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Published in: Targeted Oncology 4/2016

01-08-2016 | Review Article

Aflibercept, a New Way to Target Angiogenesis in the Second Line Treatment of Metastatic Colorectal Cancer (mCRC)

Authors: Mario Scartozzi, Loic Vincent, Marielle Chiron, Stefano Cascinu

Published in: Targeted Oncology | Issue 4/2016

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Abstract

Colorectal cancer (CRC) is a leading tumour worldwide, and the median survival of metastatic patients with the latest therapeutic options today reaches 30 months. Therefore, it is important to plan a therapeutic strategy, able to optimize the use of the available drugs (fluoropyrimides, oxaliplatin, irinotecan and target biologic therapy), with the objective of maximizing the long-term efficacy, reducing toxicities and assuring better quality of life for the patients with mCRC. Among the most recently available drugs for the treatment of mCRC, aflibercept, a new antiangiogenetic agent, should be considered a promising therapeutical option for the second line setting. In this review, the mechanism of action and preclinical evidence, as well as pharmacological and clinical aspects of aflibercept will be analysed. In particular, this drug has a peculiar and unique mechanism of action, inhibiting VEGF-A, -B and PlGF pathways, which may help to overcome tumour escape mechanisms to bevacizumab treatment. From a clinical point of view, the addition of aflibercept to FOLFIRI regimen was able to significantly improve all the clinical outcome with respect to the chemotherapy alone in second line treatment of mCRC patients, regardless of age, RAS status, and prior use of bevacizumab. Finally, the safety profile of aflibercept is well known and manageable in most of the patients. Aflibercept can be considered a novel standard of care in the second line setting and an important therapeutic option for mCRC patients.
Literature
1.
go back to reference Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49:1374–403.CrossRefPubMed Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49:1374–403.CrossRefPubMed
2.
go back to reference I NUMERI DEL CANCRO IN ITALIA 2014. AIOM-AIRTUM; 2014. I NUMERI DEL CANCRO IN ITALIA 2014. AIOM-AIRTUM; 2014.
3.
go back to reference Van Cutsem E, Cervantes A, Nordlinger B, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Supplement 3):iii1–9.CrossRefPubMed Van Cutsem E, Cervantes A, Nordlinger B, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Supplement 3):iii1–9.CrossRefPubMed
4.
go back to reference Linee guida AIOM. TUMORI DEL COLON RETTO. Edizione; 2014. Linee guida AIOM. TUMORI DEL COLON RETTO. Edizione; 2014.
5.
go back to reference National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Colon Cancer, version 2.2016. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Colon Cancer, version 2.2016.
6.
go back to reference Giordano G, Febbraro A, Venditti M et al. Targeting angiogenesis and tumor microenvironment in metastatic colorectal cancer: role of aflibercept. Gastroenterology Research and Practice 2014, Article ID 526178, 13 pages. Giordano G, Febbraro A, Venditti M et al. Targeting angiogenesis and tumor microenvironment in metastatic colorectal cancer: role of aflibercept. Gastroenterology Research and Practice 2014, Article ID 526178, 13 pages.
7.
go back to reference Verheul HM, Voest EE, Schlingemann RO. Are tumours angiogenesis-dependent? J Pathol. 2004;202(1):5–13.CrossRefPubMed Verheul HM, Voest EE, Schlingemann RO. Are tumours angiogenesis-dependent? J Pathol. 2004;202(1):5–13.CrossRefPubMed
9.
go back to reference Ferrarotto R, Hoff PM. Antiangiogenic drugs for colorectal cancer: exploring new possibilities. Clin Colorectal Cancer. 2013;12:1–7.CrossRefPubMed Ferrarotto R, Hoff PM. Antiangiogenic drugs for colorectal cancer: exploring new possibilities. Clin Colorectal Cancer. 2013;12:1–7.CrossRefPubMed
12.
go back to reference Yang X, Zhang Y, Yang Y, et al. Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 2013;110(34):13932–7.CrossRefPubMedPubMedCentral Yang X, Zhang Y, Yang Y, et al. Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 2013;110(34):13932–7.CrossRefPubMedPubMedCentral
13.
