Princess Margaret Cancer Centre, Toronto, ON, Canada.
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
Lancet Respir Med. 2019 Apr;7(4):347-357. doi: 10.1016/S2213-2600(18)30500-9. Epub 2019 Mar 12.
The anti-programmed death 1 monoclonal antibody pembrolizumab has shown antitumour activity and is a first-line and second-line treatment option for patients with programmed death ligand 1 (PD-L1)-expressing advanced non-small-cell lung cancer. We report updated 3-year safety and efficacy outcomes from the phase 1 study, KEYNOTE-001.
KEYNOTE-001 is a multicohort, open-label, phase 1 study of pembrolizumab (2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks) in treatment naive or previously treated patients with locally advanced or metastatic non-small-cell lung cancer with measurable disease at baseline. Two cohorts were randomly assigned to a pembrolizumab dose by use of a computer-generated randomisation schedule at cohort-dependent ratios, and a further four cohorts were assigned to a pembrolizumab dose without randomisation. We present 3-year outcomes for the full analysis set of patients who received at least one dose of study treatment, pooled for all pembrolizumab doses. The primary efficacy endpoint was proportion of patients with objective response, analysed here as investigator-assessed response according to immune-related response criteria. Secondary efficacy endpoints included overall survival, duration of response, and progression-free survival. Safety endpoints included incidence of adverse events. This study is registered at ClinicalTrials.gov, number NCT01295827, and is ongoing.
Between May 8, 2012 and July 13, 2014, 550 patients (101 treatment naive and 449 previously treated) were enrolled. Median follow-up was 34·5 months at data cutoff (Sept 1, 2016). At 36 months, investigator-assessed objective response according to immune-related response criteria was achieved for 41 of 101 treatment naive patients (41% [95% CI 30·9-50·8]; median duration of response was 16·7 months [95% CI 12·6-not reached]) and 102 of 449 previously treated patients (23% [18·9-26·9]; 33·3 ([22·5-not reached]). The Kaplan-Meier estimate of overall survival at 36 months was 26·4% (95% CI 14·3-40·1) for treatment naive patients and 19·0% (15·0-23·4) for previously treated patients, with median overall survival of 22·3 months (95% CI 17·1-31·5) and 10·5 months (8·6-13·2). PD-L1 tumour proportion score ≥50% was associated with longer median overall survival (95% CI) versus tumour proportion score 1-49% (treatment naive: 34·9 [20·3-not reached] vs 19·5 [10·7-26·3] months; previously treated: 15·4 [10·5-18·5] vs 8·5 [6·0-12·7] months). Grade 3-5 treatment-related adverse events occurred in 66 patients (12%), and 30 (6%) discontinued owing to a treatment-related adverse event. The most frequent grade 3-4 treatment-related adverse events were pneumonitis (10 [2%] of 550) and fatigue (5 [1%] of 550). Overall, 227 patients (41%) of 550 had serious adverse events, of which 50 (9%) were treatment related.
Pembrolizumab provides durable response and long-term effects on overall survival, with tolerable safety, for treatment naive and previously treated patients with advanced non-small-cell lung cancer expressing PD-L1.
Merck Sharp & Dohme Corp.
抗程序性死亡 1 单克隆抗体派姆单抗显示出抗肿瘤活性，是表达程序性死亡配体 1（PD-L1）的晚期非小细胞肺癌患者的一线和二线治疗选择。我们报告了来自 1 期研究 KEYNOTE-001 的更新 3 年安全性和疗效结果。
KEYNOTE-001 是一项多队列、开放标签、1 期研究，评估了 pembrolizumab（每 3 周 2mg/kg 或每 2 或 3 周 10mg/kg）在基线时可测量疾病的初治或经治局部晚期或转移性非小细胞肺癌患者中的疗效。两个队列通过基于队列的随机分组方案，以电脑生成的随机分组方案随机分配到 pembrolizumab 剂量，另外四个队列则未随机分配到 pembrolizumab 剂量。我们报告了至少接受一次研究治疗的患者全分析集的 3 年结果，所有 pembrolizumab 剂量均汇总。主要疗效终点是客观缓解患者的比例，根据免疫相关反应标准分析为研究者评估的缓解。次要疗效终点包括总生存期、缓解持续时间和无进展生存期。安全性终点包括不良事件的发生率。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT01295827，正在进行中。
2012 年 5 月 8 日至 2014 年 7 月 13 日，共纳入 550 例患者（101 例初治和 449 例经治）。数据截止日期（2016 年 9 月 1 日）的中位随访时间为 34.5 个月。在 36 个月时，根据免疫相关反应标准，101 例初治患者中有 41 例（41%[95%CI 30.9-50.8%]；中位缓解持续时间为 16.7 个月[95%CI 12.6-未达到]）和 449 例经治患者中有 102 例（23%[18.9-26.9%]；33.3[22.5-未达到]）达到了研究者评估的客观缓解。初治患者的 Kaplan-Meier 估计 36 个月总生存期为 26.4%（95%CI 14.3-40.1），经治患者为 19.0%（15.0-23.4），中位总生存期为 22.3 个月（95%CI 17.1-31.5）和 10.5 个月（8.6-13.2）。肿瘤比例评分（TPS）≥50%与更长的中位总生存期（95%CI）相关，TPS 为 1-49%（初治：34.9 [20.3-未达到] vs 19.5 [10.7-26.3] 个月；经治：15.4 [10.5-18.5] vs 8.5 [6.0-12.7] 个月）。66 例（12%）患者发生 3-5 级治疗相关不良事件，30 例（6%）因治疗相关不良事件而停药。最常见的 3-4 级治疗相关不良事件是肺炎（10 例[2%]，550 例）和疲劳（5 例[1%]，550 例）。总体而言，550 例患者中有 227 例（41%）发生严重不良事件，其中 50 例（9%）与治疗有关。
pembrolizumab 为表达 PD-L1 的初治和经治晚期非小细胞肺癌患者提供了持久的缓解和长期的总生存效果，且安全性可耐受。
默克公司 Sharp & Dohme 公司。
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