侵权，请联系删除
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