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

doi:10.1007/s11523-023-01027-8

Clinical Trial

. 2024 Jan;19(1):59-69.

doi: 10.1007/s11523-023-01027-8. Epub 2024 Jan 9.

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

Yu Sunakawa¹, Yasutoshi Kuboki², Jun Watanabe³, Tetsuji Terazawa⁴, Hisato Kawakami⁵, Mitsuru Yokota⁶, Masato Nakamura⁷, Masahito Kotaka⁸, Naotoshi Sugimoto⁹, Hitoshi Ojima¹⁰, Eiji Oki¹¹, Takeshi Kajiwara¹², Yoshiyuki Yamamoto¹³, Yasushi Tsuji¹⁴, Tadamichi Denda¹⁵, Takao Tamura¹⁶, Soichiro Ishihara¹⁷, Hiroya Taniguchi¹⁸, Takako Eguchi Nakajima¹⁹, Satoshi Morita²⁰, Kuniaki Shirao²¹, Naruhito Takenaka²², Daisuke Ozawa²², Takayuki Yoshino²³

Affiliations

¹ Department of Clinical Oncology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan. y.sunakawa@marianna-u.ac.jp.
² Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan.
³ Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
⁴ Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan.
⁵ Department of Medical Oncology, Kindai University Faculty of Medicine Hospital, Osaka-Sayama, Japan.
⁶ Department of General Surgery, Kurashiki Central Hospital, Kurashiki, Japan.
⁷ Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan.
⁸ Gastrointestinal Cancer Center, Sano Hospital, Kobe, Japan.
⁹ Department of Genetic Oncology, Osaka International Cancer Institute, Osaka, Japan.
¹⁰ Department of Gastroenterological Surgery, Gunma Prefectural Cancer Center, Ota, Japan.
¹¹ Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
¹² Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
¹³ Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁴ Department of Medical Oncology, Tonan Hospital, Sapporo, Japan.
¹⁵ Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan.
¹⁶ Department of Medical Oncology, Kindai University Nara Hospital, Ikoma, Japan.
¹⁷ Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.
¹⁸ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
¹⁹ Department of Early Clinical Development, Kyoto University Graduate School of Medicine, Kyoto, Japan.
²⁰ Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
²¹ Faculty of Medicine, Oita University, Yufu, Japan.
²² Clinical Development and Medical Affairs Division, Taiho Pharmaceutical Co., Ltd, Tokyo, Japan.
²³ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

PMID: 38194163
PMCID: PMC10830797
DOI: 10.1007/s11523-023-01027-8

Clinical Trial

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

Yu Sunakawa et al. Target Oncol. 2024 Jan.

. 2024 Jan;19(1):59-69.

doi: 10.1007/s11523-023-01027-8. Epub 2024 Jan 9.

Authors

Affiliations

¹ Department of Clinical Oncology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan. y.sunakawa@marianna-u.ac.jp.
² Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan.
³ Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
⁴ Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan.
⁵ Department of Medical Oncology, Kindai University Faculty of Medicine Hospital, Osaka-Sayama, Japan.
⁶ Department of General Surgery, Kurashiki Central Hospital, Kurashiki, Japan.
⁷ Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan.
⁸ Gastrointestinal Cancer Center, Sano Hospital, Kobe, Japan.
⁹ Department of Genetic Oncology, Osaka International Cancer Institute, Osaka, Japan.
¹⁰ Department of Gastroenterological Surgery, Gunma Prefectural Cancer Center, Ota, Japan.
¹¹ Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
¹² Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
¹³ Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁴ Department of Medical Oncology, Tonan Hospital, Sapporo, Japan.
¹⁵ Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan.
¹⁶ Department of Medical Oncology, Kindai University Nara Hospital, Ikoma, Japan.
¹⁷ Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.
¹⁸ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
¹⁹ Department of Early Clinical Development, Kyoto University Graduate School of Medicine, Kyoto, Japan.
²⁰ Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
²¹ Faculty of Medicine, Oita University, Yufu, Japan.
²² Clinical Development and Medical Affairs Division, Taiho Pharmaceutical Co., Ltd, Tokyo, Japan.
²³ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

PMID: 38194163
PMCID: PMC10830797
DOI: 10.1007/s11523-023-01027-8

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.

