Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA.
Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA.
Lung Cancer. 2015 Nov;90(2):296-301. doi: 10.1016/j.lungcan.2015.09.011. Epub 2015 Sep 15.
Linifanib, a potent and selective inhibitor of the tyrosine kinase activity of vascular endothelial growth factor and platelet-derived growth factor receptors, has clinical activity in advanced non-small cell lung cancer (NSCLC) both as monotherapy in the relapsed setting or with carboplatin and paclitaxel in the first-line setting. Though benefit was observed in unselected patient populations, identification of predictive biomarkers is critical for further development of this novel agent.
Data from 4 randomized studies in relapsed NSCLC with linifanib (n=116) or other treatments (n=125) were examined in an exploratory analysis to identify a biomarker profile predictive of favorable survival.
A signature combining the established tumor markers carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) was predictive of a favorable outcome. This signature was associated with improved survival in patients receiving linifanib monotherapy (hazard ratio [HR]=0.51 vs signature negative; p=0.002), but not in those receiving other anti-cancer treatments (p=0.716). This signature was validated on baseline plasma samples from patients enrolled in a randomized trial of daily linifanib 7.5 mg, linifanib 12.5 mg, or placebo added to first-line carboplatin and paclitaxel chemotherapy for advanced, nonsquamous NSCLC. Only linifanib-treated signature-positive patients had significant improvement in progression-free survival (PFS). Median PFS with placebo was 5.2 months versus 10.2 months (HR=0.49, p=0.049) for those receiving linifanib 7.5mg, and 8.3 months (HR=0.38, p=0.029) for linifanib 12.5 mg. Overall survival for signature-positive patients was 11.3 months with placebo, 12.5 months with linifanib 7.5mg (HR=1.02, p=0.758), and 17.4 months with linifanib 12.5 mg (HR=0.54, p=0.137).
This baseline plasma biomarker signature is associated with improved outcome in advanced NSCLC patients receiving linifanib. Utility of the biomarker signature in patient selection for linifanib therapy in NSCLC merits evaluation in larger, prospective trials that are powered to detect a survival benefit.
利尼伐尼是一种有效的、选择性的血管内皮生长因子和血小板衍生生长因子受体酪氨酸激酶抑制剂，在晚期非小细胞肺癌（NSCLC）中具有临床活性，无论是作为复发患者的单药治疗，还是与卡铂和紫杉醇联合用于一线治疗。尽管在未选择的患者人群中观察到了益处，但识别预测生物标志物对于这种新型药物的进一步开发至关重要。
对 4 项利尼伐尼治疗复发性 NSCLC（n=116）或其他治疗（n=125）的随机研究的数据进行了探索性分析，以确定预测有利生存的生物标志物特征。
一个结合了已建立的肿瘤标志物癌胚抗原（CEA）和细胞角蛋白 19 片段（CYFRA 21-1）的特征与改善的生存相关。该特征与接受利尼伐尼单药治疗的患者的生存改善相关（风险比[HR]=0.51 与特征阴性；p=0.002），但与接受其他抗癌治疗的患者无关（p=0.716）。该特征在一项随机试验的基线血浆样本中得到了验证，该试验将利尼伐尼 7.5mg、利尼伐尼 12.5mg 或安慰剂每日添加到一线卡铂和紫杉醇化疗中，用于治疗晚期非鳞状 NSCLC 患者。只有利尼伐尼治疗的特征阳性患者的无进展生存期（PFS）有显著改善。安慰剂组的中位 PFS 为 5.2 个月，而接受利尼伐尼 7.5mg 治疗的患者为 10.2 个月（HR=0.49，p=0.049），接受利尼伐尼 12.5mg 治疗的患者为 8.3 个月（HR=0.38，p=0.029）。特征阳性患者的总生存期为 11.3 个月，接受安慰剂治疗；利尼伐尼 7.5mg 治疗组为 12.5 个月（HR=1.02，p=0.758）；利尼伐尼 12.5mg 治疗组为 17.4 个月（HR=0.54，p=0.137）。
基线血浆生物标志物特征与接受利尼伐尼治疗的晚期 NSCLC 患者的改善结局相关。该生物标志物特征在 NSCLC 患者中选择利尼伐尼治疗中的应用价值需要在更大的、有生存获益检测能力的前瞻性试验中进行评估。
