Novel anti-angiogenic therapeutic strategies in colorectal cancer

ABSTRACT

Introduction: Anti-angiogenetic agents are currently the standard of care in metastatic CRC patients. Bevacizumab, aflibercept, regorafenib and recently ramucirumab have significantly improved both progression-free and overall survival in different lines of treatment. Since bevacizumab’s approval, a number of novel anti-VEGF agents have been tested in preclinical and clinical models.

Areas covered: This review is focused on the most recent clinical results of novel agents targeting VEGF and its receptors with a major focus on those investigated recently in clinical trials.

Expert opinion: In the last 15 years, a number of new anti-angiogenetic agents have been tested. Unfortunately, most of them have demonstrated unacceptable toxicities or failed to show activity. When tested as single agents, encouraging preliminary results were reported with fruquintinib, famitinib, and nintedanib. Interesting novel mechanisms of action are also being explored: VGX-100 is a monoclonal antibody (mAb) which binds to VEGF-C, inhibiting activation of VEGFR-2 and VEGFR-3 when combined with bevacizumab; tanibirumab is a mAb which binds to VEGFR-2 and vanucizumab is a bispecific mAb binding both to VEGF-A and Angiopoietin-2. Data about the combination of these agents with chemotherapy are very encouraging, even though preliminary. However, the definition of specific predictive biomarkers remains a priority.

KEYWORDS:

• Angiogenesis
• anti-VEGF inhibitors
• colorectal cancer
• receptor TKI

Article highlights

• Angiogenesis is a complex process, mainly regulated by VEGF pathway, and its inhibition is safe and active in patients with mCRC. Several mechanisms of intrinsic or acquired resistance to anti-VEGF therapy have been hypothesized.

• Several agents have been authorized by regulatory agencies for the treatment of mCRC patients: among these drugs, monoclonal antibodies (bevacizumab and ramucirumab), a recombinant fusion protein consisting of portions from human VEGF receptors 1 and 2 fused to a portion of the human IgG1 immunoglobulin (aflibercept) and an oral multi-kinase inhibitor (regorafenib).

• No patient selection is possible, because no predictive marker of response has ever been described and validated.

• Only few circulating biomarkers, dynamically evaluated during therapy, have shown a potential predictive role, although their clinical utility in this sense has not been demonstrated.

• New antiangiogenic compounds have been tested; the great majority of them are multikinase inhibitors. Unfortunately, many of them have been abandoned, due to poor activity or unfavorable safety profile.

This box summarizes key points contained in the article.

Declaration of interest

M Tampellini has received grants from Eli Lilly and Company, Bayer Healthcare and Sanofi. GV Scagliotti has received grants from Eli Lilly and Company and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.