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Conflict of interest statement

All authors report support for the present manuscript (e.g., funding, provision of study materials, medical writing, and article processing charges) from Taiho Pharmaceutical Co., Ltd K.K. Mitsuru Yokota, Hitoshi Ojima, Naotoshi Sugimoto, Yasushi Tsuji, and Soichiro Ishihara have no other conflicts of interest. Yu Sunakawa has received institutional grants or contracts from Chugai, Taiho, Takeda, Otsuka, and Eli Lilly Japan; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Eli Lilly Japan, Bristol Myers Squibb, Chugai, Takeda, Ono, Merck Biopharma, Taiho, Bayer, Daiichi Sankyo, MSD, Sysmex, and Guardant Health; and has participated on the data safety monitoring board or advisory board of Merck Biopharma, Ono, and Guardant Health. Yasutoshi Kuboki has received institutional grants or contracts from Taiho, Takeda, Ono, AbbVie, Janssen Oncology, Boehringer Ingelheim, Incyte, Amgen, Chugai, GlaxoSmithKline, Genmab, Astellas, Daiichi Sankyo, and Eli Lilly Japan; personal consulting fees from Amgen, Takeda, and Boehringer Ingelheim; and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Taiho, Ono, Bayer, Eli Lilly Japan, Bristol Myers Squibb, and Merck Serono. Jun Watanabe has received institutional grants or contracts from Medtronic, Amco, and Terumo; and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Medtronic, Johnson & Johnson, Eli Lilly Japan, and Takeda. Tetsuji Terazawa has received consulting fees from Chugai, Eli Lilly Japan, Taiho, and Sanofi; has been part of the data safety monitoring board or advisory board of Sanofi; and is an employee of Shionogi. Hisato Kawakami has received institutional grants or contracts from Eisai, Kobayashi, and Bristol Myers Squibb; personal consulting fees from Daiichi Sankyo; and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Bristol Myers Squibb, Eli Lilly Japan, Ono, Daiichi Sankyo, Takeda, Teijin, Otsuka, Bayer, MSD, Chugai, Merck Biopharma, Yakult, and Taiho. Masato Nakamura has received payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Eli Lilly Japan, Nihon Servier, Daiichi Sankyo, Ono, Taiho, Yakult, Merck & Co., Bayer, Chugai, Merck Biopharma, Otsuka, Takeda, and AstraZeneca. Masahito Kotaka has received payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Chugai, Takeda, Taiho, Yakult, and Eli Lilly Japan. Eiji Oki has received payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Taiho, Takeda, Chugai, Bristol Myers Squibb, Bayer, Eli Lilly Japan, and Ono. Takeshi Kajiwara has received payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Chugail, Eli Lilly Japan, Bristol Myers Squibb, Taiho, and Ono. Yoshiyuki Yamamoto has received payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Ono, Bristol Myers Squibb, Yakult, Chugai, Eli Lilly Japan, Bayer, Taiho, Servier, Takeda, Daiichi Sankyo, AstraZeneca, and Insight. Tadamichi Denda has received institutional grants or contracts from Ono, MSD, Bristol Myers Squibb Foundation, Amgen, and Pfizer; and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Daiichi Sankyo, Sysmex, and Ono. Takao Tamura has received institutional grants or contracts from Chugai, Ltd; and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Takeda, Eli Lilly Japan K.K., Bristol Myers Squibb, Ono, and Chugai. Hiroya Taniguchi has received institutional grants or contracts from Takeda, Daiichi Sankyo, and Ono; and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Takeda, Ono, Eli Lilly Japan, Merck Biopharma, and Chugai. Takako Eguchi Nakajima has received institutional grants or contracts from Guardant Health, Taiho, Takeda, Chugai, Nippon Kayaku Co., AbbVie, Eli Lilly Japan, Shionogi, Otsuka, and Taisho; and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Sumitomo Dainippon, Boehringer Ingelheim, Bristol Myers Squibb, Ono, Taiho, Amgen, Takeda, Chugai, Sanofi, Novartis Japan, Daiichi Sankyo, AstraZeneca, IQVIA, GlaxoSmithKline, NOBEL Pharma, and Parexel. Satoshi Morita has received payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Bristol Myers Squibb, Chugai, Taiho, Eli Lilly Japan, and AstraZeneca. Kuniaki Shirao has received institutional grants or contracts from Ono. Naruhito Takenaka and Daisuke Ozawa are employees of Taiho. Takayuki Yoshino has received institutional grants or contracts from Amgen K.K., Chugai, Daiichi Sankyo, Eisai, Falco Biosystems Ltd, Genomedia Inc., Molecular Health GmbH, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer Japan Inc., Roche Diagnostics K.K., Sanofi, Sysmex, and Taiho; personal consulting fees from Sumitomo Corporation; and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Bayer, Chugai, Merck Biopharma, MSD, Ono, and Takeda.

