A Phase II Study of FOLFIRI Plus Ziv-Aflibercept After Trifluridine/Tipiracil Plus Bevacizumab in Patients with Metastatic Colorectal Cancer: WJOG 11018G

Target Oncol. 2024 Mar;19(2):181-190. doi: 10.1007/s11523-024-01043-2. Epub 2024 Mar 1.


Background: Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients.

Objective: We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses.

Methods: This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex® multiplex assay U-kit.

Results: Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month-not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1).

Conclusions: This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment.

Clinical trial registration: jRCTs041190100.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bevacizumab / pharmacology
  • Bevacizumab / therapeutic use
  • Biomarkers
  • Colonic Neoplasms* / drug therapy
  • Colorectal Neoplasms* / pathology
  • Female
  • Frontotemporal Dementia* / drug therapy
  • Humans
  • Irinotecan / therapeutic use
  • Leucovorin / pharmacology
  • Leucovorin / therapeutic use
  • Placenta Growth Factor / therapeutic use
  • Pyrrolidines*
  • Receptors, Vascular Endothelial Growth Factor*
  • Recombinant Fusion Proteins*
  • Thymine*
  • Trifluridine / pharmacology
  • Trifluridine / therapeutic use
  • Vascular Endothelial Growth Factor A


  • aflibercept
  • Bevacizumab
  • Biomarkers
  • Irinotecan
  • Leucovorin
  • Placenta Growth Factor
  • Pyrrolidines
  • Receptors, Vascular Endothelial Growth Factor
  • Recombinant Fusion Proteins
  • Thymine
  • tipiracil
  • Trifluridine
  • Vascular Endothelial Growth Factor A

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