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

Tetsuya Hamaguchi, Tadamichi Denda, Toshihiro Kudo, Naotoshi Sugimoto, Takashi Ura, Kentaro Yamazaki, Hirofumi Fujii, Takeshi Kajiwara, Takako Eguchi Nakajima, Shin Takahashi, Satoshi Otsu, Yoshito Komatsu, Fumio Nagashima, Toshikazu Moriwaki, Taito Esaki, Takeo Sato, Michio Itabashi, Eiji Oki, Toru Sasaki, Marielle Chiron, Takayuki Yoshino, Tetsuya Hamaguchi, Tadamichi Denda, Toshihiro Kudo, Naotoshi Sugimoto, Takashi Ura, Kentaro Yamazaki, Hirofumi Fujii, Takeshi Kajiwara, Takako Eguchi Nakajima, Shin Takahashi, Satoshi Otsu, Yoshito Komatsu, Fumio Nagashima, Toshikazu Moriwaki, Taito Esaki, Takeo Sato, Michio Itabashi, Eiji Oki, Toru Sasaki, Marielle Chiron, Takayuki Yoshino

Abstract

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.

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

Figure 1
Figure 1
Flow chart of biomarkers measured, excluded from analysis, and analyzed. LLOQ, lower limit of quantification
Figure 2
Figure 2
Progression‐free survival (PFS) (A) and overall survival (OS) (B) stratified by above/below median plasma concentrations at baseline of biomarkers with adjusted P < .05 for PFS or OS. These biomarkers were extracellular newly identified receptor for advanced glycation end‐products binding protein (EN‐RAGE), insulin‐like growth factor‐binding protein 1 (IGFBP‐1), interleukin‐8 (IL‐8), kallikrein 5, pulmonary surfactant‐associated protein D (SP‐D), tenascin‐C (TN‐C), tissue inhibitor of metalloproteinases 1 (TIMP‐1), and tumor necrosis factor receptor 2 (TNFR2). ***P < .001; *P < .05; NS, not statistically significant
Figure 3
Figure 3
Kaplan‐Meier curves of overall survival (OS) stratified by median plasma concentration at baseline for eight biomarkers: (A) advanced glycation end‐products binding protein (EN‐RAGE), (B) insulin‐like growth factor‐binding protein 1 (IGFBP‐1), (C) interleukin‐8 (IL‐8), (D) kallikrein 5, (E) pulmonary surfactant‐associated protein D (SP‐D), (F) tenascin‐C (TN‐C), (G) tissue inhibitor of metalloproteinases 1 (TIMP‐1), and (H) tumor necrosis factor receptor 2 (TNFR2)
Figure 4
Figure 4
Baseline biomarker levels in patients stratified by having received prior bevacizumab. N = Patient did not receive prior bevacizumab; Y = Patient did receive prior bevacizumab. P values were determined using Welch's test. ANG‐2, angiopoietin‐2; PlGF, placental growth factor; VEGF, vascular endothelial growth factor

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