Figures

**Fig. 1**
Patient disposition. *BEV* bevacizumab, FP fluoropyrimidine, *FTD/TPI* trifluridine/tipiracil, *IRI* irinotecan

**Fig. 2**
DCR according to baseline plasma concentrations of angiogenesis-related factors and cfDNA in the FTD/TPI plus bevacizumab group. *cfDNA* cell-free DNA, CI confidence interval, *DCR* disease control rate, *FTD/TPI* trifluridine/tipiracil, *HGF* hepatocyte growth factor, *IFN*-γ interferon gamma, IL interleukin, *OPN* osteopontin, *PIGF* placental growth factor, *sICAM-1* soluble intercellular adhesion molecule-1, *sNeuropilin-1* soluble neuropilin-1, *sVCAM-1* soluble vascular cell adhesion molecule-1, *sVEGFR* soluble vascular endothelial growth factor receptor, *TIMP-1* tissue inhibitor of metalloproteinase-1, *TSP-2* thrombospondin-2, *VEGF* vascular endothelial growth factor

**Fig. 3**
PFS according to baseline plasma concentrations of angiogenesis-related factors and cfDNA in the FTD/TPI plus bevacizumab group. *cfDNA* cell-free DNA, CI confidence interval, *FTD/TPI* trifluridine/tipiracil, *HGF* hepatocyte growth factor, HR hazard ratio, *IFN-γ* interferon gamma, IL interleukin, *mPFS* median progression-free survival, *N.E.* not estimable, *OPN* osteopontin, *PFS* progression-free survival, *PIGF* placental growth factor, *sICAM-1* soluble intercellular adhesion molecule-1, *sNeuropilin-1* soluble neuropilin-1, *sVCAM-1* soluble vascular cell adhesion molecule-1, *sVEGFR* soluble vascular endothelial growth factor receptor, *TIMP-1* tissue inhibitor of metalloproteinase-1, *TSP-2* thrombospondin-2, *VEGF* vascular endothelial growth factor

**Fig. 4**
PFS by baseline cfDNA concentration in the FTD/TPI plus bevacizumab group. *cfDNA* cell-free DNA, *FTD/TPI* trifluridine/tipiracil, *PFS* progression-free survival, *qPCR* quantitative polymerase chain reaction

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[1] NCCN Clinical Practice guidelines in Oncology: Colon Cancer. 2023. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed 19 May 2023.

[2] NCCN Clinical Practice guidelines in Oncology: Colon Cancer. 2023. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed 19 May 2023.

[3] Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, et al. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388:1657–1667. doi: 10.1056/NEJMoa2214963. - DOI - PubMed

[4] Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, et al. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388:1657–1667. doi: 10.1056/NEJMoa2214963. - DOI - PubMed

[5] Mousa L, Salem ME, Mikhail S. Biomarkers of angiogenesis in colorectal cancer. Biomark Cancer. 2015;7:13–19. - PMC - PubMed

[6] Mousa L, Salem ME, Mikhail S. Biomarkers of angiogenesis in colorectal cancer. Biomark Cancer. 2015;7:13–19. - PMC - PubMed

[7] Ogunwobi OO, Mahmood F, Akingboye A. Biomarkers in colorectal cancer: current research and future prospects. Int J Mol Sci. 2020;21:5311. doi: 10.3390/ijms21155311. - DOI - PMC - PubMed

[8] Ogunwobi OO, Mahmood F, Akingboye A. Biomarkers in colorectal cancer: current research and future prospects. Int J Mol Sci. 2020;21:5311. doi: 10.3390/ijms21155311. - DOI - PMC - PubMed

[9] Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–1034. doi: 10.1056/NEJMoa1305275. - DOI - PubMed

[10] Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–1034. doi: 10.1056/NEJMoa1305275. - DOI - PubMed

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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

Affiliations

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

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