Relationship Between Thyroid-Stimulating Hormone Levels and Outcomes from the Randomized, Double-Blind, Phase 3 Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT)

Program: Abstracts - Orals, Poster Previews, and Posters
Session: THR 312-340-Endocrine Neoplasia: Tumorigenesis and Therapeutics
Thursday, March 5, 2015: 1:00 PM-3:00 PM
Hall D-F, Tumor Biology (San Diego Convention Center)

Poster Board THR-331
Steven I Sherman, MD1, Martin Schlumberger, MD2, Makoto Tahara, MD PhD3, Bruce Gregory Robinson, MD, MSC, FRAC4, Kate Newbold, MD5, Andrew George Gianoukakis, MD6, Manisha H Shah, MD7, Matthew H Taylor, MD8, Naomi Kiyota, MD PhD9, Corina E Dutcus, MD10, Angela Teng, MS10 and Lori Wirth, MD11
1The University of Texas MD Anderson Cancer Center, Houston, TX, 2Gustave Roussy and University Paris-Sud, Villejuif, France, 3National Cancer Center Hospital East, Kashiwa, Japan, 4University of Sydney, Sydney NSW, Australia, 5Royal Marsden Hospital National Health Service Trust London, 6Harbor-UCLA Medical Center, Torrance, CA, 7Ohio State University Comprehensive Cancer Center, Columbus, OH, 8Knight Cancer Institute, Oregon Health and Science University, Portland, OR, 9Kobe University Hospital, Kobe, Japan, 10Eisai Inc., Woodcliff Lake, NJ, 11Massachusetts General Hospital, Boston, MA, USA
Introduction: In the SELECT trial, 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 with 131I-refractory differentiated thyroid cancer (RR-DTC; median 18.3 vs 3.6 months, respectively; hazard ratio 0.21 [99% confidence interval 0.14–0.31]; P<0.0001). This exploratory analysis examines how thyroid abnormalities may have influenced the safety and efficacy outcomes in SELECT.

Methods: SELECT–a phase 3 double-blind study–randomized patients with RR-DTC to 24 mg/d of LEN or PBO until disease progression, unacceptable toxicity, or death. Key inclusion criteria included independently verified disease progression within 13 months, 0 or 1 prior VEGF-targeted therapy, and serum thyroid-stimulating-hormone (TSH) levels ≤5.5mIU/L. When tolerated, active TSH suppression (≤0.5 mIU/L) by concomitant levothyroxine treatment was added.

Results: 392 Patients were randomized (LEN=261; PBO=131). Median baseline TSH levels were LEN, 0.05 mIU/L; PBO, 0.04 mIU/L. All patients received concomitant levothyroxine. Patient TSH levels in the LEN arm were already elevated relative to baseline (median 0.10 mIU/L; range, 0–39.1) by the time of first assessment (cycle 1 day 15). TSH levels peaked at cycle 2 (median TSH 0.16 mIU/L; range 0–93.2), but steadily declined after cycle 4. At study end, the median TSH level for the LEN arm was 0.08 mIU/L (range 0–17.8). There were no consistent changes in TSH levels in the PBO arm. Patients receiving LEN had worst post-baseline TSH levels of ≤0.5 mIU/L (n=99; 37.9%), >0.5-2.0 mIU/L (n=53; 20.3%), >2.0-5.0 mIU/L (n=25; 9.6%), and >5.0 mIU/L (n=80; 30.7%). 5 Patients experienced LEN-related hyperthyroidism and 9 patients experienced LEN-related hypothyroidism; all were Grade 1–2 events. There were no substantial differences in rates of dose modifications, study drug withdrawals, treatment exposure, or LEN-related adverse events based on worst post-baseline TSH levels. Objective response rates based on worst post-baseline TSH levels were: ≤0.5 mIU/L, 65.7%, >0.5-2.0 mIU/L, 69.8%; >2.0-5.0 mIU/L, 48.0%, and >5.0mIU/L, 68.8%. There was also no significant difference in PFS between patients based on worst post-baseline TSH levels (adjusted log-rank P=0.747).

Conclusions: An increase in TSH levels was a frequent complication; its direct relationship to LEN therapy has not been established. In this analysis, there was no evidence of a relationship between the maximum worst post-baseline TSH level and LEN dosing, or increased toxicities. There was also no evidence that TSH levels affected tumor responses to LEN treatment. This may be indicative of properties intrinsic to LEN, or reflective of frequent adjustment of thyroid hormone dosing by the treating physician to maintain low TSH levels. Further analyses are warranted.

Disclosure: SIS: Consultant, Roche Pharmaceuticals, Consultant, Genzyme Corporation, Consultant, Eli Lilly & Company, Consultant, Novo Nordisk, Consultant, Veracyte, Inc., Consultant, Astra Zeneca, Research Funding, Pfizer, Inc., Consultant, Bayer, Inc., Consultant, Exelixis, Inc., Consultant, Eisai. MS: Consultant, Genzyme Corporation, Consultant, Eisai, Consultant, Bayer, Inc., Consultant, Astra Zeneca. MT: Advisory Group Member, Lecture Fees, Speaker, Bristol-Myers Squibb, Advisory Group Member, Merck & Co.. BGR: Advisory Group Member, Bayer, Inc., Advisory Group Member, Astra Zeneca. KN: payment of registartion fees and flight to attend European Thyroid Association Annual Meeting topresent work arising from this trial in September 2014 , Eisai. AGG: Consultant, Eisai. MHS: Clinical Researcher, Bayer, Inc., Consultant, Exelixis, Inc., Consultant, Eisai. MHT: Advisory Group Member, Eisai. NK: Consultant, Eisai. CED: Employee, Eisai. AT: Employee, Eisai. LW: Consultant, Novartis Pharmaceuticals, Consultant, Eisai.

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Sources of Research Support: This study was funded by Eisai Inc. Editorial support, provided by Oxford PharmaGenesis, Inc., was funded by Eisai Inc.