Exploration of potential prognostic biomarkers in aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer

Cancer Sci. 2019 Nov;110(11):3565-3572. doi: 10.1111/cas.14198. Epub 2019 Oct 21.


Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.

Keywords: FOLFIRI; aflibercept; biomarker; colorectal cancer; metastasis.

Publication types

  • Multicenter Study

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Asian Continental Ancestry Group
  • Biomarkers, Tumor / blood*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / therapeutic use
  • Colonic Neoplasms / blood
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / mortality
  • Colonic Neoplasms / pathology
  • Fluorouracil / therapeutic use
  • Humans
  • Insulin-Like Growth Factor Binding Protein 1 / blood
  • Interleukin-8 / blood
  • Japan
  • Kallikreins / blood
  • Leucovorin / therapeutic use
  • Placenta Growth Factor / blood
  • Prognosis
  • Progression-Free Survival
  • Prospective Studies
  • Pulmonary Surfactant-Associated Protein D / blood
  • Receptor for Advanced Glycation End Products / blood
  • Receptors, Tumor Necrosis Factor, Type II / blood
  • Receptors, Vascular Endothelial Growth Factor / therapeutic use*
  • Recombinant Fusion Proteins / therapeutic use*
  • Rectal Neoplasms / blood
  • Rectal Neoplasms / drug therapy*
  • Rectal Neoplasms / mortality
  • Rectal Neoplasms / pathology
  • Regression Analysis
  • Tenascin / blood
  • Tissue Inhibitor of Metalloproteinase-1 / blood
  • Vascular Endothelial Growth Factor Receptor-1 / blood


  • Biomarkers, Tumor
  • IGFBP1 protein, human
  • Insulin-Like Growth Factor Binding Protein 1
  • Interleukin-8
  • Pulmonary Surfactant-Associated Protein D
  • Receptor for Advanced Glycation End Products
  • Receptors, Tumor Necrosis Factor, Type II
  • Recombinant Fusion Proteins
  • TIMP1 protein, human
  • TNC protein, human
  • Tenascin
  • Tissue Inhibitor of Metalloproteinase-1
  • Placenta Growth Factor
  • aflibercept
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-1
  • Kallikreins
  • kallikrein 5, human
  • Leucovorin
  • Fluorouracil
  • Camptothecin

Supplementary concepts

  • IFL protocol

Associated data

  • ClinicalTrials.gov/NCT01882868

Grant support