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Exploring the Benefit/Risk Associated with Antiangiogenic Agents for The Author Manuscript Published OnlineFirst on December 9, 2016; DOI: 10.1158/1078-0432.CCR-16-1968 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title: Exploring the Benefit/Risk Associated With Antiangiogenic Agents for the Treatment of Non–Small Cell Lung Cancer Patients Running title: Benefit/Risk of Antiangiogenic Agents in NSCLC Authors: Razelle Kurzrock,1 David J. Stewart2 Affiliations: 1Center for Personalized Cancer Therapy and Division of Hematology & Oncology, University of California San Diego Moores Cancer Center, San Diego, CA, USA; 2Division of Medical Oncology, University of Ottawa, Ottawa, Canada. Financial Support: Writing, editorial support, and formatting assistance was provided by Melissa Brunckhorst, PhD, of MedErgy, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. Corresponding Author: Razelle Kurzrock UC San Diego - Moores Cancer Center 3855 Health Sciences Drive, MC #0658 La Jolla, California 92093-0658 Phone: (858) 246-1102 Fax: (858) 246-1915 Email: [email protected] Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 9, 2016; DOI: 10.1158/1078-0432.CCR-16-1968 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Keywords: NSCLC, antiangiogenic, biomarkers, adenocarcinoma, VEGF Disclosure of Potential Conflicts of Interest: D.J. Stewart reports receiving commercial research grants from Pfizer Canada and Roche Canada; has received speakers bureau honoraria from Pfizer Canada; and has been a consultant/advisory board member for Amgen, Amgen Canada, Roche Canada, Pfizer Canada, Boehringer Ingelheim Canada, and Novartis Canada. R. Kurzrock receives research funds from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant, as well as consultant/advisory board fees from Actuate Therapeutics, and Xbiotech, and an ownership interest in Novena, Inc., and Curematch, Inc. Authors’ Contributions: Conception and design: R. Kurzrock and D.J. Stewart Analysis and interpretation of data (e.g, statistical analysis, biostatistics, computational analysis): R. Kurzrock and D.J. Stewart Writing, review, and/or revision of the manuscript: R. Kurzrock and D.J. Stewart Word Count (excluding references): 3,481 Number of Figures/Tables: 1 Figure/3 Tables 2 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 9, 2016; DOI: 10.1158/1078-0432.CCR-16-1968 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Following the approval of bevacizumab, an antibody targeting vascular endothelial growth factor-A (VEGF-A), for advanced non-squamous non–small cell lung cancer (NSCLC) in 2006, intensive efforts were put into the clinical development of antiangiogenic agents for NSCLC. Currently, the other antiangiogenic agents approved for NSCLC are ramucirumab, a VEGF receptor-2 (VEGFR-2)-targeting antibody indicated for both squamous and non-squamous NSCLC in the United States, and nintedanib, an anti–VEGFR-1/2/3, platelet-derived growth factor receptor (PDGFR)-α/β, fibroblast growth factor receptor (FGFR)-1/2/3 angiokinase inhibitor indicated for adenocarcinoma of the lung in the European Union. Many other antiangiogenic agents are being evaluated in phase III trials for NSCLC, including aflibercept, sunitinib, sorafenib, cediranib, and vandetanib. Although many of the same signaling pathways are targeted by these novel agents, mixed efficacy results have been observed in these trials. Moreover, safety issues have raised concerns about using antiangiogenic agents in this patient population, and fatal bleeding events have been reported. Importantly, although no biomarker has yet been validated for antiangiogenic agents in NSCLC, biomarkers that show potential include circulating levels of short VEGF-A isoforms, expression of neuropilin-1 and VEGFR-1 in tumors and plasma, genetic variants in VEGF-A and VEGFR, and TP53 mutations (with the latter having been shown to correlate with increased levels of VEGF-A transcripts). This review provides an overview of the clinical benefit and risk associated with the use of antiangiogenic agents for NSCLC, and summarizes the research to date on the identification of predictive biomarkers for antiangiogenic therapies. 