Exposure-response of sunitinib in metastatic renal cell carcinoma (mRCC): A population pharmacokinetic/pharmacodynamic (PKPD) approach

Abstract

5027 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs and PDGFRs, and has shown substantial antitumor activity in mRCC (Motzer et al, JAMA 2006 and ASCO 2006). This analysis describes SU, and total drug (TD; SU+SU12662 [active metabolite]) exposure-response relationships in mRCC using a population PKPD approach. Methods: PK and efficacy data from 3 studies (phase II and III) of SU (25–62.5 mg/day; 4 wks dosing followed by 2 wks off) in treatment-naïve (N=44) and cytokine-refractory mRCC pts (N=148) were analyzed. SU and SU12662 concentrations were fitted to a population PK model (a 2- compartment model for both parent and metabolite). Estimates of pt PK were used to calculate steady-state Area Under the Curve (AUCss) for SU, SU12662 and TD, which were used as the exposure measure in a PKPD analysis of partial response (PR) rates, time to tumor progression (TTP), overall survival (OS), and tumor volume changes. Results: The probability of a PR for cytokine-refractory pts increased with increasing AUCss for SU and TD. The odds-ratio suggested a 2.6-fold increase in PR frequency for each unit increase in AUCss. Longer TTP and OS were also noted in pts with high SU and TD AUCss. In treatment-naïve pts on SU, there was very little observed tumor progression or death (only 5 pts progressed and only 1 death) limiting the ability to analyze exposure-response. A tumor growth dynamics model (developed to describe changes in tumor volume [by CT or MRI] in response to treatment, as a function of AUCss) provided a good description of tumor volume changes with SU for both treatment-naïve and cytokine-refractory pts. Efficacy was not related to baseline tumor volume, gender, or race. Based on this model, clinical trial simulations assuming perfect pt compliance predict that 62% of pts would achieve a PR with SU 50 mg/day. Conclusions: SU and TD AUCss correlated significantly with the probability of a PR in cytokine- refractory pts, and longer TTP and OS. Limited data were available for treatment-naïve pts. The tumor growth dynamics model provided a good description of tumor volume changes with SU for both populations. This exposure-response analysis indicates that increased exposure to SU is associated with clinical benefit. [Table: see text]