Challenges in the current antiangiogenic treatment paradigm for patients with non-small cell lung cancer

Abstract

Patients with non-small cell lung cancer (NSCLC) often present with advanced disease and cure rates are dismal with currently available treatment. Novel therapies including small molecule tyrosine kinase inhibitors and monoclonal antibodies are being developed to target angiogenesis, an essential step in tumorigenesis and metastasis. The only antiangiogenic agent currently approved for treatment of NSCLC is bevacizumab, although numerous other antiangiogenic inhibitors (e.g., sorafenib, sunitinib, cediranib, motesanib, BIBF 1120) are in clinical trials. Individualized treatment algorithms may improve patient outcomes and new evidence suggests that biomarkers may guide treatment decisions. We present an overview of the molecular pathways involved in angiogenesis, discuss clinical trials of bevacizumab and developmental antiangiogenic agents, and address the challenges of developing individualized treatment paradigms for NSCLC, particularly the use of biomarkers.

Introduction

Lung cancer is the leading cause of cancer-related deaths in the United States and worldwide [1], [2]. The American Cancer Society reported an estimated 222,520 new cases and 157,300 lung cancer-related deaths for 2010 in the United States alone [2]. The 5-year survival rate was 15.2% for all stages of lung cancer and 2.8% for lung cancer patients diagnosed with distant metastases [3]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases [3]. While surgery is usually recommended for patients with localized disease, approximately 80% of patients present with locally advanced or metastatic NSCLC [4], [5] and thus may also require radiation and/or systemic chemotherapy [5]. The use of platinum-based doublets (carboplatin or cisplatin plus a cytotoxic agent) is common in the treatment of NSCLC [5]. With the exception of a significant overall survival (OS) benefit with cisplatin plus pemetrexed vs cisplatin plus gemcitabine for treating tumors of nonsquamous histology (and cisplatin/pemetrexed inferior to cisplatin/gemcitabine for squamous histology) as first-line chemotherapy [6], few particular drug combinations have been identified as superior to others [7]. In general, chemotherapy only provides modest clinical benefit and can be associated with significant toxicity [8].

Recently, small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies that target specific pathways and processes have been developed and integrated into treatment algorithms for NSCLC [5]. Erlotinib (Tarceva^®, Genentech; South San Francisco, CA, USA) and gefitinib (Iressa™, AstraZeneca; Wilmington, DE, USA) are reversible TKIs that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with NSCLC [9], [10]. Another targeted agent is bevacizumab (Avastin^®, Genentech; South San Francisco, CA, USA), a monoclonal antibody that binds vascular endothelial growth factor (VEGF), a key mediator of angiogenesis. Although bevacizumab is the only antiangiogenic agent currently approved for treatment of NSCLC, many others are under development. In this article, we provide an overview of angiogenesis as a therapeutic target in NSCLC, summarize agents in use and in development for the treatment of NSCLC, and discuss current challenges in antiangiogenic treatment, with a focus on the use of biomarkers.