Early Changes in Circulating FGF19 and Ang-2 Levels as Possible Predictive Biomarkers of Clinical Response to Lenvatinib Therapy in Hepatocellular Carcinoma.

Makoto Chuma,Norio Itokawa,Hiroyuki Fukuda,Katsuaki Ogushi,Shuhei Nishigori,Nobuhiro Hattori,Shuitirou Iwasaki,Takashi Kumada,Toshifumi Tada,Kazushi Numata,Satoshi Hishiki,Taeang Arai,Shunji Hirose,Takahide Nakazawa,Yuki Miura,Manabu Morimoto,Shin Maeda,Atsushi Hiraoka,Naohisa Wada,Hidenori Toyoda,Makoto Kako,Masanori Atsukawa,Kojiro Michitaka,Tatehiro Kagawa,Haruki Uojima,Hiroyoshi Hidaka ,Akira Nozaki

doi:10.3390/cancers12020293

Abstract

Predictive biomarkers of the response of hepatocellular carcinoma (HCC) to Lenvatinib therapy have not yet been clarified. The aim of this study was to identify clinically significant biomarkers of response to Lenvatinib therapy, to target strategies against HCC. Levels of circulating angiogenic factors (CAFs) were analyzed in blood samples collected at baseline and after introducing lenvatinib, from 74 Child-Pugh class A HCC patients who received lenvatinib. As CAF biomarkers, serum vascular endothelial growth factor (VEGF), fibroblast growth factor 19 (FGF19), FGF23, and angiopoietin-2 (Ang-2) were measured using enzyme-linked immunosorbent assays. Results: Significantly increased FGF19 (FGF19-i) levels and decreased Ang-2 (Ang-2-d) levels were seen in Lenvatinib responders as compared to non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004; ratio of Ang-2 level at four weeks/baseline: 0.584 vs. 0.810, respectively, p = 0.0002). Changes in FGF23 and VEGF levels at four weeks versus baseline, however, were not significantly different in responders versus non-responders. In multivariate analysis, the combination of serum FGF19-i and Ang-2-d was the most independent predictive factor for Lenvatinib response (Odds ratio, 9.143; p = 0.0012). Furthermore, this combination biomarker showed the greatest independent association with progression-free survival (Hazard ratio, 0.171; p = 0.0240). Early changes in circulating FGF19 and Ang-2 levels might be useful for predicting clinical response and progression-free survival in HCC patients on Lenvatinib therapy.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third leading cause of cancer death worldwide [1]
The enrolled patients were divided according to their objective responses to Lenvatinib, i.e., responders (objective response (OR) group) vs. non-responders
Curve at analysis revealed that at the optimal cut-off value of 0.672 for the Ang-2 ratio, the Receiver-operating characteristic curve (ROC) curve area was 0.720 at 2 weeks, 0.766 at 4 weeks with 69.2% specificity and sensitivity (Figure 2f), and 0.833 at 8 weeks, respectively, for discriminating the Objective response (OR) group from the non-OR group. These results indicate that changes in Ang-2 levels at 2 weeks, 4 weeks and 8 weeks versus baseline levels could be superior to absolute Ang-2 levels at baseline for prediction of OR

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third leading cause of cancer death worldwide [1]. Advanced HCC is known for its poor prognosis [2]. Lenvatinib has recently become available as a new molecular targeted agent for the first-line treatment of unresectable HCC in Japan, the USA, the EU and Asia. The REFLECT trial showed the non-inferiority of Lenvatinib compared with Sorafenib in terms of the primary endpoint of overall survival (OS), and statistically significant and clinically meaningful improvement in the secondary endpoints of progression-free survival (PFS), time to progression, and objective response rate (ORR) in unresectable HCC [7]. The therapeutic potential of Lenvatinib for unresectable HCC in clinical practice has been reported in several recent literatures [8,9,10,11]

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