Relationship between everolimus exposure and safety and efficacy: Meta-analysis of clinical trials in oncology

• Published in: European journal of cancer (1990) Vol. 50; no. 3; pp. 486 - 495
• Main Authors: Ravaud, Alain, Urva, Shweta R., Grosch, Kai, Cheung, Wing K., Anak, Oezlem, Sellami, Dalila B.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.02.2014; Elsevier
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biological and medical sciences; Cancer; Clinical Trials as Topic; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors; Disease-Free Survival; Efficacy; Everolimus; Hematology, Oncology and Palliative Medicine; Humans; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacokinetics; Pharmacology. Drug treatments; Randomized Controlled Trials as Topic; Safety; Sirolimus - administration & dosage; Sirolimus - adverse effects; Sirolimus - analogs & derivatives; Sirolimus - pharmacokinetics; Tumors; Efficacy; Safety; Pharmacokinetics; Everolimus; Cancer; Toxicity; Treatment efficiency; Lactone; Exposure; Malignant tumor; Macrolide; Metaanalysis; Cancerology; Clinical trial; Protein synthesis inhibitor; Immunosuppressive agent
• ISSN: 0959-8049; 1879-0852; 1879-0852
• DOI: 10.1016/j.ejca.2013.11.022

In patients with solid tumours, daily everolimus dosing demonstrated dose proportionality and linear pharmacokinetics. A meta-analysis was conducted to characterise the relationship between everolimus Cmin and efficacy and safety and the effect of CYP3A4 and P-glycoprotein (PgP) substrate/inhibitor/inducer coadministration on everolimus trough concentration (Cmin). Individual patient data from five phase 2/3 studies, in which steady state, predose pharmacokinetic samples were taken from patients with solid tumours administered everolimus 10mg/day, were pooled. Efficacy and safety were evaluable for 945 and 938 patients, respectively. A 2-fold increase in everolimus Cmin increased the likelihood of tumour size reduction (odds ratio 1.40, 95% confidence interval (CI) 1.23–1.60), was associated with a trend for reduced risk of progression-free survival events (risk ratio [RR] 0.90, 95% CI 0.69–1.18) and increased the risk of grade ⩾3 pulmonary (RR 1.93, 95% CI 1.12–3.34), stomatitis (RR 1.49, 95% CI 1.05–2.10) and metabolic (RR 1.30, 95% CI 1.02–1.65) events. Coadministering everolimus with strong CYP3A4 and PgP inhibitors increased everolimus Cmin by 10% and 20%, respectively; coadministration with CYP3A4 inducers reduced Cmin by 7%. A 2-fold increase in everolimus Cmin was associated with improved tumour size reduction and increased risk of high-grade pulmonary, metabolic and stomatitis events. Novartis Pharmaceuticals Corporation.