Randomized Controlled Trial

. 2023 May;128(10):1897-1905.

doi: 10.1038/s41416-023-02212-2. Epub 2023 Mar 4.

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial

Yasutoshi Kuboki¹, Tetsuji Terazawa², Toshiki Masuishi³, Masato Nakamura⁴, Jun Watanabe⁵, Hitoshi Ojima⁶, Akitaka Makiyama^{7

8}, Masahito Kotaka⁹, Hiroki Hara¹⁰, Yoshinori Kagawa^{11

12}, Naotoshi Sugimoto¹³, Hisato Kawakami¹⁴, Atsuo Takashima¹⁵, Takeshi Kajiwara¹⁶, Eiji Oki¹⁷, Yu Sunakawa¹⁸, Soichiro Ishihara¹⁹, Hiroya Taniguchi³, Takako Eguchi Nakajima²⁰, Satoshi Morita²¹, Kuniaki Shirao²², Naruhito Takenaka²³, Daisuke Ozawa²³, Takayuki Yoshino²⁴

Affiliations

¹ Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan.
² Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan.
³ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
⁴ Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan.
⁵ Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
⁶ Gastrointestinal Surgery, Gunma Prefectural Cancer Center, Ota, Japan.
⁷ Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushu, Japan.
⁸ Cancer Center, Gifu University Hospital, Gifu, Japan.
⁹ Gastrointestinal Cancer Center, Sano Hospital, Kobe, Japan.
¹⁰ Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan.
¹¹ Department of Gastrointestinal Surgery, Kansai Rosai Hospital, Amagasaki, Japan.
¹² Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan.
¹³ Department of Genetic Oncology, Osaka International Cancer Institute, Osaka, Japan.
¹⁴ Department of Medical Oncology, Kindai University Hospital, Osakasayama, Japan.
¹⁵ Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁶ Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
¹⁷ Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁸ Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
¹⁹ Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²⁰ Department of Early Clinical Development, Kyoto University Graduate School of Medicine, Kyoto, Japan.
²¹ Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
²² Oita University Faculty of Medicine, Oita, Japan.
²³ Clinical Development and Medical Affairs Division, Taiho Pharmaceutical Co., Ltd., Tokyo, Japan.
²⁴ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. tyoshino@east.ncc.go.jp.

PMID: 36871043
PMCID: PMC10147634
DOI: 10.1038/s41416-023-02212-2

Randomized Controlled Trial

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial

Yasutoshi Kuboki et al. Br J Cancer. 2023 May.

. 2023 May;128(10):1897-1905.

doi: 10.1038/s41416-023-02212-2. Epub 2023 Mar 4.

Authors

Affiliations

¹ Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan.
² Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan.
³ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
⁴ Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan.
⁵ Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
⁶ Gastrointestinal Surgery, Gunma Prefectural Cancer Center, Ota, Japan.
⁷ Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushu, Japan.
⁸ Cancer Center, Gifu University Hospital, Gifu, Japan.
⁹ Gastrointestinal Cancer Center, Sano Hospital, Kobe, Japan.
¹⁰ Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan.
¹¹ Department of Gastrointestinal Surgery, Kansai Rosai Hospital, Amagasaki, Japan.
¹² Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan.
¹³ Department of Genetic Oncology, Osaka International Cancer Institute, Osaka, Japan.
¹⁴ Department of Medical Oncology, Kindai University Hospital, Osakasayama, Japan.
¹⁵ Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁶ Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
¹⁷ Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁸ Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
¹⁹ Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²⁰ Department of Early Clinical Development, Kyoto University Graduate School of Medicine, Kyoto, Japan.
²¹ Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
²² Oita University Faculty of Medicine, Oita, Japan.
²³ Clinical Development and Medical Affairs Division, Taiho Pharmaceutical Co., Ltd., Tokyo, Japan.
²⁴ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. tyoshino@east.ncc.go.jp.

PMID: 36871043
PMCID: PMC10147634
DOI: 10.1038/s41416-023-02212-2

Abstract

Background: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC).

Methods: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m² twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33.

Results: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; P_{noninferiority} = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%).

Conclusions: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC.

Clinical trial registration: JapicCTI-173618, jRCTs031180122.

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Conflict of interest statement

