Background

Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab–erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life.

Methods

This open-label, randomised, multicentre, phase 3 trial (NEJ026) was done in 69 hospitals and medical, community-based centres across Japan. Eligible patients had stage IIIB, stage IV, or postoperative recurrent, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg point mutation) NSCLC, had not previously received systemic chemotherapy, and were randomly assigned (1:1) by a computer-generated randomisation sequence and minimisation to receive either 150 mg oral erlotinib once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or intolerable toxicity. Randomisation was stratified according to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, and study personnel (including those assessing outcomes) were unmasked to treatment allocation. We report the secondary outcomes of overall survival and quality of life (the period from enrolment to confirmation of a minimally important difference on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30), and the exploratory outcome of time from enrolment to progressive disease during second-line treatment or death. Overall survival and the exploratory outcome were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients who received at least one dose of the study drug and had response evaluations. Quality of life was analysed in patients in the modified intention-to-treat population who had completed the quality of life questionnaires. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currently closed.

Findings

Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients who received bevacizumab–erlotinib and 112 who received erlotinib only were included in the modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a median follow-up of 39·2 months (IQR 23·9–43·5), the median overall survival was 50·7 months (95% CI 37·3–not estimable [NE]) in the bevacizumab–erlotinib group and 46·2 months (38·2–NE) in the erlotinib-only group (hazard ratio [HR] 1·007, 95% CI 0·681–1·490; p=0·97). In analysis of the exploratory outcome, after a median follow-up of 23·9 months (IQR 14·2–39·1), the median time from enrolment to progressive disease during second-line treatment or death was 28·6 months (95% CI 22·1–35·9) in the bevacizumab–erlotinib group and 24·3 months (20·4–29·1) in the erlotinib-only group (HR 0·773, 95% CI 0·562–1·065). The median time between enrolment and confirmation of a minimally important difference on the EORTC QLQ-C30 was 6·0 months (95% CI 5·2–11·3) in the bevacizumab–erlotinib group and 8·3 months (5·7–13·9) in the erlotinib-only group (p=0·47).

Interpretation

The addition of bevacizumab to erlotinib did not prolong survival in patients with metastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Why the addition of bevacizumab to erlotinib did not affect overall survival is unclear, but it is possible that the beneficial effects of combination therapy were not seen because overall survival was influenced by treatment regimens used after disease progression.

Funding

Chugai Pharmaceutical.

中文翻译：

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贝伐单抗加厄洛替尼对比厄洛替尼单独治疗日本晚期转移性 EGFR 突变非小细胞肺癌患者 (NEJ026)：一项开放标签、随机、多中心、3 期试验的总生存期分析

背景

贝伐单抗是与表皮生长因子受体酪氨酸激酶抑制剂（例如，厄洛替尼）联合治疗的有希望的候选药物，可以改善转移性EGFR突变非小细胞肺癌（NSCLC）患者的预后。我们之前在 NEJ026（一项 3 期试验）中表明，与单独使用厄洛替尼相比，贝伐单抗联合厄洛替尼可显着延长这些患者的无进展生存期。在进一步的分析中，我们旨在检查贝伐单抗-厄洛替尼对总生存期、二线治疗或死亡期间从入组到疾病进展的时间以及生活质量的影响。

方法

这项开放标签、随机、多中心、3 期试验 (NEJ026) 在日本的 69 家医院和医疗、社区中心进行。符合条件的患者患有 IIIB 期、IV 期或术后复发的EGFR突变（外显子 19 缺失或外显子 21 Leu858Arg 点突变）NSCLC，之前未接受过全身化疗，并通过计算机生成的随机分配 (1:1)随机化顺序和最小化为接受 150 mg 口服厄洛替尼每天一次加 15 mg/kg 静脉注射贝伐单抗每 21 天一次，或 150 mg 口服厄洛替尼每天一次，直至疾病进展或出现无法耐受的毒性。根据性别、吸烟状况、EGFR对随机化进行分层突变亚型和临床疾病分期。所有参与者、研究人员和研究人员（包括评估结果的人员）均未了解治疗分配情况。我们报告了总体生存和生活质量的次要结果（从登记到确认欧洲癌症研究和治疗组织生活质量问卷 [EORTC QLQ]-C30 的最小重要差异的时间）和探索性结果从入组到二线治疗期间疾病进展或死亡的时间。在改良意向治疗人群中分析了总生存期和探索性结果，该人群包括接受至少一剂研究药物并进行反应评估的所有随机分配的患者。对已完成生活质量问卷的改良意向治疗人群中的患者的生活质量进行了分析。该试验已在大学医院医学信息网络临床试验注册中心 UMIN000017069 和日本临床试验注册中心 jRCTs031180056 注册，目前已关闭。

发现

2015 年 6 月 3 日至 2016 年 8 月 31 日期间，共有 228 名患者入组。112 名接受贝伐单抗-厄洛替尼治疗的患者和 112 名仅接受厄洛替尼治疗的患者被纳入改良意向治疗人群。在数据截止（2019 年 11 月 30 日）和中位随访 39·2 个月（IQR 23·9–43·5）时，中位总生存期为 50·7 个月（95% CI 37·3–不可估计[NE]）在贝伐单抗-厄洛替尼组和仅厄洛替尼组 46·2 个月（38·2-NE）（风险比 [HR] 1·007, 95% CI 0·681-1·490；p =0·97)。在探索性结局分析中，中位随访 23·9 个月（IQR 14·2-39·1）后，从入组到二线治疗期间疾病进展或死亡的中位时间为 28·6 个月（贝伐单抗-厄洛替尼组 95% CI 22·1–35·9) 和厄洛替尼单独组 24·3 个月 (20·4–29·1) (HR 0·773, 95% CI 0·562–1·065）。贝伐单抗-厄洛替尼组从入组到确认 EORTC QLQ-C30 最小重要差异的中位时间为 6·0 个月（95% CI 5·2-11·3），8·3 个月（5·7 –13·9) 在仅厄洛替尼组 (p=0·47)。

解释

在厄洛替尼中加入贝伐单抗并未延长转移性EGFR突变 NSCLC 患者的生存期，但两个治疗组的生存期都相对较长。为什么在厄洛替尼中添加贝伐单抗不影响总生存期尚不清楚，但可能没有看到联合治疗的有益效果，因为总生存期受到疾病进展后使用的治疗方案的影响。

资金

中盖药业。