Treatment-Emergent Hypertension and Efficacy in the Phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (Select)

Abstract

ABSTRACT 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, PDGFRa, RET, and KIT—was HTN. This analysis examines treatment-emergent HTN (TE-HTN) and efficacy in SELECT. Methods: In this multicenter, double-blind study, pts with documented progressive 131I-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.