Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Clinical Studies

Effect of aflibercept plus FOLFIRI and potential efficacy biomarkers in patients with metastatic colorectal cancer: the POLAF trial

British Journal of Cancer volume 126, pages 874–880 (2022)Cite this article

Subjects

Abstract

Background

Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE).

Methods

Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed.

Results

In total, 101 patients were followed for a median of 12 (6–17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was <1941 versus ≥1941 pg/mL (9 versus 4 months). Patients with VEGF-A < 1941 pg/mL showed longer median OS (19 versus 8 months), TTP (9 versus 4 months) and TTF (8 versus 4 months), along with higher ORR (26% versus 9%) and DCR (81% versus 55%). No differences were identified according to ACE levels.

Conclusions

This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Progression-free survival.
Fig. 2: Overall survival.
Fig. 3: Time to treatment failure and time to progression.

Similar content being viewed by others

Data availability

All data relevant to the study are included in the article or uploaded as supplementary information. Further data are available from the authors upon reasonable request and with permission of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD).

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. https://doi.org/10.3322/caac.21492.

    Article  Google Scholar 

  2. American Cancer Society. Colorectal cancer facts & figures 2017–2019. Atlanta: American Cancer Society; 2017.

  3. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386–422. https://doi.org/10.1093/annonc/mdw235.

    Article  Google Scholar 

  4. NCCN. NCCN clinical practice guidelines in Oncology (NCCN Guidelines). Colon cancer. Version 3.2019, https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf, Accessed October 28, 2019 (2019).

  5. Stanel SC, Sjoberg J, Salmonson T, Foggi P, Caleno M, Melchiorri D, et al. European Medicines Agency approval summary: Zaltrap for the treatment of patients with oxaliplatin-resistant metastatic colorectal cancer. ESMO Open. 2017;2:e000190. https://doi.org/10.1136/esmoopen-2017-000190.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, 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;30:3499–506. https://doi.org/10.1200/JCO.2012.42.8201.

    Article  CAS  PubMed  Google Scholar 

  7. Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, van Hazel GA, 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;50:320–31. https://doi.org/10.1016/j.ejca.2013.09.013.

    Article  CAS  PubMed  Google Scholar 

  8. Van Cutsem E, Joulain F, Hoff PM, Mitchell E, Ruff P, Lakomy R, 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;11:383–400. https://doi.org/10.1007/s11523-015-0402-9.

    Article  PubMed  Google Scholar 

  9. Van Cutsem E, Paccard C, Chiron M, Tabernero J. Impact of prior bevacizumab treatment on VEGF-A and PlGF levels and outcome following second-line aflibercept treatment: Biomarker post hoc analysis of the VELOUR trial. Clin Cancer Res. 2020;26:717–25. https://doi.org/10.1158/1078-0432.CCR-19-1985.

    Article  PubMed  Google Scholar 

  10. Moreno-Munoz D, de la Haba-Rodriguez JR, Conde F, Lopez-Sanchez LM, Valverde A, Hernandez V, et al. Genetic variants in the renin-angiotensin system predict response to bevacizumab in cancer patients. Eur J Clin Investig. 2015;45:1325–32. https://doi.org/10.1111/eci.12557.

    Article  CAS  Google Scholar 

  11. Fernandez Montes A, Martinez Lago N, Covela Rua M, de la Camara Gomez J, Gonzalez Villaroel P, Mendez Mendez JC, 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;8:882–9. https://doi.org/10.1002/cam4.1903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Feliu J, Diez de Corcuera I, Manzano JL, Valladares-Ayerbes M, Alcaide J, Garcia Garcia T, et al. Effectiveness and safety of aflibercept for metastatic colorectal cancer: retrospective review within an early access program in Spain. Clin Transl Oncol. 2017;19:498–507. https://doi.org/10.1007/s12094-016-1556-3.

    Article  CAS  PubMed  Google Scholar 

  13. Hofheinz R, Scholten F, Derigs H, Thaler J, von Moos R. PD-026Quality of life in patients treated with aflibercept and FOLFIRI for metastatic colorectal cancer: interim analysis with focus on therapy lines of the non-interventional study QoLiTrap (AIO-LQ-0113). Ann Oncol. 2019;30:iv118. https://doi.org/10.1093/annonc/mdz156.025.

