在 RAISE 研究中，对转移性结直肠癌患者血浆中 VEGF-D 检测方法的临床开发和评估。
Clinical development and evaluation of a VEGF-D assay in plasma from patients with metastatic colorectal cancer in the RAISE study.
机构信息
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
出版信息
Curr Med Res Opin. 2021 Oct;37(10):1769-1778. doi: 10.1080/03007995.2021.1940908. Epub 2021 Jul 28.
BACKGROUND
Vascular endothelial growth factor (VEGF)-D was identified as a potential predictive biomarker for ramucirumab efficacy in second-line metastatic colorectal cancer using a research use only (RUO) assay. We describe results with a new assay for detecting VEGF-D in human plasma.
METHODS
In RAISE (Clinical Trial Registration: NCT01183780), 1072 patients were randomized 1:1 to ramucirumab or placebo plus FOLFIRI. All patients were then randomized 1:2 to marker exploratory (ME) and marker confirmatory (MC) groups, and those with plasma samples were analyzed accordingly. A new assay validated for investigational use only (IUO) was used to measure VEGF-D levels in plasma, which were analyzed for correlation with overall and progression-free survival (OS/PFS). IUO assay data were compared with historical RUO assay data.
RESULTS
ME subset analyses determined the optimal cutpoint of 5.4 ng/mL for defining high/low VEGF-D subgroups. In the combined ME/MC placebo arms, OS/PFS were numerically greater for patients with low vs high VEGF-D (OS: 12.8 vs 11.1 months; PFS: 5.6 vs 4.2 months). In patients with high VEGF-D, ramucirumab vs placebo demonstrated a numerically greater improvement in OS and PFS. Differential efficacy by VEGF-D level was statistically significant for PFS, but not OS.
CONCLUSION
In patients with high VEGF-D, ramucirumab demonstrated a greater improvement in OS and PFS vs placebo; however, baseline VEGF-D level was not predictive of ramucirumab OS benefit using VEGF-D assay for IUO. The RAISE intent-to-treat results remain valid.
背景
血管内皮生长因子-D（VEGF-D）被鉴定为一种研究用检测方法（RUO）检测二线转移性结直肠癌中雷莫芦单抗疗效的潜在预测生物标志物。我们描述了一种新的检测人血浆中 VEGF-D 的检测方法的结果。
方法
在 RAISE 研究（临床试验注册号：NCT01183780）中，1072 例患者按 1:1 随机分配接受雷莫芦单抗或安慰剂联合 FOLFIRI。所有患者随后按 1:2 随机分配至标志物探索（ME）和标志物确认（MC）亚组，相应地对有血浆样本的患者进行分析。使用一种新的仅用于研究的检测方法（IUO）测量血浆中 VEGF-D 水平，并分析其与总生存期（OS）和无进展生存期（PFS）的相关性。比较 IUO 检测方法数据与历史 RUO 检测方法数据。
结果
ME 亚组分析确定了 5.4ng/mL 作为定义高低 VEGF-D 亚组的最佳截断值。在联合 ME/MC 安慰剂组中，低 VEGF-D 组的 OS/PFS 长于高 VEGF-D 组（OS：12.8 个月 vs 11.1 个月；PFS：5.6 个月 vs 4.2 个月）。在 VEGF-D 高的患者中，雷莫芦单抗与安慰剂相比，OS 和 PFS 均有显著改善。VEGF-D 水平对 PFS 的疗效差异具有统计学意义，但对 OS 无统计学意义。
结论
在 VEGF-D 高的患者中，雷莫芦单抗组 OS 和 PFS 较安慰剂组显著改善；然而，使用 IUO 的 VEGF-D 检测方法，基线 VEGF-D 水平不能预测雷莫芦单抗的 OS 获益。RAISE 的意向治疗结果仍然有效。
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