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 Anti-Cancer Agents & Biologic Therapy
Thyroid Cancer
Translational Research
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.