Treatment‐emergent hypertension and efficacy in the phase 3 Study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT)

• Published in: Cancer 2018-06, Vol.124 (11), p.2365-2372
• Main Authors: Wirth, Lori J., Tahara, Makoto, Robinson, Bruce, Francis, Sanjeev, Brose, Marcia S., Habra, Mouhammed Amir, Newbold, Kate, Kiyota, Naomi, Dutcus, Corina E., Mathias, Elton, Guo, Matthew, Sherman, Steven I., Schlumberger, Martin
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antihypertensive Agents - therapeutic use; Blood Pressure Determination; Cancer; Chemotherapy, Adjuvant - adverse effects; Chemotherapy, Adjuvant - methods; Confidence intervals; differentiated thyroid cancer; Double-Blind Method; Effectiveness; efficacy; exploratory analysis; Female; Fibroblast growth factor receptor 1; Fibroblast growth factor receptor 2; Fibroblast growth factor receptor 4; Fibroblast growth factor receptors; Growth factors; Hazards; Humans; Hypertension; Hypertension - chemically induced; Hypertension - diagnosis; Hypertension - drug therapy; Hypertension - epidemiology; Iodine 131; Iodine radioisotopes; Iodine Radioisotopes - administration & dosage; Kaplan-Meier Estimate; lenvatinib; Male; Middle Aged; Oncology; Patients; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - adverse effects; Placebos - administration & dosage; Placebos - adverse effects; Progression-Free Survival; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Quinolines - administration & dosage; Quinolines - adverse effects; Radiation Tolerance; Rank tests; Response Evaluation Criteria in Solid Tumors; Ret protein; Statistical models; Stem cell factor; Stem cells; Survival; Survival Rate; Thyroid; Thyroid cancer; Thyroid Gland - pathology; Thyroid Neoplasms - mortality; Thyroid Neoplasms - pathology; Thyroid Neoplasms - therapy; treatment‐emergent hypertension; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; Young Adult
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.31344

BACKGROUND Hypertension (HTN) is an established class effect of vascular endothelial growth factor receptor (VEGFR) inhibition. In the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, HTN was the most frequent adverse event of lenvatinib, an inhibitor of VEGFR1, VEGFR2, VEGFR3, fibroblast growth factor receptor 1 (FGFR1), FGFR2, FGFR3, FGFR4, platelet‐derived growth factor receptor α (PDGFRα), ret proto‐oncogene (RET), and stem cell factor receptor (KIT). This exploratory analysis examined treatment‐emergent hypertension (TE‐HTN) and its relation with lenvatinib efficacy and safety in SELECT. METHODS In the multicenter, double‐blind SELECT trial, 392 patients with progressive radioiodine‐refractory differentiated thyroid cancer (RR‐DTC) were randomized 2:1 to lenvatinib (24 mg/d on a 28‐day cycle) or placebo. Survival endpoints were assessed with Kaplan‐Meier estimates and log‐rank tests. The influence of TE‐HTN on progression‐free survival (PFS) and overall survival (OS) was analyzed with univariate and multivariate Cox proportional hazards models. RESULTS Overall, 73% of lenvatinib‐treated patients and 15% of placebo‐treated patients experienced TE‐HTN. The median PFS for lenvatinib‐treated patients with (n = 190) and without TE‐HTN (n = 71) was 18.8 and 12.9 months, respectively (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.39‐0.88; P = .0085). For lenvatinib‐treated patients, the objective response rate was 69% with TE‐HTN and 56% without TE‐HTN (odds ratio, 1.72; 95% CI, 0.98‐3.01). The median change in tumor size for patients with and without TE‐HTN was −45% and −40%, respectively (P = .2). The median OS was not reached for patients with TE‐HTN; for those without TE‐HTN, it was 21.7 months (HR, 0.43; 95% CI, 0.27‐0.69; P = .0003). CONCLUSIONS Although HTN is a clinically significant adverse event that warrants monitoring and management, TE‐HTN was significantly correlated with improved outcomes in patients with RR‐DTC, indicating that HTN may be predictive for lenvatinib efficacy in this population. Cancer 2018;124:2365‐72. © 2018 American Cancer Society. In patients from the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, treatment‐emergent hypertension has been correlated with improved progression‐free survival, objective response rates, and overall survival. Therefore, treatment‐emergent hypertension may be considered a predictive factor for the efficacy of