Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways

Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. Erlotinib HCl is a reversible, highly selective epidermal growth factor receptor tyrosine kinase inhibitor. Additionally, both agents have shown benefit in patients with previously treated non-small cell lung cancer (NSCLC). Preclinical data in xenograft models produced greater growth inhibition with the combination than with either agent alone. A phase I/II study in two centers examined combined erlotinib and bevacizumab treatment in patients with nonsquamous stage IIIB/IV NSCLC with one or more prior chemotherapy. In phase I, 150 mg/d erlotinib orally plus 15 mg/kg bevacizumab i.v. every 21 days was established as the phase II dose. A total of 40 patients were enrolled and treated in this study (34 patients at phase II dose): 21 were female, 30 had adenocarcinoma histology, 9 were never smokers, and 22 had two or more prior regimens. The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between erlotinib and bevacizumab. Eight patients (20.0%) had partial responses and 26 (65.0%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. Encouraging antitumor activity and safety of erlotinib plus bevacizumab support further development of this combination for patients with advanced NSCLC. A randomized phase II trial has been completed, and a phase III trial is ongoing.