go back to reference Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol. 2012;30(32):4026–34.CrossRefPubMedPubMedCentral Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol. 2012;30(32):4026–34.CrossRefPubMedPubMedCentral
14.
go back to reference Kopetz S, Hoff PM, Morris JS. er al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010;28(3):453–9.CrossRefPubMed Kopetz S, Hoff PM, Morris JS. er al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010;28(3):453–9.CrossRefPubMed
15.
go back to reference Loupakis F, Cremolini C, Fioravanti A, et al. Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer. 2011;104(8):1262–9.CrossRefPubMedPubMedCentral Loupakis F, Cremolini C, Fioravanti A, et al. Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer. 2011;104(8):1262–9.CrossRefPubMedPubMedCentral
16.
go back to reference Ebos JM, Lee CR, Bogdanovic E, et al. Vascular endothelial growth factor-mediated decrease in plasma soluble vascular endothelial growth factor receptor-2 levels as a surrogate biomarker for tumor growth. Cancer Res. 2008;68(2):521–9.CrossRefPubMed Ebos JM, Lee CR, Bogdanovic E, et al. Vascular endothelial growth factor-mediated decrease in plasma soluble vascular endothelial growth factor receptor-2 levels as a surrogate biomarker for tumor growth. Cancer Res. 2008;68(2):521–9.CrossRefPubMed
17.
go back to reference Giampieri R, Scartozzi M, Del Prete M, et al. The “angiogenetic ladder”, step-wise angiogenesis inhibition in metastatic colorectal cancer. Cancer Treat Rev. 2014;40(8):934–41.CrossRefPubMed Giampieri R, Scartozzi M, Del Prete M, et al. The “angiogenetic ladder”, step-wise angiogenesis inhibition in metastatic colorectal cancer. Cancer Treat Rev. 2014;40(8):934–41.CrossRefPubMed
18.
go back to reference Patel A, Sun W. Ziv-aflibercept in metastatic colorectal cancer. Biol: Targets Ther. 2014;8:13–25. Patel A, Sun W. Ziv-aflibercept in metastatic colorectal cancer. Biol: Targets Ther. 2014;8:13–25.
19.
20.
go back to reference Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15:171–85.CrossRefPubMedPubMedCentral Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15:171–85.CrossRefPubMedPubMedCentral
21.
go back to reference Tang PA, Moore MJ. Aflibercept in the treatment of patients with metastatic colorectal cancer: latest findings and interpretations. Ther Adv Gastroenterol. 2013;6(6):459–73.CrossRef Tang PA, Moore MJ. Aflibercept in the treatment of patients with metastatic colorectal cancer: latest findings and interpretations. Ther Adv Gastroenterol. 2013;6(6):459–73.CrossRef
22.
go back to reference Chiron M, Bagley RG, Pollard J, et al. Differential antitumor activity of aflibercept and bevacizumab in patient-derived xenograft models of colorectal cancer. Mol Cancer Ther. 2014;13(6):1636–44.CrossRefPubMed Chiron M, Bagley RG, Pollard J, et al. Differential antitumor activity of aflibercept and bevacizumab in patient-derived xenograft models of colorectal cancer. Mol Cancer Ther. 2014;13(6):1636–44.CrossRefPubMed
23.
go back to reference Chiron M, Bagley RG, Pollard J et al. Switching to aflibercept treatment resulted in greater tumor responses than continuous bevacizumab treatment in patient-derived xenograft models of colorectal cancer. In: Proceedings of the 2013 AACR-NCI-EORTC International Conference on Molecular Targets. Mol Cancer Ther. 2013;12(11 Suppl.):Abstract B2. Chiron M, Bagley RG, Pollard J et al. Switching to aflibercept treatment resulted in greater tumor responses than continuous bevacizumab treatment in patient-derived xenograft models of colorectal cancer. In: Proceedings of the 2013 AACR-NCI-EORTC International Conference on Molecular Targets. Mol Cancer Ther. 2013;12(11 Suppl.):Abstract B2.
24.
go back to reference Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506.CrossRefPubMed Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506.CrossRefPubMed
25.
go back to reference Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37.CrossRefPubMed Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37.CrossRefPubMed
26.
go back to reference Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499–508.CrossRefPubMed Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499–508.CrossRefPubMed
27.
