The role of PIGF blockade in the treatment of colorectal cancer: overcoming the pitfalls

ABSTRACT

Introduction: In colorectal cancer, anti-VEGF agents have demonstrated a survival benefit when combined with chemotherapy. However, development of resistance is very common. One of the mechanisms is due not to a failure in the VEGFR blockade, but rather to development of compensatory mechanisms of resistance, such as hypoxia-triggered upregulation of other proangiogenic factors, like placental growth factor (PlGF).

Areas covered: This article summarizes the fundamental role of PlGF in the development of resistance to antiangiogenic treatment as well as the efficacy of aflibercept, ramucirumab, and regorafenib.

Expert opinion: Aflibercept functions as a soluble decoy receptor precluding VEGFs and PlGF from binding to native VEGFR, and therefore preventing the emergence of resistance. Bevacizumab limits its function to preventing the interaction between VEGF-A and VEGFR. In combination with FOLFIRI (VELOUR trial), aflibercept improves survival in patients with metastatic CRC who are resistant or have progressed to oxaliplatin-based chemotherapy. Ramucirumab, a fully humanized immunoglobulin G1 (IgG-1) monoclonal antibody and regorafenib, a multikinase inhibitor, have significant improvement for overall survival as well as for progression-free survival in chemotherapy refractory settings.

KEYWORDS:

• Colorectal cancer
• angiogenesis
• placental growth factor
• resistance to antiangiogenic treatment

Article highlights

• Angiogenesis, a pleotropic process in which multiple membrane receptors, ligands and signaling mediators are involved, is one of the key mechanisms for cancer growth, disease progression and metastasis. One of the most relevant mechanisms involved in cancer angiogenesis is the VEGF family

• In CRC development of anti-VEGF agents has demonstrated a survival benefit when combined with chemotherapy. However, development of resistance to antiangiogenic drugs is very common. One of the mechanisms is not due to a failure in the VEGFR-2 blockade, but rather to development of compensatory mechanism of resistance, such as a hypoxia-triggered upregulation of other proangiogenic factors, such as PlGF.

• Aflibercept, as opposed to bevacizumab that only prevents interaction between VEGF-A and VEGFR, functions as a soluble decoy receptor, blocking pro-angiogenetic VEGFs including VEGF-A, VEGF-B, and PlGF (PlGF-1 and-2), thereby preventing VEGFs and PlGF from binding to native VEGF receptors. In combination with chemotherapy, aflibercept improves overall survival, progression free survival and response rate in patients with metastatic CRC who are resistant or have progressed to oxaliplatin-based chemotherapy. The regimen is well tolerated and represents one of the standard of care option for this patient population.

• Ramucirumab is a fully humanized IgG-1 monoclonal antibody that binds with high affinity to the extracellular VEGF-binding domain of VEGFR-2. The RAISE trial evaluated the addition of ramucirumab to FOLFIRI after progression under first-line oxaliplatin/fluoropyrimidine-based chemotherapy combined with bevacizumab, showing a significant improvement for overall survival as well as for progression-free survival.

• Regorafenib is a multikinase inhibitor targeting BRAF, VEGFR-1/2/3, KIT, TIE-2, PDGFR-β, fibroblast growth factor receptor 1 (FGFR-1), RET, RAF-1, and p38 MAP kinase. Regorafenib was evaluated in a phase III clinical trial in chemotherapy refractory settings against placebo, showing significant improvement of overall and progression-free survival.

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Acknowledgments

The medical writing of the manuscript was supported by Sofia Perea, Pharm D, PhD, and was funded by Sanofi.

Declaration of interest

C Montagut has consulting and/or advisory role for Amgen, Merck Serono, Merrimack, MSD, Roche, Sanofi, Seattle Genetics, Servier, Symphogen; and has received research funding from Amgen, Merck Serono and Symphogen. J Sastre has consulting and/or advisory role for Amgen, Merck, Sanofi, Roche, MSD, Celgene, Bayer, Bristol, Servier, Lilly. T Macarulla has consulting and/or advisory role for Amgen, Sanofi Aventis, Servier, Celgene, Incyte, and has received research funding from Celgene, Beigene, Astra-Zeneca. M Granja has consulting and/or advisory role for Amgen, Merck, Sanofi, Roche, Celgene. H Verdaguer has advisory role for Ipsen; has received speaker’s fees from Celgene, Amgen; has received travel grants from Amgen, Celgene, Servier and Ipsen. F Javier Sánchez-Martin has received research funding from Symphogen. J Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS, and Roche Diagnostics. 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.

Reviewer Disclosures

One of the reviewers has received honorarium from Chugai and Eli-Lilly. The other two peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was funded by Sanofi.