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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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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s11523-023-01027-8.

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Most cited references 46

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Jean-Yves Douillard, Kelly S Oliner, Salvatore Siena … (2013)

Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy. In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%. Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified. Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).

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Author and article information

Contributors

Yu Sunakawa:

ORCID: http://orcid.org/0000-0002-0163-7543

y.sunakawa@marianna-u.ac.jp

Journal

Journal ID (nlm-ta): Target Oncol

Journal ID (iso-abbrev): Target Oncol

Title: Targeted Oncology

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1776-2596

ISSN (Electronic): 1776-260X

Publication date (Electronic): 9 January 2024

Publication date PMC-release: 9 January 2024

Publication date (Print): 2024

Volume: 19

Issue: 1

Pages: 59-69

Affiliations

[1 ]Department of Clinical Oncology, St. Marianna University School of Medicine, ( https://ror.org/043axf581) 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511 Japan

[2 ]Department of Experimental Therapeutics, National Cancer Center Hospital East, ( https://ror.org/03rm3gk43) Kashiwa, Japan

[3 ]Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, ( https://ror.org/03k95ve17) Yokohama, Japan

[4 ]Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, ( https://ror.org/01y2kdt21) Takatsuki, Japan

[5 ]Department of Medical Oncology, Kindai University Faculty of Medicine Hospital, ( https://ror.org/05kt9ap64) Osaka-Sayama, Japan

[6 ]Department of General Surgery, Kurashiki Central Hospital, ( https://ror.org/00947s692) Kurashiki, Japan

[7 ]Aizawa Comprehensive Cancer Center, Aizawa Hospital, ( https://ror.org/0576bwz31) Matsumoto, Japan

[8 ]GRID grid.513102.4, ISNI 0000 0004 5936 4925, Gastrointestinal Cancer Center, , Sano Hospital, ; Kobe, Japan

[9 ]Department of Genetic Oncology, Osaka International Cancer Institute, ( https://ror.org/010srfv22) Osaka, Japan

[10 ]GRID grid.517686.b, ISNI 0000 0004 1763 6849, Department of Gastroenterological Surgery, , Gunma Prefectural Cancer Center, ; Ota, Japan

[11 ]Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, ( https://ror.org/00p4k0j84) Fukuoka, Japan

[12 ]Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, ( https://ror.org/03yk8xt33) Matsuyama, Japan

[13 ]Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, ( https://ror.org/02956yf07) Tsukuba, Japan

[14 ]Department of Medical Oncology, Tonan Hospital, ( https://ror.org/01gtph098) Sapporo, Japan

[15 ]Division of Gastroenterology, Chiba Cancer Center, ( https://ror.org/02120t614) Chiba, Japan

[16 ]Department of Medical Oncology, Kindai University Nara Hospital, ( https://ror.org/05kt9ap64) Ikoma, Japan

[17 ]Department of Surgical Oncology, The University of Tokyo, ( https://ror.org/057zh3y96) Tokyo, Japan

[18 ]Department of Clinical Oncology, Aichi Cancer Center Hospital, ( https://ror.org/03kfmm080) Nagoya, Japan

[19 ]Department of Early Clinical Development, Kyoto University Graduate School of Medicine, ( https://ror.org/02kpeqv85) Kyoto, Japan

[20 ]Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, ( https://ror.org/02kpeqv85) Kyoto, Japan

[21 ]Faculty of Medicine, Oita University, ( https://ror.org/01nyv7k26) Yufu, Japan

[22 ]Clinical Development and Medical Affairs Division, Taiho Pharmaceutical Co., Ltd, ( https://ror.org/02v50dx14) Tokyo, Japan

[23 ]Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, ( https://ror.org/03rm3gk43) Kashiwa, Japan

Author information

Yu Sunakawa http://orcid.org/0000-0002-0163-7543

Yasutoshi Kuboki http://orcid.org/0000-0003-3675-953X

Jun Watanabe http://orcid.org/0000-0002-7187-3664

Hisato Kawakami http://orcid.org/0000-0002-3280-4850

Hitoshi Ojima http://orcid.org/0000-0003-3551-9796

Eiji Oki http://orcid.org/0000-0002-9763-9366

Takeshi Kajiwara http://orcid.org/0000-0001-5337-9833

Hiroya Taniguchi http://orcid.org/0000-0003-1407-6682

Takako Eguchi Nakajima http://orcid.org/0000-0002-4589-2335

Naruhito Takenaka http://orcid.org/0009-0000-7746-6982

Takayuki Yoshino http://orcid.org/0000-0002-0489-4756

Article

Publisher ID: 1027

DOI: 10.1007/s11523-023-01027-8

PMC ID: 10830797

PubMed ID: 38194163

SO-VID: 1e705c5c-7a55-4d29-8118-faa839eaf110

License:

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date accepted : 2 December 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009954, Taiho Pharmaceutical;

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ScienceOpen disciplines: Oncology & Radiotherapy

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ScienceOpen disciplines: Oncology & Radiotherapy

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A Phase II Study of FOLFIRI Plus Ziv-Aflibercept After Trifluridine/Tipiracil Plus Bevacizumab in Patients with Metastatic Colorectal Cancer: WJOG 11018G
Authors: Toshihiko Matsumoto, Yoshiyuki Yamamoto, Masahito Kotaka …

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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

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Abstract

Background

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Patients and Methods

Results

Conclusion

Clinical Trial Registration Number

Supplementary Information

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Karger: Oncology

Most cited references 46

Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.

Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials.

Role of chemokines in tumor growth.

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