Clinical Significance of Early VEGF-A Elevation Following Ramucirumab Based Chemotherapy in Gastric Cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 18K08720
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: WAKATSUKI Takeru 公益財団法人がん研究会, 有明病院 消化器化学療法科, 医長 (60443876)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Keywords: 胃癌 / ラムシルマブ / 血管新生阻害剤 / SNPs / バイオマーカー / VEGF-A/VEGFR2経路の二重阻害療法

Outline of Final Research Achievements

The aim of this study was to identify the SNPs which predict the patients whose plasma VEGF-A levels are high after ramucirumab administration. Forty-two patients were enrolled in this study with the median PFS and OS was 4.1 and 11.0 months, respectively. The SNPs, VEGFR2 rs10013228 A>G (p=0.055), rs11133360 T>C (p=0.017), and rs2071559 A>G (p=0.072), were associated with higher plasma VEGF-A levels early after ramucirumab administration, but none of them were associated with survival. Instead, the SNPs potentially associated with worse prognosis were VEGFR1 XX with HR 2.23, p=0.070 for PFS and HR 3.10, p=0.030 for OS, and VEGFR2 YY with HR 2.11, p=0.093 for PFS. In preclinical mouse model, the combination therapy of anti-VEGF-A antibody and anti-VEGFR2 antibody showed higher antitumor efficacy compared to each monotherapy. The ligand and receptor dual blockade using antibodies in angiogenesis may be a promising therapy, and clinical trials are currently being prepared.

Free Research Field

臨床腫瘍学

Academic Significance and Societal Importance of the Research Achievements

VEGF-Aは血管新生の亢進だけでなく、腫瘍免疫の抑制にも関与することが明らかとなり、血管新生阻害剤は腫瘍免疫の改善にも貢献する。本研究で導かれた抗VEGF-A抗体/抗VEGFR2抗体併用によるVEGF-A/VEGFR2経路の二重阻害療法は、より高い血管新生阻害作用のみならず腫瘍免疫の改善も期待され、新たな治療選択肢として有望である。現在、新規医師主導治験実施の準備を行っている。