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

Abstract

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.