Elsevier

European Journal of Cancer

Volume 75, April 2017, Pages 213-221
European Journal of Cancer

Original Research
Exploratory analysis of biomarkers associated with clinical outcomes from the study of lenvatinib in differentiated cancer of the thyroid

https://doi.org/10.1016/j.ejca.2017.01.013Get rights and content
Under a Creative Commons license
open access

Highlights

  • Lenvatinib prolonged progression-free survival regardless of baseline cytokine/angiogenic factor or BRAF/RAS status.

  • Baseline angiopoietin-2 was predictive of PFS in a subgroup of lenvatinib-treated patients.

  • Results suggest that lenvatinib-induced fibroblast growth factor receptor inhibition contributes to lenvatinib efficacy.

Abstract

Background

Lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in the phase III Study of (E7080) LEnvatinib in differentiated Cancer of the Thyroid (SELECT) of patients with radioiodine-refractory differentiated thyroid cancer. This exploratory analysis investigated potential predictive biomarkers of lenvatinib efficacy and target engagement.

Patients and methods

Circulating cytokine/angiogenic factors (CAFs) in blood samples collected at baseline and throughout treatment were analysed from patients randomised to receive lenvatinib or placebo from August 5, 2011 to October 4, 2012. For CAF biomarker analyses, patients were dichotomised by baseline levels. Tumour tissues were analysed for BRAF and NRAS/KRAS/HRAS mutations.

Results

Tumours and CAFs were analysed from 183/392 (47%) and 387/392 (99%) patients, respectively. Lenvatinib PFS benefit was maintained in all assessments. For lenvatinib-treated patients, interaction-term analyses revealed that low baseline Ang2 level was predictive of tumour shrinkage (Pinteraction = 0.016) and PFS (Pinteraction = 0.018). Vascular endothelial growth factor and fibroblast growth factor 23 (FGF23) were significantly upregulated with lenvatinib, and FGF23 upregulation on cycle 1/day 15 was associated with longer PFS. In mutation analyses, no significant differences in clinical outcomes were observed. BRAFWT may be a negative prognostic factor for PFS in placebo-treated patients with papillary thyroid cancer (P = 0.019).

Conclusion

The lenvatinib PFS benefit was maintained regardless of baseline CAF or BRAF/RAS status. Baseline Ang2 was predictive of PFS in a subgroup of lenvatinib-treated patients, indicating that Ang2 may be predictive of lenvatinib sensitivity. BRAFWT may be a poor prognostic factor in patients with radioiodine-refractory papillary thyroid cancer. Improved PFS associated with upregulated FGF23 suggests that lenvatinib-induced FGF receptor inhibition contributes to lenvatinib efficacy.

Trial registration ID of the main study, SELECT: ClinicalTrials.gov: NCT01321554.

Keywords

Lenvatinib
Biomarkers
Thyroid cancer
Tyrosine kinase inhibitor
Phase 3
Clinical trial

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1

Present address: Division of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.