    Article  Google Scholar 

  14. Vera R, Mata E, Gonzalez E, Juez I, Alonso V, Iranzo P, et al. Is aflibercept an optimal treatment for wt RAS mCRC patients after progression to first line containing anti-EGFR? Int J Colorectal Dis. 2020;35:739–46. https://doi.org/10.1007/s00384-020-03509-x.

    Article  PubMed  Google Scholar 

  15. Wirapati P, Pomella V, Vandenbosch B, Kerr P, Maiello E, Jeffery GM, et al. Velour trial biomarkers update: impact of RAS, BRAF, and sidedness on aflibercept activity. J Clin Oncol. 2017;35:3538–3538. https://doi.org/10.1200/JCO.2017.35.15_suppl.3538.

    Article  Google Scholar 

  16. Marisi G, Scarpi E, Passardi A, Nanni O, Ragazzini A, Valgiusti M, et al. Circulating VEGF and eNOS variations as predictors of outcome in metastatic colorectal cancer patients receiving bevacizumab. Sci Rep. 2017;7:1293. https://doi.org/10.1038/s41598-017-01420-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hayashi H, Arao T, Matsumoto K, Kimura H, Togashi Y, Hirashima Y, et al. Biomarkers of reactive resistance and early disease progression during chemotherapy plus bevacizumab treatment for colorectal carcinoma. Oncotarget. 2014;5:2588–95. https://doi.org/10.18632/oncotarget.1811.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 2009;27:3020–6. https://doi.org/10.1200/JCO.2008.21.1771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Alidzanovic L, Starlinger P, Schauer D, Maier T, Feldman A, Buchberger E, et al. The VEGF rise in blood of bevacizumab patients is not based on tumor escape but a host-blockade of VEGF clearance. Oncotarget. 2016;7:57197–212. https://doi.org/10.18632/oncotarget.11084.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank participating patients and both medical and nursing staff involved in the conduct of the study. The authors would also like to acknowledge the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) for sponsoring the study (funded by Sanofi) and the following specific people for their cooperation and support: (1) Study chairs: E. Aranda and M.A. Gómez-España (Hospital Reina Sofía, Córdoba, Spain). (2) Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD): I. Ruiz de Mena and S. Rodríguez. The medical writing support was provided by Esther Álvarez-García, DVM, PhD, at Dynamic Science S.L. (Madrid, Spain) during the preparation of this paper, funded by the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD; Madrid, Spain). The medical writing support included drafting the article, copyediting, editorial assistance and production assistance.

Funding

This work was supported by the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) through an unrestricted grant provided by Sanofi (no grant number is applicable).

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Passeig de la Vall d’Hebron, 119, 08035, Barcelona, Spain

    Elena Élez

  2. Department of Medical Oncology, IMIBIC, Reina Sofía Hospital, University of Córdoba, CIBERONC, Instituto de Salud Carlos III, Avenida Menéndez Pidal, S/N, 14004, Córdoba, Spain

    María Auxiliadora Gómez-España, María José Ortiz-Morales & Enrique Aranda

  3. Department of Medical Oncology, H. Universitario 12 de Octubre, Instituto de Investigación i + 12, Avenida de Córdoba, S/N, 28041, Madrid, Spain

    Cristina Grávalos & María del Carmen Riesco

  4. Department of Medical Oncology, H. Gregorio Marañón, Calle del Doctor Esquerdo, 46, 28007, Madrid, Spain

    Pilar García-Alfonso

  5. Department of Medical Oncology, H. Sant Joan Despí - Moisés Broggi, Carrer d’Oriol Martorell, 12, 08970, Sant Joan Despí, Barcelona, Spain

    Ferrán Losa

  6. Department of Medical Oncology, Unidad de Gestión Clínica Intercentros de Oncología Médica. Hospitales Universitarios Regional y Virgen de la Victoria. IBIMA, Campus de Teatinos, S/N, 29010, Málaga, Spain

    Inmaculada Alés Díaz

  7. Department of Medical Oncology, C. H. Universitario, Lugar, Xubias de Arriba, 84, 15006, A Coruña, Spain

    Begoña Graña

  8. Department of Medical Oncology, IMIBIC, Reina Sofía Hospital, CIBERONC, Instituto de Salud Carlos III, Avenida Menéndez Pidal, S/N, 14004, Córdoba, Spain

