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Biomarker analysis using plasma angiogenesis factors in the TRUSTY study: A randomized phase 2/3 study of trifluridine/tipiracil plus bevacizumab as second-line treatment for metastatic colorectal cancer
Background
In primary analysis from the TRUSTY study, trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) failed to show non-inferiority in terms of overall survival (OS) to irinotecan and fluoropyrimidine plus BEV as second-line treatment in patients (pts) with metastatic colorectal cancer (mCRC) who failed first-line chemotherapy with fluoropyrimidine and oxaliplatin plus either BEV or an anti-EGFR antibody (median OS: 14.8 vs. 18.1 months; hazard ratio [HR]: 1.38; 95% CI: 0.99–1.93; p = 0.59 for non-inferiority; Kuboki Y et al., ASCO 2021). Here we report the relationship between the plasma levels of angiogenesis-related factors and the efficacy of FTD/TPI plus BEV in mCRC.
Methods
Pts who provided informed consent for the biomarker research were included in this analysis. Plasma samples were collected prior to the start of study treatment. Comprehensive measurements of 17 factors (Angiopoietin-2, HGF, IFN-γ, IL-6, IL-8, PlGF, VEGF-A, VEGF-D, OPN, sNeuropilin-1, sVEGFR1, sVEGFR2, sVEGFR3, TSP-2, sICAM-1, sVCAM-1, TIMP-1) were performed using a multiplex assay with Luminex® technology. The cut-off value in this analysis was defined as the median value of each factor. Disease control rate (DCR) and progression-free survival (PFS) as measures of the efficacy of FTD/TPI plus BEV were compared between 2 groups with high and low levels of each marker.
Results
In the FTD/TPI plus BEV arm, plasma samples were available for 65 of the intention-to-treat population (N=197). Baseline characteristics were male/female: 35/30, median age: 64.0 (range: 25–84), RAS status wild-type/mutant: 29/36, and anti-EGFR antibody/bevacizumab in first-line treatment: 17/48. The DCR was 55.4% and median PFS was 3.9 months in the population for this biomarker analysis. A higher DCR was observed in pts with lower HGF (72.0 vs. 39.4%, risk ratio: 1.83; 95% CI: 1.12–2.98) and lower IL-8 (67.9 vs. 40.0%, risk ratio: 1.70; 95% CI: 1.02–2.82). The PFS was significantly longer in pts with lower HGF (5.5 vs. 3.3 months, HR: 0.33; 95% CI: 0.14–0.79) and lower IL-8 (5.5 vs. 3.3 months, HR: 0.31; 95% CI: 0.14–0.70). In addition, pts with low levels of IL-6 (6.0 vs. 3.5 months, HR: 0.19; 95% CI: 0.07–0.50), OPN (5.5 vs. 3.5 months, HR: 0.39; 95% CI: 0.17–0.88), TSP-2 (4.9 vs. 3.6 months, HR: 0.42; 95% CI: 0.18–0.98), and TIMP-1 (7.4 vs. 3.6 months, HR: 0.26; 95% CI: 0.10–0.67) had longer PFS.
Conclusions
Plasma levels of HGF and IL-8 at baseline may serve as a predictor for better DCR and PFS of FTD/TPI plus BEV as second-line treatment in pts with mCRC, although further studies are warranted.
Legal entity responsible for the study
The author.
Funding
Taiho Pharmaceutical Co., Ltd.
Disclosures
H. Taniguchi: Honoraria (self): Takeda, Taiho, Merck Biopharma; Research grant / Funding (institution): Daiichi-Sankyo, Sysmex, Takeda. Y. Kuboki: Honoraria (self): Taiho, ONO, Bayer, Sanofi, ; Advisory / Consultancy: Takeda, Boehringer Ingelheim, Taiho; Research grant / Funding (institution): Taiho, Takeda, ONO, Abbie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen,Chugai, GSK, Genmab, Astelas, Daiichi-Sankyo. H. Kawakami: Honoraria (self): Taiho Pharmaceutical Co. Ltd, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Daiichi-Sankyo Co. Ltd.; Advisory / Consultancy: Daiichi-Sankyo Co. Ltd.; Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd, Bristol-Myers Squibb Co. Ltd, Eisai Co. Ltd., Kobayashi Pharmaceutical. Co., Ltd. M. Nakamura: Honoraria (self): Bayer Yakuhin, Ltd., Bristol-Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan Co., Ltd., Merck Bio Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd. M. Kotaka: Honoraria (self): Chugai pharmaceutical, Lilly. T. Kajiwara: Honoraria (self): Taiho Pharmaceutical, Chugai Pharma. T. Moriwaki: Speaker Bureau / Expert testimony: Taiho Pharmaceutical, Chugai Pharma; Research grant / Funding (institution): Taiho Pharmaceutical, Chugai Pharma. T. Denda: Honoraria (self): Ono Pharmaceutical, Daiichi-Sankyo; Research grant / Funding (institution): Ono Pharmaceutical. T. Tamura: Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd. Y. Sunakawa: Honoraria (self): Bristol-Myers Squibb, Chugai Pharm, Eli Lilly Japan; Advisory / Consultancy: Daiichi-Sankyo, Bristol-Myers Squibb, Guardant Health; Research grant / Funding (self): Chugai Pharm, Takeda, Taiho Pharm. S. Ishihara: Research grant / Funding (institution): Taiho. T. Nakajima: Honoraria (self): Taiho Pharm; Research grant / Funding (self): Chugai Pharm, Taiho Pharm. S. Morita: Honoraria (self): Taiho Pharmaceutical Co. Ltd, AstraZeneca K.K., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co. Ltd., Eisai Co., Ltd, Eli Lilly Japan K.K., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma KK, Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc; Research grant / Funding (institution): Eisai Co., Ltd. T. Yoshino: Honoraria (self): Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical and MSD; Research grant / Funding (institution): Ono Pharmaceutical, Sanofi, Daiichi Sankyo, PAREXEL International, Pfizer Japan, Taiho Pharmaceutical, MSD, Amgen, Genomedia, Sysmex, Chugai Pharmaceutical and Nippon Boehringer Ingelheim. All other authors have declared no conflicts of interest.
