SCI
31 October
Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY)
Nakagawa Kazuhiko,Garon Edward B,Seto Takashi et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.[J] .Lancet Oncol., , undefined: undefined.
Background 背景
Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.
临床前和临床数据支持在EGFR突变的转移性非小细胞肺癌（NSCLC）中对EGFR和VEGF途径的双重阻断，但该方法尚未得到广泛实施。RELAY评估了未经治疗的EGFR突变型转移性NSCLC患者使用厄洛替尼，一种EGFR酪氨酸激酶抑制剂（TKI），加上人IgG1 VEGFR2拮抗剂雷莫西单抗或安慰剂的效果。
Methods 方法
This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomization was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population.Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.
这是一项在全球13个国家/地区的100家医院，诊所和医疗中心进行的全球双盲3期试验。符合条件的患者在研究时年龄在18岁以上进入IV期NSCLC，EGFR外显子19缺失（ex19del）或外显子21替代（Leu858Arg）突变，东部合作肿瘤小组的工作状态为0或1，无CNS转移。我们以1：1的比例随机分配符合条件的患者，每2周一次接受口服厄洛替尼（150 mg /天）加静脉内雷莫昔单抗（10 mg / kg）或匹配的安慰剂。通过具有计算机生成序列的交互式网络响应系统进行随机分组，并按性别，地理区域，EGFR突变类型和EGFR测试方法进行分层。主要终点是研究者评估的意图治疗人群的无进展生存期。在接受至少一剂研究治疗的所有患者中评估安全性。该试验已在ClinicalTrials.gov上注册，NCT02411448，正在进行长期生存随访。
Findings 发现
Between Jan 28, , and Feb 1, , 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months. At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group than in the placebo plus erlotinib group, with a stratified hazard ratio of 0·59. Grade 3–4 treatmentemergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3–4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension and dermatitis acneiform, and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.
在1月28日至2月1日之间，纳入449例合格患者，并随机分配接受雷莫昔单抗加厄洛替尼（n = 224）或安慰剂加厄洛替尼（n = 225）治疗。中位随访时间为20·7个月。在初步分析时，雷莫昔单抗联合厄洛替尼组的无进展生存期明显长于安慰剂联合厄洛替尼组，分层危险比为0·59。雷莫昔单抗加厄洛替尼组的221名患者中有159名（72％）发生了3–4级治疗紧急事件，而安慰剂加厄洛替尼组的225名患者中有121名（54％）。雷莫昔单抗加厄洛替尼组中最常见的3-4级治疗紧急事件是高血压和痤疮皮炎，安慰剂加厄洛替尼组是痤疮皮炎（20 [9％]）和丙氨酸转氨酶升高（17 [8％]） ]）。雷莫昔单抗加厄洛替尼组的221例患者中有65例（29％）出现了治疗时的严重不良事件，安慰剂加厄洛替尼组的225例中有47例（21％）发生了治疗。在拉莫昔单抗联合厄洛替尼组中，最严重的严重不良事件为任何级别，分别为肺炎（七[3％]），蜂窝织炎和气胸（各四[2％]）。安慰剂加厄洛替尼组中最常见的是发热（4 [2％]）和气胸（3 [1％]）。雷莫昔单抗联合厄洛替尼组发生了因不良事件（在胸腔积液胸腔引流后的胸腔积血）导致的与治疗相关的研究死亡。
Interpretation 解释
Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.
未经治疗的EGFR突变转移性NSCLC患者中，使用雷莫昔单抗加厄洛替尼具有优于安慰剂加厄洛替尼的无进展生存期。安全性与晚期肺癌中单药治疗的安全性一致。RELAY方案对于EGFR突变的转移性NSCLC的初始治疗是可行的新治疗选择。
