Elsevier

Clinical Lung Cancer

Volume 13, Issue 2, March 2012, Pages 96-106
Clinical Lung Cancer

Review
Safety Profile and Tolerability of Antiangiogenic Agents in Non–Small-Cell Lung Cancer

https://doi.org/10.1016/j.cllc.2011.08.006Get rights and content

Abstract

Recent advances in understanding the importance of angiogenesis to tumor growth and distant metastasis has driven the development of antiangiogenic therapies for the treatment of non–small-cell lung cancer (NSCLC). The anti–vascular endothelial growth factor (VEGF) monoclonal antibody, bevacizumab, is the only US Food and Drug Administration–approved antiangiogenic agent for advanced NSCLC. Accumulated safety data with bevacizumab in NSCLC shows that patients are at risk for hemorrhage, venous thromboembolism, hypertension, and proteinuria. Investigational agents that target VEGF via a different mechanism (such as aflibercept [VEGF Trap]) or simultaneously inhibit multiple molecular pathways involved in angiogenesis (ie, multitargeted tyrosine kinase inhibitors [TKIs]) and vascular disrupting agents (VDAs) that target existing tumor vasculature are in various stages of clinical development for NSCLC, and safety profiles are emerging for these classes of agents. This review describes the molecular rationale for targeting angiogenic pathways in anticancer therapy and summarizes safety and tolerability data from clinical trials of bevacizumab or aflibercept in combination with chemotherapy and the investigational TKIs and VDAs in patients who have advanced NSCLC.

Introduction

Lung cancer, primarily non–small-cell lung cancer (NSCLC), ranks as the primary cause of cancer-related deaths for both men and women in the United States.1 The 5-year overall survival (OS) rate of lung cancer patients remains poor at < 20%.1 Two-drug chemotherapy combinations administered for up to 4 to 6 cycles is standard first-line therapy for advanced NSCLC. Recent data have shown that use of a switch-maintenance strategy after completion of 4 cycles of two-drug combination therapies can enhance survival.2 It is well-recognized, however, that the use of chemotherapy for advanced NSCLC, albeit associated with improved survival over best supportive care, shows only modest activity,3, 4 and is a recommended option only for patients who have good performance status (PS).2

The clinical scenario for treatment options in advanced NSCLC has undergone notable changes in recent years, including the newly recognized importance of the role of angiogenesis in tumor development and disease progression5, 6 and the subsequent development of targeted antiangiogenic therapy. The anti–vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin, Genentech; South San Francisco, CA) is the first, and at present, the only US Food and Drug Administration (FDA)–approved antiangiogenic therapeutic agent for advanced NSCLC. Bevacizumab is indicated in combination with chemotherapy in patients meeting certain criteria; one of these criteria is nonsquamous histology due to an increased risk of pulmonary hemorrhage observed in the squamous cell subset of clinical trial participants.7 The accumulated clinical safety data with bevacizumab across tumor types has revealed a risk of serious nonhematologic toxicities, including bleeding/hemorrhage, thromboembolic events (TEs), gastrointestinal perforation, hypertension, and proteinuria. In NSCLC, the highest relative risks were for hemorrhage, venous thromboembolic events (VTEs), and proteinuria.8, 9, 10 Bevacizumab is therefore not recommended for patients with hemorrhage or recent hemoptysis.11 It is also becoming apparent that the risk of some relatively rare adverse events (AEs) may be increased in specific treatment settings; for example, tracheoesophageal fistula formation has been reported among patients treated with bevacizumab plus chemotherapy during or after radiation for lung cancer (NSCLC or small-cell lung cancer).12, 13, 14

Antiangiogenic agents that target VEGF by a different mechanism of action or target multiple angiogenic-signaling pathways such as the tyrosine kinase inhibitors (TKIs), as well as those that exert their effects on existing tumor vasculature such as vascular disrupting agents (VDAs), are being investigated in phase II/III clinical trials in NSCLC. Emerging safety and tolerability data for these agents as a class and as individual therapies are being evaluated.

This review provides an overview of the molecular rationale for targeting angiogenic pathways as anticancer therapy and focuses on safety/tolerability data obtained in phase II/III clinical trials with bevacizumab, the antiangiogenic fusion protein aflibercept (VEGF Trap, Regeneron; Tarrytown, NY), and the multitargeted TKIs (sorafenib [Nexavar, Bayer; Leverkusen, Germany], sunitinib [Sutent, Pfizer; New London, CT], BIBF 1120 [Boehringer Ingelheim; Ingelheim, Germany], cediranib [Recentin, AstraZeneca; Wilmington, DE], and axitinib [Pfizer; New London, CT]), and with VDAs (ASA404 [Novartis; Cambridge, MA]), each of which is currently being evaluated in clinical trials in NSCLC.

Section snippets

Rationale

The elucidation that angiogenesis plays a fundamental role in both tumor development and disease progression5, 6 represents one of the most notable advancements in cancer biology from a therapeutic standpoint. In fact, intratumoral microvessel density, which has become the gold standard for the quantification of tumor angiogenic activity, has been shown to have independent prognostic value for survival in patients with various malignancies, including lung cancer.15, 16, 17 Of all known

Targeting Existing Vasculature in NSCLC

Antiangiogenic approaches to anticancer therapy are capable of affecting new blood vessel growth, thereby affecting the growth and spread of tumor cells. However, VDAs represent a means of attenuating already established tumor vasculature, with the ultimate goal of tumor ischemia and necrosis.69 There are two main types of VDAs: ligand-directed and small-molecule agents, the latter of which consists of flavonoids and tubulin-binding agents.69 ASA404, a small-molecule flavonoid undergoing phase

Future Directions

Because of the safety and efficacy limitations of currently available targeted antiangiogenic therapy, additional agents are needed for the treatment of patients who have NSCLC. Trials are ongoing that will further elucidate the toxicities associated with multitargeted TKIs compared with bevacizumab or traditional chemotherapy. Trials with bevacizumab are also investigating its use for patients who were previously excluded from treatment (eg, those with squamous histology).

Using prognostic and

Conclusions

Because of the safety and efficacy limitations of currently available chemotherapy regimens, novel agents are needed for the treatment of patients who have advanced NSCLC. The safety/tolerability profile of bevacizumab in patients with advanced NSCLC has been well-documented based on published phase III experience, and trials are ongoing in combination regimens, and in patients who were previously excluded from treatment (eg, those with squamous histology). Accumulation of safety data is also

Disclosure

Dr. Gadgeel has received research support from AstraZeneca Pharmaceuticals LP. He has served as a member of the Speakers' bureau for Genentech, Inc., and as a member of the Advisory Board for AstraZeneca Pharmaceuticals LP, Genentech, Inc., and Boehringer Ingelheim Pharmaceuticals, Inc.

Acknowledgments

This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). Writing and editorial assistance was provided by Alyssa Tippens, PhD, of MedErgy, which was contracted by BIPI for these services. The author met criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), was fully responsible for all content and editorial decisions, and was involved at all stages of manuscript development. The author received no compensation related to

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