Review
Targeted Therapy for Metastatic Colorectal Cancer: Role of Aflibercept

https://doi.org/10.1016/j.clcc.2012.08.001Get rights and content

Abstract

Worldwide, colorectal cancer (CRC) is the third most commonly diagnosed cancer in male individuals and the second most commonly diagnosed cancer in female individuals. Survival outcomes are less than optimal for patients with metastatic disease, with a 5-year survival in the 5% to 8% range. The development of new chemotherapeutic agents and effective combination regimens for metastatic colorectal cancer (mCRC) has increased median overall survival (OS) to the 24- to 28-month range. Because of the recognition that vascular endothelial growth factors (VEGFs) and their receptors are primary regulators of physiologic and pathologic angiogenesis and lymphangiogenesis, leading to neovascularization and tumor growth, the targeting of the angiogenic pathway has become a focus of key therapeutic strategies in mCRC. Therapeutic regimens that include bevacizumab, an inhibitor of VEGF-A, in combination with cytotoxic chemotherapy, have resulted in improved response rate (RR) and survival in mCRC. However, the effects of VEGF-A inhibition are often temporary, with resistance and disease progression developing in most patients. Proposed models include intrinsic and adaptive resistance, mediated by factors other than VEGF-A. Aflibercept (known as ziv-aflibercept in the United States; Zaltrap®, Regeneron Pharmaceuticals; sanofi-aventis), a novel recombinant fusion protein, is an angiogenic factor trap that blocks the binding of VEGF-A, VEGF-B, and placental growth factor. Phase I/II clinical trials have demonstrated effective activity in mCRC, with acceptable safety and tolerability. A recent phase III randomized double-blind trial in patients previously treated with oxaliplatin reported significant improvement in OS, progression-free survival (PFS), and RR with aflibercept compared with placebo when administered in combination with irinotecan and fluorouracil. Adverse events were consistent with anti-VEGF therapy. Thus aflibercept represents a potential new treatment option for patients with mCRC.

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in male individuals and the second most commonly diagnosed cancer in female individuals, with more than 1.2 million new cases worldwide; in 2008 it was the cause of 608,700 deaths.1 Although CRC incidence and death rates have shown decreases in the United States, it is anticipated that 143,460 new cases of CRC will be diagnosed and approximately 51,690 Americans will die of the disease, accounting for approximately 9% of cancer deaths.2 The lifetime incidence of CRC in patients at average risk is approximately 5%, with 90% of cases occurring after age 50 years.3 In the United States, CRC incidence declined roughly 2% to 3% per year between 1992 and 2008.4 Information from the Surveillance Epidemiology and End Results (SEER) database suggests that incidence rates are increasing in the 40- to 44-year age group.5 Furthermore, CRC incidence in the United States is 25% higher in men than in women and is almost 20% higher in African Americans than in whites.2 For most patients with metastatic disease, treatment remains palliative, and survival outcomes are less than optimal. Despite advances in management, metastatic disease is associated with poor 5-year survival, with a rate of approximately 10%.6 It is estimated that 20% of patients with CRC have metastatic disease at the time of diagnosis, whereas many others will experience metastases during the course of the disease.7 SEER data suggest that 64% of all patients, including all stages of disease, who are treated for CRC survive 5 years.3 A recent clinical trial achieved an overall survival (OS) rate of 72.9% at 6 years in patients with stage III disease who were treated with oxaliplatin-based postoperative adjuvant chemotherapy.8

In the early 1970s, Folkman et al reported the importance of novel growth and remodeling of blood vessels in the growth and proliferation of tumors.9 This work led to the development of biological agents that target angiogenesis. The elucidation of the role of vascular endothelial growth factors (VEGFs) in tumorigenesis contributed to important advances for the treatment of patients with a variety of solid tumors, including metastatic CRC (mCRC). During the past 2 decades, the addition of bevacizumab combined with cytotoxic chemotherapy has resulted in unprecedented advances in the treatment of mCRC, with improved response, progression-free survival (PFS), and OS.10, 11 This review will discuss the role of angiogenesis in mCRC, the principles of resistance to antiangiogenic therapy, and the development of aflibercept (known as ziv-aflibercept in the United States; Zaltrap®, Regeneron Pharmaceuticals; sanofi-aventis) as a novel antiangiogenic agent for mCRC.

Section snippets

Angiogenesis

Angiogenesis is a pivotal process for growth, invasion, and metastasis in many solid tumors.9, 12 Although physiologic angiogenesis is a highly regulated process,13, 14 pathologic angiogenesis manifests as an abnormal increase in proliferating endothelial cells and as structural and functional abnormalities of tumor vasculature.15, 16 These abnormalities include loss of normal vascular hierarchy, development of an irregular and leaky endothelial layer, compression of vessels, abnormal blood

Aflibercept

Aflibercept, a soluble recombinant fusion protein, is a multiple angiogenic factor trap rationally designed to block the angiogenesis network by not only binding VEGF-A but also uniquely targeting VEGF-B and PlGF.55, 56, 57 Aflibercept was developed by fusing sections of the second immunoglobulin (Ig) domain of VEGFR-1 and the third Ig domain of VEGFR-2 to the Fc portion of human IgG1 (Figure 2).55, 58 Aflibercept has now been approved by the US Food and Drug Administration, with the US name of

Clinical Trials

The efficacy and safety of aflibercept alone or in combination with various chemotherapy regimens has been explored in several phase I56, 63, 71, 72, 73, 74, 75, 76 and phase II77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 trials in patients with advanced solid tumors or non-Hodgkin lymphoma. Solid tumors included breast, colorectal, endometrial, gastric, glioblastoma, lung, melanoma, ovarian, pancreas, sarcoma, thyroid, urothelial, and others. Aflibercept has also been investigated in a phase III

Possible Role for Aflibercept in Therapy

As new therapies for second-line treatment of mCRC are introduced, it is important to develop an understanding of their potential role in treatment. Since bevacizumab is a standard treatment for second-line management of patients with mCRC, comparison of aflibercept with bevacizumab may provide some insight regarding the potential role for aflibercept. Although there is no prospective comparison of aflibercept with bevacizumab, examination of relevant clinical trials such as the phase III

Conclusion

Aflibercept is a multiple angiogenic factor trap that binds VEGF-A, VEGF-B, and PlGF. Clinical trials demonstrate effective antitumor activity with an acceptable safety and tolerability profile. In VELOUR and a phase II trial of patients with mCRC, no unexpected AEs were reported, and AEs observed were those typically associated with anti-VEGF agents, namely hypertension and proteinuria. The phase III VELOUR trial showed that patients with mCRC receiving aflibercept in combination with FOLFIRI

Disclosure

The author retained full editorial control over the content of the manuscript and received no compensation from any party for her work. E.P.M. discloses that she acts as a consultant to sanofi-aventis, U.S. LLC and Regeneron Pharmaceuticals; her institution also receives research support from Genentech Inc.

Acknowledgments

Medical editorial writing assistance was provided by Samantha Taylor, PhD, and Alfredo Toschi, PhD, of Phase Five Communications Inc., supported by sanofi-aventis, U.S. LLC, in collaboration with Regeneron Pharmaceuticals. The author retained full editorial control over the content of the manuscript and received no compensation from any party for her work. E.P.M. discloses that she acts as a consultant to sanofi-aventis, U.S. LLC and Regeneron Pharmaceuticals; her institution also receives

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