LBA30 - Comprehensive analysis of serum biomarker and tumor gene mutation associated with clinical outcomes in the phase 3 study of (E7080) lenvatinib in d...

Date 27 September 2014
Event ESMO 2014
Session Head and neck cancer
Topics Cytotoxic agents
Thyroid Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Biological therapy
Presenter Makoto Tahara
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors M. Tahara1, M.J. Schlumberger2, L.J. Wirth3, R. Elisei4, M. Brose5, M.A. Habra6, K. Newbold7, N. Kiyota8, C. Dutcus9, J. Zhu10, T. Kadowaki11, Y. Funahashi12, B. Robinson13, S. Sherman14
  • 1Department Of Head And Neck Medical Oncology, National Cancer Center Hospital East, 2778577 - Kashiwa/JP
  • 2Department Of Nuclear Medicine And Endocrine Oncology, Gustave Roussy and University Paris-Sud, Villejuif/FR
  • 3Department Of Medicine, Massachusetts General Hospital, 02114 - Boston/US
  • 4Endocrine Unit, Department Of Clinical And Experimental Medicine, University of Pisa, Pisa/IT
  • 5Department Of Otorhinolaryngology: Head And Neck Surgery, Abramson Cancer Center of the University of Pennsylvania Health System, Philadelphia/US
  • 6Department Of Endocrine Neoplasia And Hormonal Disorders, The University of Texas M.D. Anderson Cancer Center, Houston/US
  • 7National Health Service Trust, Royal Marsden Hospital, London/GB
  • 8Medical Oncology And Hematology, Kobe University Hospital, JP-650-0017 - Kobe/JP
  • 9Eisai, Eisai Inc., Woodcliff Lake/US
  • 10Clinical Department, Eisai Inc, Woodcliff Lake/US
  • 11Tsukuba, Eisai Co., Ltd,, Ibaraki/JP
  • 12Eisai, Eisai Inc., Andover/US
  • 13Kolling Institute Of Medical Research, The University of Sydney, Sydney/AU
  • 14Department Of Endocrine Neoplasia And Hormonal Disorders, Division Of Internal Medicine,, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;, Houston/US



Lenvatinib (LEN)—an oral multikinase inhibitor of VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT—significantly prolonged progression-free survival (PFS) vs placebo (PBO) in patients (pts) with 131I-refractory differentiated thyroid cancer in the phase 3 SELECT study. This analysis investigated potential LEN efficacy biomarkers from SELECT.


Blood samples were collected at baseline, Cycle 1/Day 15 (C1D15), Day 1 of subsequent cycles, and at treatment end. Circulating cytokine/angiogenic factors (CAFs) were measured by ELISA. Tumor tissues were analyzed for mutations of BRAF, NRAS, KRAS and HRAS (Ion Torrent PGM® Sequencer). For prognostic (disease) and predictive (response) biomarker analyses (P for interaction) of baseline CAFs, pts were dichotomized: low (1st quartile) vs high (others).


CAF and tissue samples were analyzed from 387 (99%) and 183 (47%) of all randomized pts (N = 392), respectively. PFS hazard ratio (HR) and 95% CI were similar between these groups and the overall study; LEN PFS benefit was maintained in all assessments. Low baseline angiopoietin-2 (Ang2) was significantly associated with tumor shrinkage in LEN (P = 0.017), but not PBO. PFS HR of LEN to PBO for low Ang2 (0.08, 95% CI 0.04–0.17; P < 0.001) was lower than high Ang2 (0.24, 95% CI 0.18–0.33; P < 0.001); low Ang2 was a positive predictive factor for LEN PFS (P = 0.018). High baseline thyroglobulin (Tg) was a negative prognostic factor for PFS (P = 0.023); PFS HR of LEN to PBO for high Tg (0.14, 95% CI 0.10–0.21; P < 0.001) was lower than low Tg (0.32, 95% CI 0.18–0.58; P < 0.001). With LEN, Tg rapidly decreased by C1D15; a large change correlated to better objective response (C1D15 and later). In mutation analyses, no significant differences in clinical outcomes were observed; BRAFMU was an independent positive prognostic factor for PFS in papillary thyroid cancer (P = 0.019). BRAFMU and NRASMU have significantly low and high baseline Tg, respectively, compared with wild type.


LEN PFS benefit vs PBO was maintained regardless of baseline CAF or BRAF/RAS mutational status. Baseline Ang2 was predictive of tumor shrinkage and PFS in a subset of patients (lowest quartile, 0-25%) with LEN, indicating that Ang2 may play a predictive role in defining sensitivity to LEN. Additionally, BRAFMU may be a positive prognostic factor in RR-DTC.


M. Tahara: Research Funding: Eisai, Boehringer-Ingelheim; M. Schlumberger: Advisory Role/Expert Testimony: AstraZeneca, Bayer, Eisai, Genzyme-Sanofi. Honoraria: AstraZeneca, Bayer, Eisai, Genzyme-Sanofi, Sobi. Research funding: AstraZeneca, Bayer, Eisai, Genzyme-Sanofi; M. Brose: Advisory Role: Eisai. Research Funding: Eisai; N. Kiyota: Research Funding: Eisai; C. Dutcus: and J. Zhu: Employee of Eisai Inc.; T. Kadowaki: Employee of Eisai Co., Ltd. Stock Ownership: Eisai Co., Ltd.; Y. Funahashi: Employee of Eisai Inc. Andover, MA; B. Robinson: Advisory Role: AstraZeneca, Bayer, Eisai; S. Sherman: Advisory Role: Yes, AstraZeneca, Amgen, Eisai, Exelixis, NovoNordisk, Eli Lilly Expert Testimony: No Stock Ownership: No Research Funding: Yes, Amgen. All other authors have declared no conflicts of interest.