Effect of Erlotinib Plus Bevacizumab vs Erlotinib Alone on Progression-Free Survival in Patients With Advanced EGFR-Mutant Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial
Effect of Erlotinib Plus Bevacizumab vs Erlotinib Alone on Progression-Free Survival in Patients With Advanced EGFR-Mutant Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2019.1847
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发表时间：
2019-10-01
期刊：
影响因子：
28.4
通讯作者：
Vokes, Everett E.
中科院分区：
文献类型：
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作者：
Stinchcombe, Thomas E.;Janne, Pasi A.;Vokes, Everett E.
关键点：厄洛替尼联合贝伐单抗治疗表皮生长因子受体（EGFR）突变型非小细胞肺癌是否上级厄洛替尼单药治疗？结果：这项2期随机临床试验发现，与厄洛替尼单药治疗相比，厄洛替尼和贝伐单抗联合治疗并没有获得上级无进展生存率。意义厄洛替尼和贝伐单抗联合治疗与厄洛替尼单药治疗相比并不具有上级疗效，本项2期多中心随机临床试验包括88例患者，比较了无进展生存期，其次是总生存期、总缓解率和不良事件，厄洛替尼联合贝伐单抗与厄洛替尼单药治疗4期EGFR突变型非小细胞肺癌患者的疗效比较。表皮生长因子受体（EGFR）突变型非小细胞肺癌（NSCLC）患者的一线治疗。厄洛替尼的中位无进展生存期（PFS）约为10个月。目的确定贝伐单抗联合厄洛替尼治疗与厄洛替尼单药治疗相比是否能获得上级无进展生存期。设计、背景和患者：这项2期随机临床试验比较了厄洛替尼联合贝伐单抗与厄洛替尼单药治疗EGFR突变型NSCLC的疗效。该试验在17家美国学术和社区医疗中心进行，纳入了88例EGFR 19号外显子缺失或21号外显子L 858 R突变（基于当地检测）和4期NSCLC患者，这些患者符合贝伐珠单抗治疗条件。患者在2012年11月2日至2016年8月22日期间入组，随访中位时间（范围）为33（0.7-62.5）个月。2018年8月28日分析了数据，包括2012年11月2日至2018年8月20日的数据。干预措施患者被随机平均分配到150 mg口服厄洛替尼每日单独或15 mg/kg静脉贝伐单抗每3周一次。研究治疗持续至疾病进展、不可接受的不良事件或撤回知情同意。主要结局和指标主要结局是研究者评估的PFS;次要结局是客观缓解率（ORR）、不良事件和总生存期（OS）。分析旨在检测PFS的风险比（HR）为0.667（中位PFS为10至15个月）。结果88例患者中位年龄63岁（31-84岁），女性62例（70%），白色75例（85%），非裔美国人8例（9%），亚裔3例（3%），未获得人种数据2例（2%）。48例患者（55%）从不吸烟，45例患者（51%）为东部肿瘤协作组体能状态1，59例患者（67%）存在EGFR外显子19缺失。与厄洛替尼相比，联合用药未导致PFS的显著差异（HR，0.81; 95% CI，0.50-1.31; P= 0.39;中位PFS 17.9个月[联合用药]和13.5个月[厄洛替尼]），ORR（81% vs 83%; P=.81）和OS（HR，1.41; 95% CI，0.71-2.81; P=.33;中位OS，32.4个月[联合用药]和50.6个月[厄洛替尼]）。在联合治疗组和厄洛替尼组5例或以上患者中观察到的3级或以上不良事件为11例（26%）vs 7例（16%）患者的皮疹，4例（9%）vs 6例（13%）患者的腹泻，17例（40%）vs 9例（20%）患者的高血压，5例（12%）vs 0例（0%）患者的蛋白尿。结论和相关性厄洛替尼联合贝伐单抗与厄洛替尼相比，EGFR突变型NSCLC患者的PFS没有显著改善。试用版RegistrationClinicalTrials.gov标识符：NCT 01532089。
Key PointsQuestionIs the combination of erlotinib and bevacizumab superior to erlotinib alone to treat epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer? FindingsThis phase 2 randomized clinical trial found that compared with erlotinib alone, the combination of erlotinib and bevacizumab did not result in superior progression-free survival. MeaningThe combination of erlotinib and bevacizumab does not have superior efficacy compared with erlotinib alone.This phase 2 multicenter randomized clinical trial including 88 patients compares progression-free survival, and secondarily overall survival, overall response rate, and adverse events, in patients with stage 4 EGFR-mutant non-small cell lung cancer treated with erlotinib plus bevacizumab vs erlotinib alone.ImportanceErlotinib is a standard first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) with erlotinib is approximately 10 months. ObjectiveTo determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone. Design, Setting, and ParticipantsThis phase 2 randomized clinical trial compared erlotinib plus bevacizumab with erlotinib alone in EGFR-mutant NSCLC. The trial was conducted in 17 US academic and community medical centers among 88 patients with EGFR exon 19 deletion or exon 21 L858R mutation based on local testing and stage 4 NSCLC who were eligible for bevacizumab. Patients were enrolled between November 2, 2012, and August 22, 2016, and followed up for a median (range) of 33 (0.7-62.5) months. Data were analyzed on August 28, 2018, and included data from November 2, 2012, to August 20, 2018. InterventionsPatients were randomized with equal allocation to 150 mg of oral erlotinib daily alone or with 15 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent. Main Outcomes and MeasuresThe primary outcome was PFS as assessed by the investigator; secondary outcomes were objective response rate (ORR), adverse events, and overall survival (OS). Analysis was designed to detect a hazard ratio (HR) of 0.667 for PFS (an improvement from a median PFS of 10 to 15 months). ResultsAmong 88 patients enrolled, the median (range) age was 63 (31-84) years; 62 patients (70%) were female; 75 (85%) were white, 8 (9%) were African American, 3 (3%) were Asian, and for 2 (2%), data on race were not available. Forty-eight patients (55%) were never smokers, 45 patients (51%) were of Eastern Cooperative Oncology Group performance status 1, and 59 patients (67%) had EGFR exon 19 deletion. Compared with erlotinib, the combination did not result in a significant difference in PFS (HR,0.81; 95% CI, 0.50-1.31; P=.39; median PFS 17.9 [combination] and 13.5 months [erlotinib]), ORR (81% vs 83%; P=.81), and OS (HR,1.41; 95% CI, 0.71-2.81; P=.33; median OS, 32.4 months [combination] and 50.6 months [erlotinib]). Adverse events of grade 3 or higher observed in 5 or more patients in the combination and erlotinib arms were skin eruption in 11 (26%) vs 7 (16%) patients, diarrhea in 4 (9%) vs 6 (13%) patients, hypertension in 17 (40%) vs 9 (20%) patients, and proteinuria in 5 (12%) vs 0 (0%) patients. Conclusions and RelevanceErlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC. Trial RegistrationClinicalTrials.gov identifier: NCT01532089.