title: 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: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy. Electronic address: cgridelli@libero.it.
authors.forename: Cesare
authors.initials: C
authors.lastname: Gridelli
authors.affiliation: Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Division of Medical Oncology and Hematology, Second University of Naples, Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: De Marinis
authors.affiliation: Division of Medical Oncology, University of Perugia, Perugia, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Crinò
authors.affiliation: Thoraco-Pulmonary Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"- IRCCS, Naples, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morabito
authors.affiliation: Division of Medical Oncology and Hematology, Second University of Naples, Naples, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Morgillo
authors.affiliation: Thoraco-Pulmonary Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"- IRCCS, Naples, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Montanino
authors.affiliation: Clinical Trials Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"- IRCCS, Naples, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Daniele
authors.affiliation: Clinical Trials Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"- IRCCS, Naples, Italy.
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Piccirillo
authors.affiliation: Cellular Biology and Biotherapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione Giovanni Pascale, IRCCS, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Normanno
authors.affiliation: Medical Statistics, Second University of Naples, Naples, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Gallo
authors.affiliation: Clinical Trials Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"- IRCCS, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perrone
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011788:Quality of Life; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Adenocarcinoma; Epidermal growth factor receptor; Metastatic; NSCLC; Tyrosine kinase inhibitor