Surgery and OncologySurgery and OncologyХирургия и онкология2949-5857Publishing House ABV Press52210.17650/2686-9594-2021-11-3-4-35-39LITERATURE REVIEWОБЗОР ЛИТЕРАТУРЫAflibercept as a treatment for malignant tumorsАфлиберцепт и его применение в лечении злокачественных новообразованийhttps://orcid.org/0000-0003-3028-7578IvanovV.  A. ИвановВ. А.
Russian Federation

Valeriy Anatolyevich Ivanov

Department of Radiotherapy

26 50 let VLKSM St., Podolsk 142110

Валерий Анатольевич Иванов 

Отделение радиотерапии

142110 Подольск, ул. 50 лет ВЛКСМ, 26

dr.valeryivanov@gmail.comhttps://orcid.org/0000-0002-9303-8379GordeevS.  S. ГордеевС. С.
Russian Federation

Department of Surgical Oncology No. 3 (Coloproctology)

24 Kashirskoe Shosse, Moscow 115478

Отделение онкологическое хирургических методов лечения № 3 (колопроктологии)

115478 Москва, Каширское шоссе, 24

Oncoradiological Center “PET-Technology Podolsk”Онкорадиологический центр «ПЭТ-Технолоджи Подольск»Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaНИИ клинической онкологии ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина»15032022113-435391503202215032022Copyright ©; 2022, Ivanov V.A., Gordeev S.S.Copyright ©; 2022, Иванов В.А., Гордеев С.С.2022Ivanov V.A., Gordeev S.S.Иванов В.А., Гордеев С.С.https://creativecommons.org/licenses/by/4.0https://onco-surgery.info/jour/article/view/522

Targeted therapy for colorectal cancer usually includes anti-vEgf and anti-EgfR antibodies. The initiation of first-line therapy for metastatic colorectal cancer depends on the baseline patient’s characteristics, tumor spread, and its mutational status. Despite the wide range of possible combinations of these factors, an oncologist should choose between standard platinum-based chemotherapy regimens and combination of similar chemotherapeutic agents with bevacizumab or cetuximab. Disease progression after first-line therapy poses a dilemma to an oncologist, since the range of potentially beneficial targeted drugs or immunotherapeutic agents is much wider along with the lack of sufficient evidence. This article focuses on the efficacy of aflibercept as a second-line treatment for colorectal cancer, indications for its use, and outlooks.

Таргетная терапия колоректального рака представлена в основном анти-vEgf- и анти-EgfR-антителами. Назначение 1-й линии терапии метастатического колоректального рака зависит от исходного состояния пациента, степени генерализации опухолевого процесса и мутационного статуса опухоли, и, несмотря на широкий спектр вариабельности перечисленных факторов, выбор онколога колеблется между назначением стандартных платиносодержащих режимов химиотерапии и назначением таких же химиопрепаратов с бевацизумабом или цетуксимабом. Прогрессирование после 1-й линии лечения ставит онколога перед более сложным выбором, так как в данной ситуации спектр назначаемых таргетных или иммунопрепаратов расширяется, а данных доказательной медицины может не хватать. В статье пойдет речь о препарате 2-й линии химиотерапии колоректального рака афлиберцепте, его эффективности, показаниях к применению и перспективах.

