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Analysis of plasma angiogenesis factors on the efficacy of FOLFIRI plus ramucirumab and FOLFOXIRI plus ramucirumab as first-line treatment for metastatic colorectal cancer from WJOG9216G randomized phase II study
Vascular endothelial growth factor (VEGF)-D high have been reported as a negative prognostic marker and potential predictive marker for ramucirumab (RAM) efficacy in metastatic colorectal cancer. We investigated the impact of plasma angiogenesis factors including VEGF-D on the efficacy of RAM-containing regimens, using data of the WJOG9216G study of FOLFIRI plus RAM (arm A) versus FOLFOXIRI plus RAM (arm B) as first-line treatment for mCRC.
Plasma samples were collected at pre-treatment, start of cycle 2, and post-treatment. Sixteen plasma angiogenesis factors were measured by magnetic bead panel Milliplex MAP kits. The patients were divided into two groups based on the median plasma level at the baseline and evaluated by pearson’s chi-square test and log-rank test. The quartiles (Q) were defined as follows: Q1 25%, 50%, 75%.
A total of 100 patients (47/53 in arm A/B) were evaluated for this study. The baseline characteristics (median age, 62/65 years; performance status 0, 79/72%; Right-sided tumor, 30/32%; RAS mutant, 64/64%) and efficacy (objective response rate [ORR], 55/66%; median progression-free survival [PFS], 11.8/11.1 months; median PFS2, 18.4/16.0 months) of the study population were comparable to those of the intent to treat population (n = 122). Plasma levels of VEGF-A, VEGF-D, placental growth factor (PlGF), and hepatocyte growth factor (HGF) were significantly increased during the treatment. In analysis combined arm A and B, patients with high VEGF-D had significant higher ORR compared to those with low VEGF-D (71% vs. 49%, p=0.029). The ORR significantly increased as the concentration of VEGF-D increased by quartile (44/54/71/71% in Q1/2/3/4, p for trend=0.026). However, there were no differences in PFS and PFS2 between high and low groups (median PFS, 11.7 vs. 11.5 months, hazard ratio [HR] 0.94 [95% confidence interval, 0.58-1.52]; median PFS2, 17.5 vs. 16.0 months, HR 1.32 [0.80-2.17]). Patients with high angiopoietin-2 (Ang-2), compared to those with low Ang-2, had significant lower ORR (48% vs. 74%, p=0.008) and trend toward shorter PFS (9.6 vs. 11.8 months, HR 0.67 [0.42-1.08], p=0.096).
This biomarker study showed associations of baseline VEGF-D and Ang-2 level with the ORRs of RAM-containing regimens. We are conducting an analysis of these plasma angiogenesis factors on updated efficacy outcomes including overall survival.
jRCTs041180166.
West Japan Oncology Group.
Eli Lilly Japan K.K.
K. Sakai: Honoraria (self): Takeda Pharmaceutical Co., Ltd., Yodosha Co., Ltd. K. Nishio: Speaker Bureau / Expert testimony: Merck Biopharma Co., Ltd., Roche Diagnostics K.K., Otsuka Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Nippon Boehringer Ingelheim Co.,Ltd., West Japan Oncology Group. K. Yamazaki: Honoraria (self): Chugai Pharma, Takeda, Taiho; Research grant / Funding (institution): Taiho Pharmaceutical. S. Mitani: Honoraria (self): Taiho Pharmaceutical Co., Ono Pharmaceutical Co.; Advisory / Consultancy: Chugai Pharmaceutical Co.; Research grant / Funding (institution): Taiho Pharmaceutical Co., Eli Lilly. H. Yasui: Honoraria (self): Daiichi Sankyo, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb Japan, TERUMO, Eli Lilly Japan, Merk Biopharma, Yakult Honsha, Bayer Yakuhin, Takeda Pharmaceutical; Research grant / Funding (self): MSD, Ono Pharmaceutical, Daiichi Sankyo, Astellas Pharma, Amgen. H. Hara: Honoraria (self): Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD, Ono, Sanofi, Taiho, Takeda and Yakult; Advisory / Consultancy: Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Lilly, MSD and Ono; Research grant / Funding (institution): Amgen, Astellas, AstraZeneca, Bayel, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Elevar Therapeutics, GSK, Incyte, Merck Biopharma, MSD, Ono, Pfizer, and Taiho. T. Esaki: Honoraria (self): Daiichi Sankyo, Chugai, Taiho; Research grant / Funding (institution): MSD, Chugai, Daiichi Sankyo,. T. Masuishi: Honoraria (self): Ono, Merck Biopharma. E. Baba: Honoraria (self): BMS, Eli Lilly, Daiichi Sankyo,Ono,Takeda,Taiho,Chugai,Bayer,Tsumura,Merck ; Advisory / Consultancy: Daiichi Sankyo, Astellas Pharma, Astra Zaneca; Speaker Bureau / Expert testimony: Janssen, Daiichi Sankyo, Chugai; Research grant / Funding (institution): Chugai, Taiho. K. Yoshimura: Honoraria (self): Eli Lilly, Astra Zeneca, Chugai Pharma. H. Kawakami: Honoraria (self): Taiho Pharmaceutical Co. Ltd, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Daiichi-Sankyo Co. Ltd.., MSD, K.K., Eli Lilly Japan, K.K.; 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.. S. Hironaka: Honoraria (self): Eli Lilly, Yakult Honsha, Takeda Pharm. K. Muro: Honoraria (self): Ono Pharmaceutical, Taiho Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Daiichi Sankyo, MSD, and Bristol-Myers Squibb, ; Advisory / Consultancy: Amgen, AstraZeneca, Astellas Pharma, Ono Pharmaceutical, and Chugai; Research grant / Funding (institution): Ono Pharmaceutical, Astellas Pharma, Eisai, Amgen, Daiichi Sankyo, Novartis Pharma, Taiho Pharmaceutical, Sanofi, and Pfizer. All other authors have declared no conflicts of interest.