    Marta Toledano-Fonseca & Antonio Rodriguez-Ariza

  9. Department of Medical Oncology, H. Virgen del Rocío, IBIS, Av. Manuel Siurot s/n, 41013, Sevilla, Spain

    Manuel Valladares-Ayerbes

  10. Department of Medical Oncology, H. Miguel Servet, Paseo Isabel la Católica, 1-3, 50009, Zaragoza, Spain

    Eduardo Polo

  11. Department of Medical Oncology, C. H. Universitario de Ourense, Calle Ramón Puga Noguerol, 54, 32005, Orense, Spain

    Mercedes Salgado

  12. Department of Medical Oncology, H. Universitario Marqués de Valdecilla, IDIVAL, Avenida de Valdecilla, 25, 39008, Santander, Spain

    Eva Martínez de Castro

  13. Department of Medical Oncology, H. General Universitario, CIBERONC, Avenida de les Tres Creus, 2, 46014, Valencia, Spain

    María José Safont

  14. Department of Medical Oncology, H. de Lleida Arnau de Vilanova, Avenida Alcalde Rovira Roure, 80, 25198, Lérida, Spain

    Antonieta Salud

  15. Department of Medical Oncology, H. Puerta de Hierro Majadahonda, Calle Joaquín Rodrigo, 1, 28222, Majadahonda, Spain

    Ana Ruiz-Casado

  16. Department of Medical Oncology, Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO), Passeig de la Vall d’Hebron, 119, 08035, Barcelona, Spain

    Josep Tabernero

Authors
  1. Elena Élez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. María Auxiliadora Gómez-España
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristina Grávalos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pilar García-Alfonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. María José Ortiz-Morales
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ferrán Losa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Inmaculada Alés Díaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Begoña Graña
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marta Toledano-Fonseca
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Manuel Valladares-Ayerbes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eduardo Polo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mercedes Salgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Eva Martínez de Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. María José Safont
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Antonieta Salud
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ana Ruiz-Casado
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Josep Tabernero
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. María del Carmen Riesco
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Antonio Rodriguez-Ariza
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Enrique Aranda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

EA and MAGE contributed to the study design. All authors contributed to the acquisition, analysis, and/or interpretation of data. All authors revised critically the manuscript for important intellectual content, approved the version to be published and are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Enrique Aranda.

Ethics declarations

Competing interests

MAGE reports other from ROCHE, other from MYLAN, other from SERVIER, other from AMGEN, other from MERCK, other from BAYER, outside the submitted work. MJOM reports personal fees and non-financial support from ROCHE, personal fees and non-financial support from AMGEN, personal fees from SERVIER, personal fees from SANOFI, outside the submitted work. MVA reports grants and personal fees from ROCHE, personal fees from MERCK, personal fees from AMGEN, personal fees from SANOFI, during the conduct of the study; personal fees from SERVIER, personal fees from BAYER, personal fees from CELGENE, outside the submitted work. MS reports grants from AMGEN, grants from MERCK, grants from CELGENE, grants from SERVIER, grants from ROVI, grants from BMS, grants from LEOPHARMA, grants from ROCHE, grants from MYLAN, grants from KHERM PHARMA, outside the submitted work. EMC reports having acted as a speaker for SANOFI. JT reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Taiho, Tessa Therapeutics and TheraMyc. And also the educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). JT also declares institutional financial interest in form of financial support for clinical trials or contracted research for Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK. MCR reports personal fees and non-financial support from ROCHE, non-financial support from AMGEN, personal fees from NOVARTIS, non-financial support from SERVIER, personal fees and non-financial support from BAYER, personal fees and non-financial support from MERCK, outside the submitted work. EA reports honoraria for the advisory roles from AMGEN, BAYER, CELGENE, MERCK, ROCHE, SANOFI. The remaining authors declare no competing interests.

Ethics approval and consent to participate

The study was conducted according to the Helsinki Declaration and national regulations. It was approved by the ethics committee of Hospital Reina Sofía (Córdoba, Spain; approval number/ID: 255) and patients gave their written informed consent before taking part.

Consent to publish

Not applicable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Élez, E., Gómez-España, M.A., Grávalos, C. et al. Effect of aflibercept plus FOLFIRI and potential efficacy biomarkers in patients with metastatic colorectal cancer: the POLAF trial. Br J Cancer 126, 874–880 (2022). https://doi.org/10.1038/s41416-021-01638-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-021-01638-w

Search

Advanced search

Quick links