Pharmacodynamic biomarkers predictive of survival benefit with lenvatinib in unresectable hepatocellular carcinoma: From the phase III REFLECT study
Journal
Clinical Cancer Research
Journal Volume
27
Journal Issue
17
Pages
4848-4858
Date Issued
2021
Author(s)
Finn R.S.
Kudo M.
Wyrwicz L.
Ngan R.K.C.
Blanc J.-F.
Baron A.D.
Vogel A.
Ikeda M.
Piscaglia F.
Han K.-H.
Qin S.
Minoshima Y.
Kanekiyo M.
Ren M.
Dairiki R.
Tamai T.
Dutcus C.E.
Ikezawa H.
Funahashi Y.
Evans T.R.J.
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 Pan- Cancer 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. ? 2021 American Association for Cancer Research.
SDGs
Other Subjects
angiopoietin 2; biological marker; fibroblast growth factor 19; fibroblast growth factor 21; fibroblast growth factor 23; lenvatinib; sorafenib; vasculotropin; Article; cancer prognosis; cancer survival; clinical outcome; controlled study; disease association; enzyme linked immunosorbent assay; gene expression; human; human tissue; liver cell carcinoma; major clinical study; multiple cycle treatment; overall survival; pharmacodynamics; phase 3 clinical trial (topic); prediction; protein blood level; treatment outcome
Publisher
American Association for Cancer Research Inc.
Type
journal article