Introduction: Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. Methods: Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p #x3c; 0.05 and predictive if p #x3c; 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. Results: In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. Conclusion: Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.
Liver Cancer

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基于血浆生物标志物的卡博替尼与安慰剂治疗晚期肝细胞癌 3 期 CELESTIAL 试验的结果

介绍：卡博替尼是一种 MET、AXL 和 VEGF 受体抑制剂，与安慰剂相比，在先前接受过治疗的晚期肝细胞癌 (HCC) 患者中显着提高了总生存期 (OS) 和无进展生存期 (PFS)。在这项探索性分析中，根据血浆生物标志物水平评估结果。方法：评估了 674/707 名随机患者的 MET、AXL、VEGFR2、HGF、GAS6、VEGF-A、PlGF、IL-8、EPO、ANG2、IGF-1、VEGF-C 和 c-KIT 的基线血浆水平；第 4 周评估了 614 名患者的 MET、AXL、VEGFR2、HGF、GAS6、VEGF-A、PlGF、IL-8 和 EPO 水平。OS 和 PFS 通过基线水平作为二分变量或连续变量进行分析，并通过第 4 周的治疗变化作为连续变量进行分析；如果p #x3c，则认为生物标志物具有潜在的预后意义；0.05 和预测如果p #x3c; 治疗与生物标志物之间的相互作用为 0.05。还进行了针对临床协变量进行调整的多变量分析。结果：在安慰剂组中，在单变量和多变量分析中，高水平的 MET、HGF、GAS6、IL-8 和 ANG2 以及低水平的 IGF-1 与较短的 OS 相关；在卡博替尼组中也观察到 MET、IL-8 和 ANG2 的这些关联。在所有生物标志物的低和高基线水平上，OS 和 PFS 的风险比均优于安慰剂。没有基线生物标志物可以预测治疗益处。卡博替尼促进了几种生物标志物的药效学变化，包括 VEGF-A、PlGF、AXL 和 GAS6 水平的增加以及 VEGFR2 和 HGF 水平的降低；这些变化与 OS 或 PFS 无关。结论：对于所有分析的生物标志物，卡博替尼在高和低基线浓度下与安慰剂相比改善了 OS 和 PFS。MET、HGF、GAS6、IL-8 和 ANG2 的低基线水平和高水平的 IGF-1 被确定为先前治疗的晚期 HCC 生存的潜在有利预后生物标志物。尽管卡博替尼促进了几种生物标志物的药效学变化，但这些变化与生存率无关。
肝癌