YKu has received (in the past 36 months) institutional grants or contracts from Taiho, Takeda, Ono, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GlaxoSmithKline, Genmab, Astellas, and Daiichi Sankyo; personal consulting fees from Taiho, Takeda, and Boehringer Ingelheim; and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Taiho, Ono, Bayer, and Sanofi. TT has received (in the past 36 months) payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Chugai, Eli Lilly Japan, Taiho Pharmaceutical, and Sanofi; has been part of the data safety monitoring board or advisory board of Sanofi; and is an employee for Shionogi. TM has received (in the past 36 months) institutional grants or contracts from MSD, Daiichi Sankyo, Ono, and Novartis and personal consulting fees from Takeda, Chugai, Merck Biopharma, Taiho, Bayer, Eli Lilly Japan, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, and Bristol Myers Squibb. MN has received (in the past 36 months) payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Bayer, Daiichi Sankyo, Merck Biopharma, Taiho Pharmaceutical, Yakult, Chugai, Eli Lilly Japan, Ono, and Takeda. JW has received (in the past 36 months) 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, and Eli Lilly. AM has received (in the past 36 months) payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Eli Lilly Japan, Ono, Daiichi Sankyo, Taiho, and Bristol Myers Squibb. MK has received (in the past 36 months) payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Chugai, Taiho, and Yakult. HH has received (in the past 36 months) institutional grants from Amgen, AstraZeneca, BeiGene, Chugai, Sumitomo Dainippon, Janssen, MSD, Taiho, Astellas, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eisai, Merck Biopharma, and Ono; personal consulting fees from Bristol Myers Squibb, Daiichi Sankyo, MSD, Boehringer Ingelheim, Sumitomo Dainippon, and Ono; and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Bayer, Chugai, Kyowa Kirin, Merck Biopharma, Ono, Taiho, Yakult, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, MSD, Sanofi, and Takeda. YKa has received (in the past 36 months) payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Taiho, Eli Lilly, Chugai, Takeda, Ono, Yakult, Sanofi, Merck, and MSD. HK has received (in the past 36 months) institutional grants or contracts from Chugai Pharmaceutical, Kobayashi Pharmaceutical Co. Ltd., Taiho, and Eisai; 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 Pharma Ltd., GlaxoSmithKline K.K., Bayer, MSD K.K., Chugai, Merck Biopharma, Yakult, Taiho, and Otsuka. AT has received (in the past 36 months) institutional grants or contracts from MSD, Daiichi Sankyo, Taiho Pharmaceutical, Hutchison MediPharma, Incyte, Ono, Sumitomo Dainippon, Pfizer Inc., and Isofol Medical AB and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Chugai Pharmaceutical, Taiho Pharmaceutical, Ono, Eli Lilly, and MSD. TK has received (in the past 36 months) payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Taiho Pharmaceutical, Chugai Pharmaceutical, Ono, and Eli Lilly Japan. EO has received (in the past 36 months) payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Taiho. YS has received (in the past 36 months) institutional grants or contracts from Chugai, Taiho, Takeda, Sanofi, 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 Daiichi Sankyo, MSD, and Guardant Health. SI has received (in the past 36 months) institutional grants or contracts from Yakult and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Taiho and Yakult. HT has received (in the past 36 months) 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, Taiho, Eli Lilly Japan, Merck Biopharma, Ono, and Chugai. TEN has received (in the past 36 months) institutional royalties or licenses from Sumitomo Dainippon, Ono, Taiho, Takeda, Chugai, Sanofi K.K., Nippon Kayaku Co., MSD K.K., and Eli Lilly Japan; personal consulting fees from Thyas Co. Ltd. and Rebirthel Co. Ltd.; and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Sumitomo Dainippon, Boehringer Ingelheim, Bristol Myers Squibb, Ono, Taiho, Amgen, Takeda, Chugai, Sanofi K.K., Novartis Japan, Nippon Kayaku Co., MSD K.K., Eli Lilly Japan, Bayer, Pfizer Japan Inc., Daiichi Sankyo, Yakult, Nipro Co., Merck Serono Co., AstraZeneca, IQVIA, and GlaxoSmithKline. SM has received (in the past 36 months) payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from AstraZeneca K.K., Bristol Myers Squibb Company, Chugai, Eli Lilly Japan, MSD K.K., Nippon Boehringer Ingelheim, Novartis Pharma K.K., Ono, Pfizer Japan Inc., and Taiho. NT and DO are employees of Taiho. TY has received (in the past 36 months) institutional grants or contracts from Ono, Sanofi K.K., Daiichi Sankyo, Parexel International Inc., Pfizer Japan Inc., Taiho Pharmaceutical, MSD K.K., Amgen K.K., Genomedia Inc., Sysmex Corporation, Chugai, and Nippon Boehringer Ingelheim and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Taiho, Chugai, Eli Lilly Japan, Merck Biopharma, Bayer, Ono, and MSD K.K. HO, NS, and KS have nothing to disclose.

Figures

**Fig. 1. CONSORT diagram.**
AE adverse event, BEV bevacizumab, FAS full analysis set, FOLFIRI 5-fluorouracil, leucovorin, and irinotecan, FP fluoropyrimidine, FTD/TPI trifluridine/tipiracil, IRI irinotecan, SAS safety analysis set, wk week. ^aAs of data cutoff (16 July 2020).

**Fig. 2. Kaplan–Meier curves.**
a overall survival, b progression-free survival, c time to treatment failure, and d time to treatment failure 2. BEV bevacizumab, CI confidence interval, FP fluoropyrimidine, FTD/TPI trifluridine/tipiracil, HR hazard ratio, IRI irinotecan, mo months. ^aAdjusted based on stratification factors. ^bAd hoc unplanned two-sided superiority test.

**Fig. 3. Subgroup baseline analyses of overall survival.**
5-FU 5-fluorouracil, BEV bevacizumab, CI confidence interval, ECOG PS Eastern Cooperative Oncology Group performance status, EGFR epidermal growth factor receptor, FOLFIRI 5-FU, leucovorin, and irinotecan, FP fluoropyrimidine, FTD/TPI trifluridine/tipiracil, HR hazard ratio, IRI irinotecan, *RAS* rat sarcoma virus, y years.

**Fig. 4. Adjusted overall survival curves.**
a intent-to-use 5-FU, b intent-to-use S-1, c baseline sum of the diameter of target lesions ≥60 mm, and d baseline sum of the diameter of target lesions <60 mm. 5-FU 5-fluorouracil, BEV bevacizumab, CI confidence interval, FOLFIRI 5-FU, leucovorin, and irinotecan, FP fluoropyrimidine, FTD/TPI trifluridine/tipiracil, HR hazard ratio, IRI irinotecan, NE not estimable. ^aAdjusted based on stratification factors.

See this image and copyright information in PMC

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Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial

Affiliations

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial

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Abstract

Conflict of interest statement

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