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Treatment-Emergent Hypertension and Efficacy in the Phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (Select)
Annals of Oncology 25 (Supplement 4): iv340–iv356, 2014 doi:10.1093/annonc/mdu340.45
head and neck cancer 1030P
TREATMENT-EMERGENT HYPERTENSION AND EFFICACY IN THE PHASE 3 STUDY OF (E7080) LENVATINIB IN DIFFERENTIATED CANCER OF THE THYROID (SELECT)
abstracts
Aim: Hypertension (HTN), an on-target adverse event (AE) of VEGFR inhibition, is a biomarker for tyrosine kinase inhibitor efficacy in renal cell carcinoma treatment. In the phase 3 Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT), the most frequent AE in patients ( pts) on lenvatinib (LEN)—an inhibitor of VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT—was HTN. This analysis examines treatment-emergent HTN (TE-HTN) and efficacy in SELECT.
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at University of Alabama at Birmingham on July 16, 2015
L.J. Wirth1, M. Tahara2, B. Robinson3, S. Francis1, M. Brose4, M.A. Habra5, K. Newbold6, N. Kiyota7, C. Dutcus8, B.D.L. Heras9, J. Zhu8, S. Sherman5, M. Schlumberger10 1 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA 2 Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, JAPAN 3 Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, AUSTRALIA 4 Department of Otorhinolaryngology: Head and Neck Surgery, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA 5 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 6 National Health Service Trust, The Royal Marsden Hospital, London, UK 7 Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, JAPAN 8 Eisai, Eisai Inc., Woodcliff Lake, NJ, USA 9 Eisai, Eisai Ltd, England, UK 10 Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris-Sud, Villejuif, FRANCE
Methods: In this multicenter, double-blind study, pts with documented progressive I-refractory differentiated thyroid cancer (RR-DTC) were randomized 2:1 to LEN or placebo (24mg/d; 28-d cycle). Primary endpoint was progression-free survival (PFS); secondary endpoints were objective response rate (ORR), overall survival (OS), and safety. This analysis of investigator-assessed TE-HTN included increased blood pressure and prehypertension AEs. Results: Overall, 190/261 (73%) LEN-treated and 20/131 (15%) placebo-treated pts experienced TE-HTN. For LEN, percentages of pts with TE-HTN were: Grade 1, 7%; Grade 2, 22%; Grade 3, 44%; Grade 4, 0.4%. Median time to first onset of TE-HTN was 2.3 weeks (range, 1.4–5.0). Median PFS in LEN-treated pts with and without TE-HTN was 18.8 months (95% confidence interval [CI] 16.5–not estimable [NE]) and 12.9 months (95% CI 7.4–NE), respectively. Pts with TE-HTN had a 5.9-month median PFS advantage (hazard ratio 0.59 [95% CI 0.39–0.88]; P = 0.009). ORR for LEN-treated pts with TE-HTN was 69% vs 56% for those without (odds ratio 1.72 [95% CI 0.98– 3.01]). Median change in tumor size for pts with and without TE-HTN was −45% and −40%, respectively (P = 0.2). Median OS had not been reached in pts with TE-HTN; in pts without TE-HTN: 21.7 months (95% CI 15.7–NE). LEN-HTN was managed concomitantly with antihypertensive agents (68%): calcium channel blockers (51%), ACE inhibitors (38%), and angiotensin II receptor antagonists (29%). TE-HTN led to LEN dose interruption in 34 (13%), dose reduction in 35 (13%), and drug discontinuation in 3 (1%) pts. Conclusions: Although HTN is a clinically significant AE that warrants careful monitoring and management, LEN-emergent HTN was significantly correlated with improved clinical outcome in pts with RR-DTC. Further studies will investigate HTN as a predictive indicator of LEN response. Disclosure: M. Tahara: Research Funding: Eisai, Boehringer-Ingelheim; B. Robinson: Advisory Role: AstraZeneca, Bayer, Eisai; M. Brose: Advisory Role: Eisai Research Funding: Eisai; N. Kiyota: Research Funding: Eisai C. Dutcus: Employee of Eisai Inc.; B. D.L. Heras: Employee of Eisai Ltd; J. Zhu: Employee of Eisai Inc. S. Sherman: Advisory Role: AstraZeneca, Amgen, Eisai, Exelixis, NovoNordisk, Eli Lilly Research Funding: Amgen; 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. All other authors have declared no conflicts of interest. 131
head and neck cancer 1030P
TREATMENT-EMERGENT HYPERTENSION AND EFFICACY IN THE PHASE 3 STUDY OF (E7080) LENVATINIB IN DIFFERENTIATED CANCER OF THE THYROID (SELECT)
abstracts
Aim: Hypertension (HTN), an on-target adverse event (AE) of VEGFR inhibition, is a biomarker for tyrosine kinase inhibitor efficacy in renal cell carcinoma treatment. In the phase 3 Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT), the most frequent AE in patients ( pts) on lenvatinib (LEN)—an inhibitor of VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT—was HTN. This analysis examines treatment-emergent HTN (TE-HTN) and efficacy in SELECT.
