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Abstract Details
Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase 3 REFLECT Study
Clin Cancer Res. 2021 Jun 9;clincanres.4219.2020. doi: 10.1158/1078-0432.CCR-20-4219.Online ahead of print.
Richard S Finn1, Masatoshi Kudo2, Ann-Lii Cheng3, Lucjan Wyrwicz4, Roger Kai-Cheong Ngan5, Jean-Frederic Blanc6, Ari D Baron7, Arndt Vogel8, Masafumi Ikeda9, Fabio Piscaglia10, Kwang-Hyub Han11, Shu-Kui Qin12, Yukinori Minoshima13, Michio Kanekiyo14, Min Ren15, Ryo Dairiki16, Toshiyuki Tamai17, Corina E Dutcus18, Hiroki Ikezawa19, Yasuhiro Funahashi13, Thomas R Jeffry Evans20
Author information
1Department of Hematology-Oncology, UCLA Medical Center rfinn@mednet.ucla.edu.
2Gastroenterology and Hepatology, Kindai University School of Medicine.
3Department of Medical Oncology, National Taiwan University Cancer Center.
4Laboratory of Booinformatics and Biostatistics, M Sklodowska Curie Memorial Cancer Center.
5Clinical Oncology, University of Hong Kong.
6Hepato-Gastroenterology and Digestive Oncology, University Hospital Of Bordeaux.
8Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover.
9Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East.
10IRCCS Azienda Ospedaliero-Universitaria di Bologna, Division of Internal Medicine.
11Department of Internal Medicine, Yonsei University College of Medicine.
12Department of Oncology, No.81 Hospital of People's Liberation Army.
13Tsukuba Research Laboratories, Eisai Co., Ltd.
14Eisai Inc.
15Oncology, Eisai Product Creation Systems.
16hhc Data Creation Center, Eisai.Co.,Ltd.
17Clinical Development, Eisai Co. Ltd.
18n/a, Eisai Inc.
19Eisai Co., Ltd.
20Beatson West of Scotland Cancer Centre, University of Glasgow.
Abstract
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: 407 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 timepoints. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus non-responders at C4D1 (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% CI, 0.33-0.85; P=0.0075; 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.