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Journal of Pharmacokinetics and Pharmacodynamics

, Volume 46, Issue 6, pp 577–589 | Cite as

Cabozantinib exposure–response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma

  • Linh NguyenEmail author
  • Sunny Chapel
  • Benjamin Duy Tran
  • Steven Lacy
Original Paper
  • 157 Downloads

Abstract

Cabozantinib, a multi-kinase inhibitor, is approved in the United States and European Union for treatment of patients with hepatocellular carcinoma following prior sorafenib treatment. In the Phase III CELESTIAL trial, hepatocellular carcinoma patients receiving cabozantinib showed longer overall survival (OS) and progression-free survival (PFS) than those receiving placebo. The approved cabozantinib (Cabometyx®) dose is 60 mg once daily with allowable dose modifications to manage adverse events (AE). Time-to-event Cox proportional hazard exposure–response (ER) models were developed to characterize the relationship between predicted cabozantinib exposure and the likelihood of various efficacy and safety endpoints. The ER models were used to predict hazard ratios (HR) for efficacy and safety endpoints for starting doses of 60, 40, or 20 mg daily. Statistically significant relationships between cabozantinib exposure and efficacy and safety endpoints were observed. For efficacy endpoints, predicted HR were lower for OS and PFS at 40 and 60 mg relative to the 20 mg dose: HR for death (OS) are 0.84 (40 mg) and 0.70 (60 mg); HR for disease progression/death (PFS) are 0.73 (40 mg) and 0.62 (60 mg). For safety endpoints, predicted HR were lower for palmar-plantar erythrodysaesthesia (PPE), diarrhea, and hypertension at 20 or 40 mg relative to the 60 mg dose: HR for PPE are 0.31 (20 mg) and 0.66 (40 mg); HR for diarrhea are 0.61 (20 mg) and 0.86 (40 mg); HR for hypertension are 0.46 (20 mg) and 0.76 (40 mg). The rate of dose modifications was predicted to increase in patients with lower cabozantinib apparent clearance. OS and PFS showed the greatest benefit at the 60 mg dose. However, higher cabozantinib exposure was predicted to increase the likelihood of AE and subsequent dose reductions appeared to decrease these risks.

Keywords

Cabozantinib PK/PD Exposure–response modeling Time-to-event analysis Hepatocellular carcinoma 

Notes

Compliance with ethical standards

Disclosures

Steven Lacy, Linh Nguyen, and Benjamin Duy Tran are stockholders and current employees of Exelixis, Inc.

Supplementary material

10928_2019_9659_MOESM1_ESM.docx (258 kb)
Supplementary material 1 (DOCX 257 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Exelixis, IncAlamedaUSA
  2. 2.Ann Arbor Pharmacometrics Group, IncAnn ArborUSA

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