go back to reference Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539–44.CrossRefPubMed Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539–44.CrossRefPubMed
28.
go back to reference Ruff P, Ferry DR, Lakom R, et al. Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy. Eur J Cancer. 2015;51:18–26.CrossRefPubMed Ruff P, Ferry DR, Lakom R, et al. Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy. Eur J Cancer. 2015;51:18–26.CrossRefPubMed
29.
go back to reference Ruff P, Ferry DR, Papamichael D et al. Observed Benefit of Aflibercept in mCRC Patients ≥ 65 Years: Results of a Prespecified Age-Based Analysis of the VELOUR Study. Ann Oncol. 2013;24(4 Suppl.):iv11–iv24 (O-0017). Ruff P, Ferry DR, Papamichael D et al. Observed Benefit of Aflibercept in mCRC Patients ≥ 65 Years: Results of a Prespecified Age-Based Analysis of the VELOUR Study. Ann Oncol. 2013;24(4 Suppl.):iv11–iv24 (O-0017).
30.
go back to reference Tabernero J, Van Cutsem E, Lakomý R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014;50(2):320–31.CrossRefPubMed Tabernero J, Van Cutsem E, Lakomý R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014;50(2):320–31.CrossRefPubMed
31.
go back to reference Hoff PM. The consistency of effect of ziv-aflibercept (Z) in the bevacizumab (B) pre-treated subgroup of patients (pts) in the velour trial stratified by first-line progression ≥ 9 months (mos) versus < 9 mos. J Clin Oncol. 2014;32:5s(Suppl; Abstract 3639). Hoff PM. The consistency of effect of ziv-aflibercept (Z) in the bevacizumab (B) pre-treated subgroup of patients (pts) in the velour trial stratified by first-line progression ≥ 9 months (mos) versus < 9 mos. J Clin Oncol. 2014;32:5s(Suppl; Abstract 3639).
32.
go back to reference Mitchell E, Van Hazel G, Cunningham D et al. Evaluation of the Effect of Aflibercept (Z) on OS by Timing of 1st Line Disease Progression: A Post-Hoc Analysis of the VELOUR Trial. Ann Oncol. 2014;25(2 Suppl.):ii84 (P-0226). Mitchell E, Van Hazel G, Cunningham D et al. Evaluation of the Effect of Aflibercept (Z) on OS by Timing of 1st Line Disease Progression: A Post-Hoc Analysis of the VELOUR Trial. Ann Oncol. 2014;25(2 Suppl.):ii84 (P-0226).
33.
go back to reference Van Cutsem E, Joulain F, Hoff PM et al. Aflibercept Plus FOLFIRI vs. Placebo Plus FOLFIRI in Second-Line Metastatic Colorectal Cancer: a Post Hoc Analysis of Survival from the Phase III VELOUR Study Subsequent to Exclusion of Patients who had Recurrence During or Within 6 Months of Completing Adjuvant Oxaliplatin-Based Therapy. Target Oncol. 2016;11(3):383–400. Van Cutsem E, Joulain F, Hoff PM et al. Aflibercept Plus FOLFIRI vs. Placebo Plus FOLFIRI in Second-Line Metastatic Colorectal Cancer: a Post Hoc Analysis of Survival from the Phase III VELOUR Study Subsequent to Exclusion of Patients who had Recurrence During or Within 6 Months of Completing Adjuvant Oxaliplatin-Based Therapy. Target Oncol. 2016;11(3):383–400.
34.
go back to reference Tabernero J, Macarulla T, Humblet Y et al. Aflibercept/FOLFIRI vs. Placebo/FOLFIRI in Metastatic Colorectal Cancer: A Post-Hoc Analysis of Median Overall Survival in VELOUR From the Retrospectively Assessed Time of Starting First-Line Treatment. Ann Oncol. 2014;25(2 Suppl.):ii14–ii104 (P-0288). Tabernero J, Macarulla T, Humblet Y et al. Aflibercept/FOLFIRI vs. Placebo/FOLFIRI in Metastatic Colorectal Cancer: A Post-Hoc Analysis of Median Overall Survival in VELOUR From the Retrospectively Assessed Time of Starting First-Line Treatment. Ann Oncol. 2014;25(2 Suppl.):ii14–ii104 (P-0288).
35.
go back to reference Chau I, Joulain F, Iqbal SU, et al. A VELOUR post hoc subset analysis: prognostic groups and treatment outcomes in patients with metastatic colorectal cancer treated with aflibercept and FOLFIRI. BMC Cancer. 2014;14:605.CrossRefPubMedPubMedCentral Chau I, Joulain F, Iqbal SU, et al. A VELOUR post hoc subset analysis: prognostic groups and treatment outcomes in patients with metastatic colorectal cancer treated with aflibercept and FOLFIRI. BMC Cancer. 2014;14:605.CrossRefPubMedPubMedCentral
36.
