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Clinical Studies

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



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).


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.


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.


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

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

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).


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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.


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).

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Authors and Affiliations



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.

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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.

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Not applicable.

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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).

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