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Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study
Clinical Cancer Research ( IF 10.0 ) Pub Date : 2021-09-01 , DOI: 10.1158/1078-0432.ccr-20-4219
Richard S. Finn, Masatoshi Kudo, Ann-Lii Cheng, Lucjan Wyrwicz, Roger K.C. Ngan, Jean-Frederic Blanc, Ari D. Baron, Arndt Vogel, Masafumi Ikeda, Fabio Piscaglia, Kwang-Hyub Han, Shukui Qin, Yukinori Minoshima, Michio Kanekiyo, Min Ren, Ryo Dairiki, Toshiyuki Tamai, Corina E. Dutcus, Hiroki Ikezawa, Yasuhiro Funahashi, Thomas R. Jeffry Evans

Purpose: 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. Experimental Design: 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. Results: 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). Conclusions: 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.

中文翻译:


预测乐伐替尼治疗不可切除肝细胞癌生存获益的药效生物标志物:来自 III 期 REFLECT 研究



目的:在 REFLECT 中,通过证实乐伐替尼在不可切除的肝细胞癌中相对于索拉非尼的非劣效性,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 疗效结果之间的相关性。实验设计:通过 ELISA 测量血清生物标志物(VEGF、ANG2、FGF19、FGF21 和 FGF23)。通过 nCounter PanCancer Pathways Panel 测量肿瘤组织中的基因表达。评估了血清生物标志物水平相对于基线的药效变化,以及临床结果与基线生物标志物水平的关联。结果:407 名患者纳入血清分析组(乐伐替尼 n = 279,索拉非尼 n = 128);基因表达分析组包括 58 名患者(乐伐替尼 n = 34,索拉非尼 n = 24)。两种治疗均与 VEGF 增加有关。只有乐伐替尼在所有时间点都与 FGF19 和 FGF23 的增加相关。在第 4 周期第 1 天,乐伐替尼治疗的应答​​者的 FGF19 和 FGF23 与无应答者相比有更大的增加(FGF19:分别为 55.2% vs. 18.3%,P = 0.014;FGF23:48.4% vs. 16.4%,P = 0.0022)。两个治疗组中较高的基线 VEGF、ANG2 和 FGF21 与较短的 OS 相关。仑伐替尼的 OS 比索拉非尼更长[中位分别为 10.9 个月和 6.8 个月;心率,0.53; 95% 置信区间 (CI),0.33–0.85; P- 相互作用 = 0.0397] 与较高基线 FGF21。在肿瘤组织生物标志物分析中,与中等 VEGF/FGF 组相比,富含 VEGF/FGF 的组显示乐伐替尼改善了 OS(HR,0.39;95% CI,0.16-0.91;P = 0.0253)。结论:较高的 VEGF、FGF21 和 ANG2 基线水平可能预示着较短的 OS。 与索拉非尼相比,更高的基线 FGF21 可能预示乐伐替尼的 OS 更长,但这需要证实。
更新日期:2021-09-01
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