Multitargeted Tyrosine Kinase Inhibitors in Unselected Patients With Advanced Non–Small-Cell Lung Cancer (NSCLC): Impressions From MONET (the Motesanib NSCLC Efficacy and Tolerability Study)

Abstract

Angiogenesis is a complex and tightly regulated process that is defined as the growth of new blood vessels, especially those that supply oxygen and nutrients to cancerous tissue, from existing vasculature. Because of the critical role of angiogenesis in the growth and metastases from solid tumors, including non–small-cell lung cancer (NSCLC), its inhibition represents a rational therapeutic strategy. Vascular endothelial growth factor (VEGF) is a key ligand and regulator of both physiologic and pathologic angiogenesis, including that of tumors, with signaling occurring mainly through the VEGF receptor 2 (VEGFR-2). Bevacizumab, a humanized monoclonal antibody against circulating VEGF, was the first antiangiogenesis drug to enter clinical practice for NSCLC. Because of an increased risk of life-threatening bleeding among patients with squamous cell carcinoma in the phase II trial, subsequent trials were limited to nonsquamous histology. The addition of bevacizumab to chemotherapy was associated with improved response rate (RR) and progression-free survival (PFS) in two large randomized trials, Eastern Cooperative Oncology Group (ECOG) 4599 and Avastin in Lung (AVAiL), although only ECOG 4599 was associated with improved overall survival (OS). Unfortunately, the benefit from bevacizumab in patients with advanced NSCLC is modest and transient, with essentially all responding patients developing secondary resistance. One of the mechanisms that is implicated in the development of resistance is the stimulation of compensatory proangiogenic factors such as fibroblast growth factor and platelet-derived growth factor(PDFGR). Tyrosine kinase inhibitors (TKIs) compete with adenosine triphosphate for the active site of the kinase domain. Because of the well-conserved adenosine triphosphate binding sites of the kinases, many TKIs (unlike bevacizumab, which exclusively targets the VEGF ligand) inhibit multiple receptors. This ability to inhibit multiple angiogenesis pathways offers the potential for increased efficacy and decreased development of secondary resistance through redundant pathways. Nevertheless, the decreased specificity may be associated with increased toxicity. Given that single-agent TKIs directed against similar targets such as sorafenib (VEGF-R2, VEGFR-3, PDGFR, RAF-1, BRAF, c-KIT, FLT-3), sunitinib (VEGFR-2, PDGFR, FLT-3, c-KIT, RET), and axitinib (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, c-KIT) have been well tolerated in NSCLC, the next step would be to pursue their combination with chemotherapy or other biologic agents. Several randomized clinical trials comparing chemotherapy alone or with the addition of TKIs have been conducted (Table 1). In phase II studies, neither the addition of vandetanib nor cediranib improved the median PFS or OS compared with chemotherapy alone using carboplatin and paclitaxel. Lack of OS improvement was also observed in the two randomized phase III studies in the first-line setting, the Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy (ESCAPE) and NSCLC Research Experience Utilizing Sorafenib (NExUS), as well as in previously treated patients. Motesanib is a small-molecule targeted antagonist of VEGF receptors 1, 2, and 3, PDGFR, and KIT. In the phase IB study, five (17%) of 29 patients who were treated with motesanib (50 mg per day, 125 mg per day, or 75 mg twice per day) in combination with carboplatin and paclitaxel achieved partial response. Because of increased toxicity, the twice-daily cohort was discontinued. The recommended motesanib dose for subsequent studies was 125 mg once per day, which had already been established as the maximum-tolerated dose for singleagent therapy. In the phase II study, there were no significant differences in outcomes between patients treated with carboplatin plus paclitaxel and either bevacizumab or motesanib. In the article that accompanies this editorial, Scagliotti et al present the results of the Motesanib NSCLC Efficacy and Tolerability (MONET1) trial, a multicenter, randomized, double-blind phase III trial comparing carboplatin and paclitaxel alone or in combination with motesanib 125 mg per day as first-line therapy for NSCLC. The primary end point was OS. All tumor types were initially included, but squamous cell carcinoma was excluded after increasing gross hemoptysis and mortality JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 23 AUGUST 1