colorectal cancermetastatic colorectal cancertargeted therapyafliberceptколоректальный ракметастатический колоректальный рактаргетная терапияафлиберцепт1. Senger D.R., Galli S.J., Dvorak A.M. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219(4587):983–5. DOI: 10.1126/science.6823562.Senger D.R., Galli S.J., Dvorak A.M. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219(4587):983–5. DOI: 10.1126/science.6823562.2. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25(4):581–611. 3. Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 2004;9(Suppl 1):2–10.Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25(4):581–611. 3. Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 2004;9(Suppl 1):2–10.4. List A.F. Vascular endothelial growth factor signaling pathway as an emerging target in hematologic malignancies. Oncologist 2001;6(Suppl 5):24–31. DOI: 10.1634/theoncologist.6-suppl_5-24.List A.F. Vascular endothelial growth factor signaling pathway as an emerging target in hematologic malignancies. Oncologist 2001;6(Suppl 5):24–31. DOI: 10.1634/theoncologist.6-suppl_5-24.5. Chu Q.S. Aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors. Expert Opin Biol Ther 2009;9(2):263–71.Chu Q.S. Aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors. Expert Opin Biol Ther 2009;9(2):263–71.6. Holash J., Davis S., Papadopoulos N. et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 2002;99(17):11393–8. DOI: 10.1073/pnas.172398299.Holash J., Davis S., Papadopoulos N. et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 2002;99(17):11393–8. DOI: 10.1073/pnas.172398299.7. Lockhart A.C., Rothenberg M.L., Dupont J. et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 2010;28(2):207–14.Lockhart A.C., Rothenberg M.L., Dupont J. et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 2010;28(2):207–14.8. De Groot J.F., Lamborn K.R., Chang S.M. et al. Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol 2011;29(19):2689–95. DOI: 10.1200/JCO.2010.34.1636.De Groot J.F., Lamborn K.R., Chang S.M. et al. Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol 2011;29(19):2689–95. DOI: 10.1200/JCO.2010.34.1636.9. Leighl N.B., Raez L.E., Besse B. et al. A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinum- and erlotinibresistant adenocarcinoma of the lung. J Thorac Oncol 2010;5(7):1054–9.Leighl N.B., Raez L.E., Besse B. et al. A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinum- and erlotinibresistant adenocarcinoma of the lung. J Thorac Oncol 2010;5(7):1054–9.10. Ramlau R., Gorbunova V., Ciuleanu T.E. et al. Aflibercept and Docetaxel versus Docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol 2012;30(29):3640–7.Ramlau R., Gorbunova V., Ciuleanu T.E. et al. Aflibercept and Docetaxel versus Docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol 2012;30(29):3640–7.11. Twardowski P., Stadler W.M., Frankel P. et al. Phase II study of Aflibercept (VEGF-Trap) in patients with recurrent or metastatic urothelial cancer, a California Cancer Consortium Trial. Urology 2010;76(4):923–6. DOI: 10.1016/j.urology.2011.12.038.Twardowski P., Stadler W.M., Frankel P. et al. Phase II study of Aflibercept (VEGF-Trap) in patients with recurrent or metastatic urothelial cancer, a California Cancer Consortium Trial. Urology 2010;76(4):923–6. DOI: 10.1016/j.urology.2011.12.038.12. Yamazaki K., Yoshino T., Yamaguchi K. et al. Phase I dose escalation and pharmacokinetics study of intravenous aflibercept plus irinotecan, 5-fluorouracil, and folinic acid (FOLFIRI) in patients with metastatic colorectal cancer. J Clin Oncol 2011;29(4 Suppl):538.Yamazaki K., Yoshino T., Yamaguchi K. et al. Phase I dose escalation and pharmacokinetics study of intravenous aflibercept plus irinotecan, 5-fluorouracil, and folinic acid (FOLFIRI) in patients with metastatic colorectal cancer. J Clin Oncol 2011;29(4 Suppl):538.13. Yoshino T., Yamazaki K., Yamaguchi K. et al. A phase I study of intravenous aflibercept with FOLFIRI in Japanese patients with previously treated metastatic colorectal cancer. Invest New Drugs 2013;31(4):910–7.Yoshino T., Yamazaki K., Yamaguchi K. et al. A phase I study of intravenous aflibercept with FOLFIRI in Japanese patients with previously treated metastatic colorectal cancer. Invest New Drugs 2013;31(4):910–7.14. Tang P.A., Cohen S.J., Kollmannsberger C. et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res 2012;18(21):6023–31.Tang P.A., Cohen S.J., Kollmannsberger C. et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res 2012;18(21):6023–31.15. 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.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):3499–506.16. 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.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):320–31.17. Folprecht G., Pericay C., Saunders M.P. 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 M.P. 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):1273–9.18. Fernández Montes A., Martínez Lago N., Covela Rúa M. et al. Efficacy and safety of FOLFIRI/aflibercept in second-line treatment of metastatic colorectal cancer in a real-world population: Prognostic and predictive markers. Cancer Med 2019;8(3):882–9. DOI: 10.1002/cam4.1903.Fernández Montes A., Martínez Lago N., Covela Rúa M. et al. Efficacy and safety of FOLFIRI/aflibercept in second-line treatment of metastatic colorectal cancer in a real-world population: Prognostic and predictive markers. Cancer Med 2019;8(3):882–9. DOI: 10.1002/cam4.1903.19. Riechelmann R.P., Srimuninnimit V., Bordonaro R. et al. Aflibercept Plus FOLFIRI for Second-line Treatment of Metastatic Colorectal Cancer: Observations from the Global Aflibercept Safety and Health-Related Quality-of-Life Program (ASQoP). Clin Colorectal Cancer 2019;18(3):183–191.e183.Riechelmann R.P., Srimuninnimit V., Bordonaro R. et al. Aflibercept Plus FOLFIRI for Second-line Treatment of Metastatic Colorectal Cancer: Observations from the Global Aflibercept Safety and Health-Related Quality-of-Life Program (ASQoP). Clin Colorectal Cancer 2019;18(3):183–191.e183.20. Buchler T., Kiss I., Hornova J. et al. Sequential treatment with bevacizumab and aflibercept for metastatic colorectal cancer in real-world clinical practice. Target Oncol 2020;15(2):193–201.Buchler T., Kiss I., Hornova J. et al. Sequential treatment with bevacizumab and aflibercept for metastatic colorectal cancer in real-world clinical practice. Target Oncol 2020;15(2):193–201.21. Vera R., Mata E., González E. et al. Is aflibercept an optimal treatment for wtRAS mCRC patients after progression to first line containing anti-EGFR? Int J Colorectal Dis 2020;35(4):739–46.Vera R., Mata E., González E. et al. Is aflibercept an optimal treatment for wtRAS mCRC patients after progression to first line containing anti-EGFR? Int J Colorectal Dis 2020;35(4):739–46.22. Hofheinz R.D., Kröning H., Zahn M.-O. et al. Impact of RAS status and prior targeted therapy on the activity of aflibercept plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) in daily practice. Final results of the QoLiTrap prospective non-interventional study. J Clin Oncol 2021;39(Suppl 15):e15570–e15570.Hofheinz R.D., Kröning H., Zahn M.-O. et al. Impact of RAS status and prior targeted therapy on the activity of aflibercept plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) in daily practice. Final results of the QoLiTrap prospective non-interventional study. J Clin Oncol 2021;39(Suppl 15):e15570–e15570.23. Ottaiano A., Capozzi M., Tafuto S. et al. FOLFIRI-aflibercept vs. FOLFIRI-bevacizumab as second line treatment of RAS mutated metastatic colorectal cancer in real practice. Front Oncol 2019;9:766.Ottaiano A., Capozzi M., Tafuto S. et al. FOLFIRI-aflibercept vs. FOLFIRI-bevacizumab as second line treatment of RAS mutated metastatic colorectal cancer in real practice. Front Oncol 2019;9:766.