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Original Investigation
August 8, 2019

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

Author Affiliations
  • 1Duke Cancer Institute, Durham, North Carolina
  • 2Dana Farber Cancer Institute, Boston, Massachusetts
  • 3Alliance Data and Statistical Center, Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
  • 4The Ohio State University Comprehensive Cancer Center, Columbus
  • 5University of North Carolina Lineberger Cancer Center at Chapel Hill
  • 6Moores Cancer Center, University of California, San Diego
  • 7Saint Vincent Hospital Cancer Center, Green Bay, Wisconsin
  • 8Illinois Cancer Care-Peoria, Peoria, Illinois
  • 9Division of Medical Oncology, Washington University School of Medicine in St Louis, Missouri
  • 10Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse
  • 11Spartanburg Regional Health, Spartanburg, South Carolina
  • 12Biological Sciences Division, University of Chicago Medicine, Chicago, Illinois
JAMA Oncol. Published online August 8, 2019. doi:10.1001/jamaoncol.2019.1847
Key Points

Question  Is the combination of erlotinib and bevacizumab superior to erlotinib alone to treat epidermal growth factor receptor (EGFR)–mutant non–small cell lung cancer?

Findings  This 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.

Meaning  The combination of erlotinib and bevacizumab does not have superior efficacy compared with erlotinib alone.


Importance  Erlotinib 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.

Objective  To determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone.

Design, Setting, and Participants  This 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.

Interventions  Patients 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 Measures  The 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).

Results  Among 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 Relevance  Erlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC.

Trial Registration  ClinicalTrials.gov identifier: NCT01532089.