Cabozantinib exposure–response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma
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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.
KeywordsCabozantinib PK/PD Exposure–response modeling Time-to-event analysis Hepatocellular carcinoma
Compliance with ethical standards
Steven Lacy, Linh Nguyen, and Benjamin Duy Tran are stockholders and current employees of Exelixis, Inc.
- 1.Global Burden of Disease Liver Cancer Collaboration (2017) The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015. JAMA Oncol 3:1683–1691. https://doi.org/10.1001/jamaoncol.2017.3055 CrossRefPubMedCentralGoogle Scholar
- 3.Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou Y-C, Joly AH (2011) Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10:2298–2308. https://doi.org/10.1158/1535-7163.MCT-11-0264 CrossRefPubMedGoogle Scholar
- 5.Cabometyx® (cabozantinib) tablets (2019) US prescribing information. Exelix. Inc., Alameda, California. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208692s003lbl.pdf. Accessed 9 Jan 2019
- 6.Cabometyx® (cabozantinib) tablets (2018) Summary of product characteristics. Ipsen Pharma, Boulogne-Billancourt, France. https://www.medicines.org.uk/emc/product/4331/smpc. Accessed 1 Feb 2019
- 7.Abou-Alfa GK, Meyer T, Cheng A-L, El-Khoueiry AB, Rimassa L, Ryoo B-Y, Cicin I, Merle P, Chen Y, Park J-W, Blanc J-F, Bolondi L, Klumpen H-J, Chan SL, Zagonel V, Pressiani T, Ryu M-H, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK (2018) Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 379:54–63. https://doi.org/10.1056/NEJMoa1717002 CrossRefPubMedGoogle Scholar
- 10.Lacy S, Nielsen J, Yang B, Miles D, Nguyen L, Hutmacher M (2018) Population exposure-response analysis of cabozantinib efficacy and safety endpoints in patients with renal cell carcinoma. Cancer Chemother Pharmacol 81:1061–1070. https://doi.org/10.1007/s00280-018-3579-7 CrossRefPubMedPubMedCentralGoogle Scholar