Kanagawa Cancer Center, Yokohama, Japan.
Miyagi Cancer Center, Natori, Japan.
Lancet Oncol. 2019 May;20(5):625-635. doi: 10.1016/S1470-2045(19)30035-X. Epub 2019 Apr 8.
Resistance to first-generation or second-generation EGFR tyrosine kinase inhibitor (TKI) monotherapy develops in almost half of patients with EGFR-positive non-small-cell lung cancer (NSCLC) after 1 year of treatment. The JO25567 phase 2 trial comparing erlotinib plus bevacizumab combination therapy with erlotinib monotherapy established the activity and manageable toxicity of erlotinib plus bevacizumab in patients with NSCLC. We did a phase 3 trial to validate the results of the JO25567 study and report here the results from the preplanned interim analysis.
In this prespecified interim analysis of the randomised, open-label, phase 3 NEJ026 trial, we recruited patients with stage IIIB-IV disease or recurrent, cytologically or histologically confirmed non-squamous NSCLC with activating EGFR genomic aberrations from 69 centres across Japan. Eligible patients were at least 20 years old, and had an Eastern Cooperative Oncology Group performance status of 2 or lower, no previous chemotherapy for advanced disease, and one or more measurable lesions based on Response Evaluation Criteria in Solid Tumours (1.1). Patients were randomly assigned (1:1) to receive oral erlotinib 150 mg per day plus intravenous bevacizumab 15 mg/kg once every 21 days, or erlotinib 150 mg per day monotherapy. Randomisation was done by minimisation, stratified by sex, smoking status, clinical stage, and EGFR mutation subtype. The primary endpoint was progression-free survival. This study is ongoing; the data cutoff for this prespecified interim analysis was Sept 21, 2017. Efficacy was analysed in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of treatment and had at least one response evaluation. Safety was analysed in all patients who received at least one dose of study drug. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000017069.
Between June 3, 2015, and Aug 31, 2016, 228 patients were randomly assigned to receive erlotinib plus bevacizumab (n=114) or erlotinib alone (n=114). 112 patients in each group were evaluable for efficacy, and safety was evaluated in 112 patients in the combination therapy group and 114 in the monotherapy group. Median follow-up was 12·4 months (IQR 7·0-15·7). At the time of interim analysis, median progression-free survival for patients in the erlotinib plus bevacizumab group was 16·9 months (95% CI 14·2-21·0) compared with 13·3 months (11·1-15·3) for patients in the erlotinib group (hazard ratio 0·605, 95% CI 0·417-0·877; p=0·016). 98 (88%) of 112 patients in the erlotinib plus bevacizumab group and 53 (46%) of 114 patients in the erlotinib alone group had grade 3 or worse adverse events. The most common grade 3-4 adverse event was rash (23 [21%] of 112 patients in the erlotinib plus bevacizumab group vs 24 [21%] of 114 patients in the erlotinib alone group). Nine (8%) of 112 patients in the erlotinib plus bevacizumab group and five (4%) of 114 patients in the erlotinib alone group had serious adverse events. The most common serious adverse events were grade 4 neutropenia (two [2%] of 112 patients in the erlotinib plus bevacizumab group) and grade 4 hepatic dysfunction (one [1%] of 112 patients in the erlotinib plus bevacizumab group and one [1%] of 114 patients in the erlotinib alone group). No treatment-related deaths occurred.
The results of this interim analysis showed that bevacizumab plus erlotinib combination therapy improves progression-free survival compared with erlotinib alone in patients with EGFR-positive NSCLC. Future studies with longer follow-up, and overall survival and quality-of-life data will be required to further assess the efficacy of this combination in this setting.
Chugai Pharmaceutical.
在接受 1 年治疗后，近一半的 EGFR 阳性非小细胞肺癌（NSCLC）患者会对第一代或第二代 EGFR 酪氨酸激酶抑制剂（TKI）单药治疗产生耐药。JO25567 期试验比较了厄洛替尼联合贝伐珠单抗与厄洛替尼单药治疗在 NSCLC 患者中的疗效和可管理的毒性，结果证实厄洛替尼联合贝伐珠单抗在 NSCLC 患者中的疗效和可管理的毒性。我们进行了一项 3 期试验来验证 JO25567 研究的结果，并在此报告预先设定的中期分析结果。
在这项随机、开放标签、3 期 NEJ026 试验的预先设定的中期分析中，我们从日本 69 个中心招募了患有 IIIB-IV 期疾病或复发性、细胞学或组织学证实的非鳞状 NSCLC 且存在激活型 EGFR 基因组异常的患者。入组患者年龄至少 20 岁，ECOG 体能状态为 2 或更低，无晚期疾病的既往化疗，并且根据实体瘤反应评估标准（1.1）有一个或多个可测量的病变。患者按照 1:1 的比例随机分配（1:1）接受口服厄洛替尼 150 mg 每天一次联合贝伐珠单抗 15 mg/kg 每 21 天一次，或厄洛替尼 150 mg 每天一次单药治疗。随机化采用最小化方法，按性别、吸烟状态、临床分期和 EGFR 突变亚型分层。主要终点是无进展生存期。该研究正在进行中；本次预先设定的中期分析数据截止日期为 2017 年 9 月 21 日。在改良意向治疗人群中进行疗效分析，该人群包括所有接受至少一剂治疗且至少有一次疗效评估的随机分配患者。在至少接受一剂研究药物的所有患者中进行安全性分析。该试验在大学医院医学信息网络临床试验注册中心注册，编号为 UMIN000017069。
在 2015 年 6 月 3 日至 2016 年 8 月 31 日期间，共招募了 228 名患者，随机分配接受厄洛替尼联合贝伐珠单抗（n=114）或厄洛替尼单药治疗（n=114）。每组各有 112 名患者可进行疗效评估，112 名接受联合治疗的患者和 114 名接受单药治疗的患者可进行安全性评估。中位随访时间为 12.4 个月（IQR 7.0-15.7）。在中期分析时，厄洛替尼联合贝伐珠单抗组的中位无进展生存期为 16.9 个月（95%CI 14.2-21.0），而厄洛替尼组为 13.3 个月（11.1-15.3）（风险比 0.605，95%CI 0.417-0.877；p=0.016）。厄洛替尼联合贝伐珠单抗组的 112 名患者中有 98 名（88%）和厄洛替尼组的 114 名患者中有 53 名（46%）发生了 3 级或更高级别的不良事件。最常见的 3-4 级不良事件是皮疹（厄洛替尼联合贝伐珠单抗组的 112 名患者中有 23 名[21%]，厄洛替尼单药组的 114 名患者中有 24 名[21%]）。厄洛替尼联合贝伐珠单抗组的 112 名患者中有 9 名（8%）和厄洛替尼单药组的 114 名患者中有 5 名（4%）发生了严重不良事件。最常见的严重不良事件是 4 级中性粒细胞减少症（厄洛替尼联合贝伐珠单抗组的 112 名患者中有 2 名[2%]）和 4 级肝功能障碍（厄洛替尼联合贝伐珠单抗组的 112 名患者中有 1 名[1%]，厄洛替尼单药组的 114 名患者中有 1 名[1%]）。没有与治疗相关的死亡。
该中期分析结果表明，在 EGFR 阳性 NSCLC 患者中，贝伐珠单抗联合厄洛替尼治疗可改善无进展生存期，优于厄洛替尼单药治疗。未来需要进行随访时间更长、总生存期和生活质量数据的研究，以进一步评估该联合治疗在该人群中的疗效。
Chugai Pharmaceutical。
