Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.

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:

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 17 Pg. 4848-4858 (09 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34108184 (Publication Type: Clinical Trial, Phase III, Equivalence Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Phenylurea Compounds
• Quinolines
• Sorafenib
• lenvatinib

Topics

• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (analysis, pharmacokinetics)
• Carcinoma, Hepatocellular (blood, chemistry, drug therapy, mortality)
• Humans
• Liver Neoplasms (blood, chemistry, drug therapy, mortality)
• Phenylurea Compounds (therapeutic use)
• Predictive Value of Tests
• Quinolines (therapeutic use)
• Sorafenib (therapeutic use)
• Survival Rate