Overall survival (OS) data and patient samples from a phase III trial comparing lenvatinib to sorafenib in patients with unresectable hepatocellular carcinoma (HCC) that were used to detect putative biomarkers for response to both agents revealed that VEGF- and FGF-family gene expression levels that were associated with greater OS. Findings from a biomarker analysis of phase III trial data were presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Richard S. Finn, Division of Hematology/Oncology, Geffen School of Medicine, UCLA Medical Center, Santa Monica, CA, USA and an international team of investigators conducted this analysis of serum and tissue biomarkers in patients from a comparison of lenvatinib to sorafenib as first-line treatment for unresectable HCC.
Lenvatinib is an oral multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT.
In the open label phase III trial(NCT01761266),first-line treatment with lenvatinib was found to be non-inferior for OS compared with sorafenib for patients with unresectable HCC; the median OS with lenvatinib was 13.6 months compared with 12.3 months for sorafenib, the current standard of care (hazard ratio [HR], 0.92; 95% confidence interval [CI] 0.79, 1.06).
In the trial, 954 patients who were previously untreated in the first-line, were randomised 1:1 to frontline treatment with lenvatinib at either 8 mg or 12 mg once per day based on body weight (n = 478) or sorafenib at 400 mg twice daily (n = 476). The trial’s primary endpoint was OS.
Archival tumour tissue were collected at baseline and blood samples were obtained prior to treatment and at specified time points during treatment. Using clinical data and patient samples from this trial, the investigators performed biomarker analyses on serum samples to identify potential markers of benefit to each agent.
The biomarker subgroup analysis set included 119 patients with both archival tissue and serum samples. The investigators assessed serum samples from 114 of these patients at baseline and over time using the ELISA protocol or chemiluminescence for VEGF, ANG2, FGF21, FGF23, and PIVKA-II. Of 119 patients in the biomarker set, 58 tissue samples passed quality assurance.
Serum assays were done on samples from 66 patients in the lenvatinib arm and 48 patients in the sorafenib arm. A trend was observed between lower VEGF, ANG2, and FGF21 serum levels at baseline and better outcomes with both agents. Both lenvatinib and sorafenib treatments resulted in an increase in serum VEGF over time that was greater for lenvatinib. Modulation of ANG2, FGF19, and FGF23 levels were only observed with lenvatinib. Data with FGF19 and FGF23 were not consistent.
The results of the biomarker analyses were correlated with OS
Gene-expression analysis was performed in 34 patients receiving lenvatinib and 24 patients on sorafenib. Supervised clustering was performed using angiogenic and growth-factor pathway gene expression based on 36 genes that identified 3 groups of expression.
Median OS was longer with lenvatinib in patients having higher VEGF- and FGF-family gene-expression levels but, conversely, OS was longer with sorafenib in patients having lower VEGF- and FGF-family gene-expression levels. These results are based on a relatively small subset of samples from the overall study and are meant to be hypotheses generating.
The investigators concluded that these results are hypotheses generating and require confirmation. Nonetheless, lenvatinib was found to be noninferior to sorafenib in terms of OS in patients with unresectable HCC. Among the subset of patients with evaluable samples, serum biomarker and gene expression levels appeared to correlate with survival outcomes.
An additional finding was that change in biomarker levels after lenvatinib and sorafenib treatments differed according to the agent used.
Lorenza Rimassa of the Medical Oncology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano (Milan), Italy who discussed the study results said that biomarker analyses in HCC is challenging due to molecular heterogeneity, clonal evolution driving drug resistance, and being often conducted in uncontrolled studies. This study was preplanned, exploratory, optional biomarker analysis to identify blood and tumour biomarkers correlating with clinical outcomes. Investigators are to be credited for their efforts to identify clinically useful biomarkers. Due to the small number of patients and the differences in the baseline results can be considered only hypotheses generating. Efficacy in biomarker-defined subgroups may support lenvatinib as a new first-line treatment option (non-inferior compared to sorafenib).
This trial was sponsored by Eisai Inc.
LBA30 – Finn RS, et al. Analysis of serum biomarkers (BM) in patients (pts) from a phase 3 study of lenvatinib (LEN) vs sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC).