Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France.
Department of Respiratory Oncology, University Hospital KU Leuven, Leuven, Belgium.
Lancet Oncol. 2018 Nov;19(11):1468-1479. doi: 10.1016/S1470-2045(18)30673-9. Epub 2018 Sep 24.
Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy.
JAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m every 3 weeks. Randomisation was stratified by PD-L1 expression (≥1% vs <1% of tumour cells), which was measured with the 73-10 assay, and histology (squamous vs non-squamous). The primary endpoint was overall survival, analysed when roughly 337 events (deaths) had occurred in the PD-L1-positive population. Efficacy was analysed in all PD-L1-positive patients (ie, PD-L1 expression in ≥1% of tumour cells) randomly assigned to study treatment (the primary analysis population) and then in all randomly assigned patients through a hierarchical testing procedure. Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02395172. Enrolment is complete, but the trial is ongoing.
Between March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11·4 months [95% CI 9·4-13·9] vs 10·3 months [8·5-13·0]; hazard ratio 0·90 [96% CI 0·72-1·12]; one-sided p=0·16). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes.
Compared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile.
Merck and Pfizer.
针对免疫检查点分子 PD-1 或 PD-L1 的抗体在转移性非小细胞肺癌（NSCLC）患者中显示出临床疗效。在这项试验中，我们研究了avelumab（一种抗 PD-L1 抗体）在已接受铂类化疗的 NSCLC 患者中的疗效和安全性。
JAVELIN Lung 200 是一项多中心、开放性、随机、3 期试验，在 31 个国家的 173 家医院和癌症治疗中心进行。纳入标准为年龄 18 岁或以上，患有 IIIB 或 IV 期或复发性 NSCLC，且在接受含铂双药化疗、东部肿瘤协作组体能状态评分为 0 或 1、预期寿命超过 12 周、血液学、肾功能和肝功能足够的患者。参与者通过具有可变块长度的分层随机化区组方法（区组长度为 1）以 1:1 的比例随机分配至接受avelumab 10 mg/kg 每 2 周或多西他赛 75 mg/m 每 3 周治疗。随机分组按 PD-L1 表达（≥1%与＜1%肿瘤细胞）分层，使用 73-10 测定法进行测量，并按组织学（鳞状与非鳞状）分层。主要终点是总生存期，当 PD-L1 阳性人群中约发生 337 例（死亡）事件时进行分析。疗效在所有随机分配至研究治疗的 PD-L1 阳性患者（即肿瘤细胞中 PD-L1 表达≥1%）中进行分析（主要分析人群），然后通过分层检验程序在所有随机分配的患者中进行分析。安全性在至少接受一剂研究治疗的所有患者中进行分析。该试验在 ClinicalTrials.gov 上注册，编号为 NCT02395172。入组已完成，但试验仍在进行中。
2015 年 3 月 24 日至 2017 年 1 月 23 日，共纳入 792 例患者并随机分配至接受avelumab（n=396）或多西他赛（n=396）治疗。avelumab 组和多西他赛组中分别有 264 例和 265 例患者的肿瘤 PD-L1 阳性。在 PD-L1 阳性肿瘤患者中，avelumab 组和多西他赛组的中位总生存期无显著差异（11.4 个月[95%CI 9.4-13.9]与 10.3 个月[8.5-13.0]；风险比 0.90[96%CI 0.72-1.12]；单侧 p=0.16）。avelumab 治疗组 393 例患者中有 251 例（64%）和多西他赛治疗组 365 例患者中有 313 例（86%）发生治疗相关不良事件，包括 3 级或 5 级事件分别为 39 例（10%）和 180 例（49%）。最常见的 3 级或 5 级治疗相关不良事件是输注相关反应（6 例[2%]）和脂肪酶升高（4 例[1%]），在 avelumab 组和多西他赛组中分别有 6 例（2%）和 180 例（49%）患者发生；中性粒细胞减少症（51 例[14%]）、发热性中性粒细胞减少症（37 例[10%]）和中性粒细胞计数减少（36 例[10%]）在多西他赛组中更为常见。avelumab 组有 34 例（9%）患者和多西他赛组有 75 例（21%）患者发生严重治疗相关不良事件。avelumab 组有 4 例（1%）患者发生治疗相关死亡，2 例死于间质性肺病，1 例死于急性肾损伤，1 例死于自身免疫性心肌炎、急性心功能衰竭和呼吸功能衰竭的联合作用。多西他赛组有 14 例（4%）患者发生治疗相关死亡，3 例死于肺炎，1 例分别死于发热性中性粒细胞减少症、败血症性休克、发热性中性粒细胞减少症合并败血症性休克、急性呼吸功能衰竭、心功能不全、肾功能不全、伴粘膜炎症和发热的白细胞减少症、感染、中性粒细胞减少症感染、脱水和未知原因。
与多西他赛相比，avelumab 并未改善铂类治疗的 PD-L1 阳性 NSCLC 患者的总生存期，但具有良好的安全性。
默克公司和辉瑞公司。
