445PD - Clinical activity and pharmacokinetics (PK) of cabozantinib (XL184) in patients with progressive medullary thyroid carcinoma (MTC)

Date 30 September 2012
Event ESMO Congress 2012
Session Developmental therapeutics
Topics Drug Development
Thyroid Cancer
Pharmacology
Presenter Ezra Cohen
Authors E. Cohen1, R. Elisei2, M.J. Schlumberger3, S.P. Müller4, P. Schöffski5, M. Brose6, M. Shah7, D.R. Miles8, L.T. Nguyen8, S. Sherman9
  • 1Dept. Of Medicine, University of Chicago Medical Center, 60637 - Chicago/US
  • 2Department Of Endocrinology, University of Pisa, Pisa/IT
  • 3Medical Imaging, Institut de Canc, FR-94805 - Villejuif CEDEX/FR
  • 4Klinik Und Poliklinik Für Nuklearmedizin, Universitätsklinikum Essen, Essen/DE
  • 5Department Of General Medical Oncology, University Hospitals Leuven, 3000 - Leuven/BE
  • 6Dept Of Medicine, University of Pennsylvania Health System, Philadelphia/US
  • 7College Of Medicine, Ohio State University, Columbus/US
  • 8Nonclinical Development, Exelixis, Inc., 94080 - South San Francisco/US
  • 9Department Of Endocrine Neoplasia And Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston/US

Abstract

Background

Cabozantinib (cabo) is a potent oral therapy that inhibits MET, VEGFR2, and RET. In a phase 1 study, cabo demonstrated anti-tumor activity in patients with MTC, and a long terminal half-life of 120 hours. We report clinical activity and PK analyses from a Phase 3 study of cabo versus placebo (P) in patients with progressive, unresectable, locally advanced or metastatic MTC.

Methods

Patients with MTC and documented RECIST progression within 14 months (mo) of screening were randomized 2:1 to receive cabo (140 mg freebase qd, n = 219) or placebo (n = 111). Blood samples for PK were collected on days 1 and 29. Baseline tumor and blood samples were evaluated for RET mutation status. Tumor assessments occurred every 12 weeks, and the primary efficacy measure was progression-free survival (PFS), assessed by an independent radiology committee using RECIST.

Results

Statistically significant PFS prolongation was observed, with median PFS for cabo of 11.2 mo versus 4.0 mo for P (HR 0.28, 95% CI 0.19-0.40, p < 0.0001). PFS results favored the cabo group across all RET mutation subgroups with hazard ratios 0.24, 0.47, and 0.30 for RET mutation positive, negative, and unknown subgroups. The 12-mo progression-free landmark estimate is 47.3% for cabo and 7.2% for P; objective response rate was 28% for cabo vs 0% for P. Cabo demonstrated moderate accumulation, with plasma Cmax ∼3.6-fold increased at steady-state (Day 29) relative to Day 1. Plasma concentrations did not fluctuate markedly over the 24 hr dosing interval on Day 29. In a population-PK analysis, moderate inter-subject variability in clearance (CL/F) was observed (CV of ∼35%). No clinically significant covariates on PK were identified which would require dose adjustment, and PFS for cabo-treated subjects did not correlate with individual subject steady-state AUC predicted for uninterrupted 140 mg qd dosing.

Conclusions

Cabo significantly prolonged PFS compared to placebo in a patient population with progressive MTC. PK analysis supports administration of cabo as a fixed dose without adjustment for patient covariates.

Disclosure

M.J. Schlumberger: MJ Schlumberger has been a compensated consultant for Exelixis.

M. Brose: Dr. Brose has received research funding and honoraria from Exelixis.

M. Shah: Dr. Shah has received research funding from Exelixis.

D.R. Miles: D. Miles is an employee and stockholder of Exelixis.

L.T. Nguyen: Linh Nguyen is an employee and stockholder in Exelixis.

S. Sherman: Dr. Sherman is a compensated consultant to Exelixis.

All other authors have declared no conflicts of interest.