PO.CL01.06 · 临床研究
探索晚期癌症患者对尼达尼布(nintedanib)与贝伐珠单抗(bevacizumab)联合治疗应答的生物标志物预测因子：一项1b期研究的相关性研究
Exploring biomarker predictors of response to nintedanib and bevacizumab combination therapy in advanced cancer patients: Correlative studies from Phase 1b study
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：贝伐珠单抗及其他VEGF抑制剂在多种癌症中提供临床获益，但受限于耐药性，这种耐药性主要由通过替代促血管生成通路（包括PDGFR和FGFR）的血管再生所驱动。尼达尼布是一种靶向VEGFR、PDGFR和FGFR的三重激酶抑制剂，可能克服这些逃逸机制。我们此前在1B期研究中探索了尼达尼布联合贝伐珠单抗的安全性和疗效并已发表。我们在此展示对预先设定终点时采集的血浆样本进行的相关性生物标志物研究。
方法：血浆样本取自入组于一项评估尼达尼布联合贝伐珠单抗治疗晚期实体瘤的1期剂量递增研究的患者（肺癌n=9、结肠癌n=8、宫颈癌n=1）。分析了基线血浆生物标志物——包括IL-8、ICAM-1、Angiopoietin-2、KDR/VEGFR2、E-selectin、VEGF和SDF-1alpha——并将其与临床结局进行相关性分析。生物标志物定量采用基于多重微珠的免疫测定法（Luminex），部分分析物通过ELISA验证。
结果：尼达尼布200 mg每日两次耐受性良好，未出现剂量限制性毒性。在既往接受过贝伐珠单抗治疗的患者中，55%实现了持久的疾病控制，包括1例完全缓解和4例疾病稳定。较高的基线KDR/VEGFR2和E-selectin水平以及较低的SDF-1alpha水平与更好的结局相关。ANOVA识别出多个与疾病控制显著相关的生物标志物，包括KDR/VEGFR2（p=0.004）、PDGF-AA（p=0.037）和Endoglin（p=0.020）。
结论：尼达尼布联合贝伐珠单抗安全、耐受性良好，并在既往接受过大量治疗的患者中展现出有意义的临床活性。基线KDR/VEGFR2、E-selectin和SDF-1alpha成为潜在的预测性生物标志物。这些数据支持在更大队列中进一步验证，作为一种优化生物标志物驱动的患者选择策略，用于肺癌和结直肠癌的治疗。
查看英文原文 English abstract
Background: Bevacizumab and other VEGF inhibitors provide clinical benefit across multiple cancers but are limited by resistance driven largely by revascularization through alternate pro-angiogenic pathways, including PDGFR and FGFR. Nintedanib, a triple kinase inhibitor targeting VEGFR, PDGFR, and FGFR, may overcome these escape mechanisms. The safety and efficacy of nintedanib plus bevacizumab was previously explored in our phase 1B study and published. We are presenting correlative biomarker studies on the plasma samples acquired at prespecified endpoints.
Methods: Plasma samples were obtained from patients enrolled in a phase 1 dose-escalation study evaluating nintedanib in combination with bevacizumab for advanced solid tumors (lung n=9, colon n=8, cervical n=1). Baseline plasma biomarkers-including IL-8, ICAM-1, Angiopoietin-2, KDR/VEGFR2, E-selectin, VEGF, and SDF-1alpha-were analyzed and correlated with clinical outcomes. Biomarker quantification was performed using multiplex bead-based immunoassays (Luminex), with select analytes validated by ELISA.
Results: Nintedanib 200 mg twice daily was well tolerated with no dose-limiting toxicities. . Among bevacizumab-pretreated patients, 55% achieved durable disease control, including one complete response and four stable diseases. Higher baseline levels of KDR/VEGFR2 and E-selectin and lower SDF-1alpha were associated with improved outcomes. ANOVA identified several biomarkers significantly linked to disease control, including KDR/VEGFR2 (p=0.004), PDGF-AA (p=0.037), and Endoglin (p=0.020).
Conclusion: Nintedanib combined with bevacizumab was safe, well tolerated, and demonstrated meaningful clinical activity in heavily pretreated patients. Baseline KDR/VEGFR2, E-selectin, and SDF-1alpha emerged as potential predictive biomarkers. These data support further validation in larger cohort as a strategy to refine biomarker-driven patient selection for treatments in lung and colorectal cancers.
利益披露 Disclosure
R. K. Paluri,
Exelixis Other, Speaker bureau.
Ipsen Speaker bureau.
Pfizer ).
F. Robert, None.