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Open Access Research article

Dynamic tumor modeling of the dose–response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial

Andrew Stein1*, Wenping Wang2, Alison A Carter3, Ovidiu Chiparus4, Norbert Hollaender5, Hyewon Kim6, Robert J Motzer7 and Celine Sarr8

Author Affiliations

1 Modeling & Simulation, Novartis Institutes for Biomedical Research, 45 Sidney St, Cambridge, MA, USA

2 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

3 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

4 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

5 Novartis Pharma AG, Basel, Switzerland

6 Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA

7 Department of Medicine, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

8 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

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BMC Cancer 2012, 12:311  doi:10.1186/1471-2407-12-311

Published: 23 July 2012

Abstract

Background

The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose–response relationship of everolimus.

Results

The model predicts that after 1 year of continuous dosing, the change in SLD of target lesions will be +142.1% ± 98.3%, +22.4% ± 17.2%, and –15.7% ± 11.5% in the average patient treated with placebo, 5 mg everolimus, and 10 mg everolimus, respectively. This nonlinear, mixed-effects modeling approach can be used to describe the dynamics of each individual patient, as well as the overall population. This allows evaluation of how an actual dosing history and individual covariates impact on the observed drug effect, and offers the possibility of predicting clinical observations as a function of time.

Conclusions

In this pharmacodynamic model of tumor response, everolimus more effectively shrinks target lesions in mRCC when dosed 10 mg daily versus 5 mg daily, although a 5-mg dose still shows an antitumor effect. These data support earlier studies that established 10 mg daily as the preferred clinical dose of everolimus, and improve our understanding of the everolimus dose–response relationship.

Keywords:
Efficacy; Kidney; Oncology; Pharmacodynamics; Therapeutics