3 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 9, 2016; DOI: 10.1158/1078-0432.CCR-16-1968 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Lung cancer ranks as the leading cause of cancer-related death in the United States (US), accounting for approximately 150,000 deaths (about 27% of all cancer deaths) in 2015 alone (1), and is the second overall leading cause of death in the US after heart disease (2). For the lung cancer population diagnosed between 2003 and 2009, the 1-year and 5- year survival rates were 43% and 17%, respectively (3), reflecting the high rate of surgically unresectable, advanced disease that is not amenable to curative treatment. Furthermore, patients with lung cancer exhibit lower survival rates at each stage (I-IV) than those of patients with other common cancers, such as breast and colon cancer (4-7). Non–small cell lung cancer (NSCLC) accounts for approximately 84% of lung cancer diagnoses in the US (3). In terms of targeted therapy for advanced NSCLC, initial success was observed with epidermal growth factor receptor (EGFR) inhibitors in the setting of activating EGFR mutations (8). Another approach has been to target angiogenesis, which is important in tumor growth and metastasis (9), by directing agents against the vascular endothelial growth factor (VEGF) family of growth factors and receptor tyrosine kinases, as well as other proangiogenic factors (10). Although VEGF is expressed by many types of cancer cells, including NSCLC (11), several proangiogenic factors also impact tumorigenesis, including platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF; Figure 1) (12). The different types of NSCLC have exhibited different angiogenic vascular patterns. Microvascular density was consistently higher in adenocarcinoma than in squamous 4 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 9, 2016; DOI: 10.1158/1078-0432.CCR-16-1968 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. NSCLC (13-15), and was variable in large cell NSCLC (13, 14). As visualized by narrow band imaging videobronchoscopy, dotted blood vessels (short capillary loops visible as pinpoint dots) were more common in adenocarcinoma than in squamous cell NSCLC and were not observed in large cell NSCLC. Tortuous blood vessels were much more common in squamous cell NSCLC than in adenocarcinoma and large cell NSCLC, and abruptly ending blood vessels were more common in squamous cell NSCLC than in adenocarcinoma and were not observed in large cell NSCLC (16). The mean diameter of microvessels appeared to be greater in squamous cell and large cell NSCLC than in adenocarcinoma (15, 17). Despite the impact of multiple proangiogenic factors on tumorigenesis, the anti-VEGF monoclonal antibody (mAb) bevacizumab, the anti-VEGF receptor-2 (VEGFR-2) mAb ramucirumab, and the anti-VEGFR-1/2/3, PDGF receptor (PDGFR)-α/β, and FGF receptor (FGFR)-1/2/3 multitargeted tyrosine kinase inhibitor (TKI) nintedanib are the only antiangiogenic agents approved for NSCLC in the US and/or Europe as of this writing, with large clinical trials demonstrating efficacy in combination with chemotherapy (all containing taxanes) in advanced non-squamous NSCLC (bevacizumab and ramucirumab), squamous NSCLC (ramucirumab), or adenocarcinoma of the lung (nintedanib) (18-22). While clinical development of other antiangiogenic therapies for advanced NSCLC remains an important priority in this field, identification of predictive biomarkers for 5 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 9, 2016; DOI: 10.1158/1078-0432.CCR-16-1968 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. antiangiogenic agents is still a source of unrealized clinical benefit for this class of agents. The Benefits and Risks of Approved Antiangiogenic Therapy for Advanced NSCLC A major limitation associated with antiangiogenic agents is that many of these drugs, including bevacizumab, are suitable only for patients with non-squamous disease (21). Concerns surrounding treatment of squamous NSCLC with antiangiogenic agents stemmed from an increased risk of serious bleeding events observed in an early randomized trial of bevacizumab (23), as well as reports of adverse safety signals in subsequent trials involving antiangiogenic agents (24, 25); at the same time, however, clinical development of other antiangiogenic agents has not been restricted based on NSCLC histology (Table 1). In addition, the small population of patients with uncommon non-squamous tumors (those other than adenocarcinoma)
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