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 protein-uria. Preliminary data showed no pharmacokinetic interaction between erlotinib and a 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.