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at University of Alabama at Birmingham on July 16, 2015
L.J. Wirth1, M. Tahara2, B. Robinson3, S. Francis1, M. Brose4, M.A. Habra5, K. Newbold6, N. Kiyota7, C. Dutcus8, B.D.L. Heras9, J. Zhu8, S. Sherman5, M. Schlumberger10 1 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA 2 Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, JAPAN 3 Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, AUSTRALIA 4 Department of Otorhinolaryngology: Head and Neck Surgery, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA 5 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 6 National Health Service Trust, The Royal Marsden Hospital, London, UK 7 Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, JAPAN 8 Eisai, Eisai Inc., Woodcliff Lake, NJ, USA 9 Eisai, Eisai Ltd, England, UK 10 Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris-Sud, Villejuif, FRANCE
Methods: In this multicenter, double-blind study, pts with documented progressive I-refractory differentiated thyroid cancer (RR-DTC) were randomized 2:1 to LEN or placebo (24mg/d; 28-d cycle). Primary endpoint was progression-free survival (PFS); secondary endpoints were objective response rate (ORR), overall survival (OS), and safety. This analysis of investigator-assessed TE-HTN included increased blood pressure and prehypertension AEs. Results: Overall, 190/261 (73%) LEN-treated and 20/131 (15%) placebo-treated pts experienced TE-HTN. For LEN, percentages of pts with TE-HTN were: Grade 1, 7%; Grade 2, 22%; Grade 3, 44%; Grade 4, 0.4%. Median time to first onset of TE-HTN was 2.3 weeks (range, 1.4–5.0). Median PFS in LEN-treated pts with and without TE-HTN was 18.8 months (95% confidence interval [CI] 16.5–not estimable [NE]) and 12.9 months (95% CI 7.4–NE), respectively. Pts with TE-HTN had a 5.9-month median PFS advantage (hazard ratio 0.59 [95% CI 0.39–0.88]; P = 0.009). ORR for LEN-treated pts with TE-HTN was 69% vs 56% for those without (odds ratio 1.72 [95% CI 0.98– 3.01]). Median change in tumor size for pts with and without TE-HTN was −45% and −40%, respectively (P = 0.2). Median OS had not been reached in pts with TE-HTN; in pts without TE-HTN: 21.7 months (95% CI 15.7–NE). LEN-HTN was managed concomitantly with antihypertensive agents (68%): calcium channel blockers (51%), ACE inhibitors (38%), and angiotensin II receptor antagonists (29%). TE-HTN led to LEN dose interruption in 34 (13%), dose reduction in 35 (13%), and drug discontinuation in 3 (1%) pts. Conclusions: Although HTN is a clinically significant AE that warrants careful monitoring and management, LEN-emergent HTN was significantly correlated with improved clinical outcome in pts with RR-DTC. Further studies will investigate HTN as a predictive indicator of LEN response. Disclosure: M. Tahara: Research Funding: Eisai, Boehringer-Ingelheim; B. Robinson: Advisory Role: AstraZeneca, Bayer, Eisai; M. Brose: Advisory Role: Eisai Research Funding: Eisai; N. Kiyota: Research Funding: Eisai C. Dutcus: Employee of Eisai Inc.; B. D.L. Heras: Employee of Eisai Ltd; J. Zhu: Employee of Eisai Inc. S. Sherman: Advisory Role: AstraZeneca, Amgen, Eisai, Exelixis, NovoNordisk, Eli Lilly Research Funding: Amgen; 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. All other authors have declared no conflicts of interest. 131