Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2019 Dec;46(6):577-589.
doi: 10.1007/s10928-019-09659-y. Epub 2019 Oct 21.

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

Affiliations
Clinical Trial

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

Linh Nguyen et al. J Pharmacokinet Pharmacodyn. 2019 Dec.

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

PubMed Disclaimer

References

    1. Cancer Sci. 2016 Apr;107(4):407-16 - PubMed
    1. JAMA Oncol. 2017 Dec 1;3(12):1683-1691 - PubMed
    1. Mol Cancer Ther. 2011 Dec;10(12):2298-308 - PubMed
    1. World J Hepatol. 2017 Jan 18;9(2):80-90 - PubMed
    1. Drug Metab Dispos. 2015 Aug;43(8):1190-207 - PubMed

Publication types

MeSH terms

LinkOut - more resources