go back to reference Folprecht G, Pericay C, Saunders MP et al. Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first line treatment of patients with metastatic colorectal cancer – the AFFIRM study. Ann Oncol. 2016;27(7):1273–9. Folprecht G, Pericay C, Saunders MP et al. Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first line treatment of patients with metastatic colorectal cancer – the AFFIRM study. Ann Oncol. 2016;27(7):1273–9.
37.
go back to reference Sims T, Gao B, Phillips R, Lowy I. Potential predictive and prognostic biomarkers identified in baseline plasma samples from the VELOUR trial. J Clin Oncol. 2015; 33 (suppl 3; abstr 638). Sims T, Gao B, Phillips R, Lowy I. Potential predictive and prognostic biomarkers identified in baseline plasma samples from the VELOUR trial. J Clin Oncol. 2015; 33 (suppl 3; abstr 638).
38.
go back to reference Lambrechts D, Thienpont B, Thuillier, et al. Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting. Br J Cancer. 2015;113(7):1027–34.CrossRefPubMed Lambrechts D, Thienpont B, Thuillier, et al. Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting. Br J Cancer. 2015;113(7):1027–34.CrossRefPubMed
39.
go back to reference Frassineti L, Di Bartolomeo M, Heinemann V et al. Aflibercept+FOLFIRI for treatment of metastatic colorectal cancer after oxaliplatin failure:4th Interim Safety Data From the Global Aflibercept Safety and Quality-of-Life Program (ASQoP/AFEQT Studies). Ann Oncol. 2014;25(4 Suppl.):iv167–iv209 (528P). Frassineti L, Di Bartolomeo M, Heinemann V et al. Aflibercept+FOLFIRI for treatment of metastatic colorectal cancer after oxaliplatin failure:4th Interim Safety Data From the Global Aflibercept Safety and Quality-of-Life Program (ASQoP/AFEQT Studies). Ann Oncol. 2014;25(4 Suppl.):iv167–iv209 (528P).
40.
go back to reference Iaffaioli VR, Pietrantonio F, Pastorino A et al. Aflibercept (afl) plus FOLFIRI for the 2nd-line treatment of patients (pts) with metastatic colorectal cancer (mCRC): 4th interim safety data from the Italian cohort of the Aflibercept Safety and Quality-of-Life Program (ASQoP). AIOM 2014, Poster G14. Iaffaioli VR, Pietrantonio F, Pastorino A et al. Aflibercept (afl) plus FOLFIRI for the 2nd-line treatment of patients (pts) with metastatic colorectal cancer (mCRC): 4th interim safety data from the Italian cohort of the Aflibercept Safety and Quality-of-Life Program (ASQoP). AIOM 2014, Poster G14.
41.
go back to reference Taieb J, Bordonaro R, Bencardino K et al. Quality of Life (QoL) on the Aflibercept/FOLFIRI Regimen: 4th Interim Analysis of the Global Aflibercept Safety and Health-Related QoL Program. Ann Oncol. 2014;25(4 Suppl.):iv167–iv209 (529P). Taieb J, Bordonaro R, Bencardino K et al. Quality of Life (QoL) on the Aflibercept/FOLFIRI Regimen: 4th Interim Analysis of the Global Aflibercept Safety and Health-Related QoL Program. Ann Oncol. 2014;25(4 Suppl.):iv167–iv209 (529P).
42.
go back to reference Giampieri R, Caporale M, Pietrantonio F, et al. Second-line angiogenesis inhibition in metastatic colorectal cancer patients: Straightforward or overcrowded? Crit Rev Oncol Hematol. 2016;100:99–106.CrossRefPubMed Giampieri R, Caporale M, Pietrantonio F, et al. Second-line angiogenesis inhibition in metastatic colorectal cancer patients: Straightforward or overcrowded? Crit Rev Oncol Hematol. 2016;100:99–106.CrossRefPubMed
44.
go back to reference Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(3 Suppl.):iii1–9. Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(3 Suppl.):iii1–9.
45.
go back to reference Echave M, Oyagüez I, Lamas MJ, et al. Aflibercept in combination with Folfiri in patients with metastatic colorectal cancer: cost-effectiveness based on velour best efficacy subgroup post-hoc analysis. Value Health. 2015;18(7):A454.CrossRefPubMed Echave M, Oyagüez I, Lamas MJ, et al. Aflibercept in combination with Folfiri in patients with metastatic colorectal cancer: cost-effectiveness based on velour best efficacy subgroup post-hoc analysis. Value Health. 2015;18(7):A454.CrossRefPubMed
Metadata
Title
Aflibercept, a New Way to Target Angiogenesis in the Second Line Treatment of Metastatic Colorectal Cancer (mCRC)
Authors
Mario Scartozzi
Loic Vincent
Marielle Chiron
Stefano Cascinu
Publication date
01-08-2016
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 4/2016
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-016-0447-4

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