Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.
Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.
复制标题
DOI：
10.1158/1078-0432.ccr-20-4219
复制
发表时间：
2021-09-01
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
在REFLECT中，通过证实乐伐替尼在不可切除肝细胞癌中的非劣效性，证明了乐伐替尼对总生存期（OS）的影响。该分析评估了血清或组织生物标志物与REFLECT疗效结局之间的相关性。通过ELISA测量血清生物标志物（VEGF、ANG 2、FGF 19、FGF 21和FGF 23）。通过nCounter PanCancer Pathways Panel测量肿瘤组织中的基因表达。评价了血清生物标志物水平相对于基线的药效学变化以及临床结局与基线生物标志物水平的相关性。407例患者被纳入血清分析集（乐伐替尼n = 279，索拉非尼n = 128）; 58例患者被纳入基因表达分析集（乐伐替尼n = 34，索拉非尼n = 24）。两种治疗均与VEGF升高相关;在所有时间点，仅乐伐替尼与FGF 19和FGF 23升高相关。在第4周期第1天，乐伐替尼治疗应答者的FGF 19和FGF 23增加幅度大于无应答者（分别为FGF 19：55.2% vs. 18.3%，P = 0.014; FGF 23：48.4% vs. 16.4%，P = 0.0022）。在两个治疗组中，较高的基线VEGF、ANG 2和FGF 21与较短的OS相关。乐伐替尼的OS长于索拉非尼[中位数分别为10.9个月和6.8个月; HR为0.53; 95%置信区间（CI）为0.33-0.85; P-相互作用= 0.0397]，基线FGF 21更高。在肿瘤组织生物标志物分析中，与中等VEGF/FGF组相比，VEGF/FGF富集组显示乐伐替尼改善了OS（HR，0.39; 95% CI，0.16-0.91; P = 0.0253）。基线水平较高的VEGF、FGF 21和ANG 2可能预示OS较短。与索拉非尼相比，基线水平较高的FGF 21可能预示乐伐替尼OS较长，但这需要证实。
In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT. Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated. Four hundred and seven patients were included in the serum analysis set (lenvatinib n = 279, sorafenib n = 128); 58 patients were included in the gene-expression analysis set (lenvatinib n = 34, sorafenib n = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, P = 0.014; FGF23: 48.4% vs. 16.4%, P = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33–0.85; P-interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16–0.91; P = 0.0253). Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.