BEVERLY: Rationale and Design of a Randomized Open-Label Phase III Trial Comparing Bevacizumab Plus Erlotinib Versus Erlotinib Alone as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous Non-Small-Cell Lung Cancer

Clin Lung Cancer. 2016 Sep;17(5):461-465. doi: 10.1016/j.cllc.2016.04.001. Epub 2016 Apr 22.


Background: About 20% of advanced non-small-cell lung cancer (NSCLC) cases harbor somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene. In these patients, the standard first-line treatments are the EGFR-tyrosine kinase inhibitors, such as gefitinib, erlotinib, or afatinib. Most of these patients develop resistance and relapse within about 1 year of initiation of an EGFR-tyrosine kinase inhibitor. Consequently, it is important to develop new combination strategies to delay this resistance. Preclinical data have showed that EGFR and vascular endothelial growth factor (VEGF) share a common downstream pathway, suggesting the important role of VEGF in the resistance to EGFR blockade. The combination of erlotinib and bevacizumab, an anti-VEGF agent, showed very interesting clinical results.

Patients and methods: The bevacizumab plus erlotinib study (BEVERLY) is a randomized, open-label, phase III trial investigating first-line erlotinib plus bevacizumab versus erlotinib in patients with advanced NSCLC harboring activating EGFR mutations. The co-primary endpoints are investigator-assessed progression-free survival (PFS) and blinded, independent centrally reviewed PFS. The secondary endpoints include overall survival, quality of life, objective response rate, and safety. A total of 200 patients will be randomized 1:1 to receive oral erlotinib (150 mg daily) plus bevacizumab (15 mg/kg, intravenously, on day 1 of every 21-day cycle) or erlotinib alone, until objective disease progression or unacceptable toxicity or the patient's or physician's motivated decision to stop the treatment.

Conclusion: If the primary endpoint of PFS is met, the erlotinib plus bevacizumab combination will be confirmed as the best first-line treatment for patients with advanced NSCLC harboring activating EGFR mutations.

Keywords: Adenocarcinoma; Epidermal growth factor receptor; Metastatic; NSCLC; Tyrosine kinase inhibitor.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab / administration & dosage
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics*
  • Erlotinib Hydrochloride / administration & dosage
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mutation
  • Neoplasm Recurrence, Local
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / therapeutic use
  • Quality of Life
  • Survival Rate
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors


  • Protein Kinase Inhibitors
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors