title: Exploratory analysis of biomarkers associated with clinical outcomes from the study of lenvatinib in differentiated cancer of the thyroid.
abstract: 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.
  
  
  
  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.
  
  
  
  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. BRAFWTmay be a negative prognostic factor for PFS in placebo-treated patients with papillary thyroid cancer (P = 0.019).
  
  
  
  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. BRAFWTmay 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.
authors.affiliation: Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: matahara@east.ncc.go.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tahara
authors.affiliation: Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris-Sud, Villejuif, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlumberger
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Elisei
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mouhammed Amir
authors.initials: MA
authors.lastname: Habra
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kiyota
authors.affiliation: Division of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paschke
authors.affiliation: Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Corina E
authors.initials: CE
authors.lastname: Dutcus
authors.affiliation: Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Hihara
authors.affiliation: Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: McGrath
authors.affiliation: Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Matijevic
authors.affiliation: Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kadowaki
authors.affiliation: Eisai Inc., Andover, MA, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Funahashi
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Steven I
authors.initials: SI
authors.lastname: Sherman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042702:Angiopoietin-2 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
chemical_list: C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C000717427:FGF23 protein, human; C117307:KRAS protein, human; D008565:Membrane Proteins; D010671:Phenylurea Compounds; D011804:Quinolines; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); C531958:lenvatinib
keywords: Biomarkers; Clinical trial; Lenvatinib; Phase 3; Thyroid cancer; Tyrosine kinase inhibitor