Exploratory Biomarker Analysis Using Plasma Angiogenesis-Related Factors and Cell-Free DNA in the TRUSTY Study: A Randomized, Phase II/III Study of Trifluridine/Tipiracil Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer

Target Oncol. 2024 Jan;19(1):59-69. doi: 10.1007/s11523-023-01027-8. Epub 2024 Jan 9.

Abstract

Background: The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC).

Objective: This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC.

Patients and methods: The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed.

Results: Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS.

Conclusion: Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted.

Clinical trial registration number: jRCTs031180122.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bevacizumab / pharmacology
  • Bevacizumab / therapeutic use
  • Biomarkers
  • Cell-Free Nucleic Acids* / therapeutic use
  • Colonic Neoplasms* / drug therapy
  • Colorectal Neoplasms* / pathology
  • Female
  • Frontotemporal Dementia* / drug therapy
  • Humans
  • Interleukin-8 / therapeutic use
  • Male
  • Middle Aged
  • Pyrrolidines*
  • Thymine*
  • Tissue Inhibitor of Metalloproteinase-1 / therapeutic use
  • Trifluridine / pharmacology
  • Trifluridine / therapeutic use
  • Uracil / therapeutic use

Substances

  • tipiracil
  • Bevacizumab
  • Interleukin-8
  • Uracil
  • Trifluridine
  • Tissue Inhibitor of Metalloproteinase-1
  • Cell-Free Nucleic Acids
  • Biomarkers
  • Pyrrolidines
  • Thymine