Jianping Zhang, Kevin Koch
GlaxoSmithKline, Research Triangle Park, North Carolina, USA
Objectives: Lapatinib (TykerbTM) is a potent and selective inhibitor of the EGFR and HER2 tyrosine kinases. It is approved for the treatment of patients with advanced or metastatic breast cancer overexpressing HER2. The aim of this work was to characterize the effect of lapatinib on tumor growth dynamics and to predict progression free survival (PFS) based on tumor size measurements.
Methods: Data from 3 Phase II studies including 314 patients contributing 975 tumor size measurements for up to 92 weeks were utilized. Dosing regimens were 1250 or 1500 mg once daily (QD) or 500 mg twice daily (BID). Tumor size was measured as the sum of the longest diameter of selected lesions. The tumor growth inhibition model was based on Claret et al. (2009) with a slight variation. Progression-free survival (PFS) analysis was conducted based on data from 1 of the Phase II studies. PFS results were recorded from a total of 124 patients ranging from 7 to 93 weeks. A survival model with log-normal distribution was constructed to characterize the PFS as a function of various covariates. The population analysis was performed using the nonlinear mixed effects modelling approach. Visual predictive check was implemented for final model evaluation.
Results: Treatment with lapatinib resulted in an average 39% (KD) suppression of tumor growth rate (KL). Lapatinib was more effective in patients with FISH ratio ≥2 resulting in an average 96% suppression of KL. Asian and Hispanic patients were more responsive to lapatinib with an average 81% suppression of KL. Patients with twice daily dosing regimen were 32% less likely to develop drug resistance. Percentage tumor reduction from baseline at Week 8 was found to be the best predictor of PFS.
Conclusions: The population models developed in this analysis adequately characterized tumor growth inhibition by Lapatinib and its impact on progression-free survival in patients with advanced/metastatic breast cancer. Our findings confirm some aspects of clinical practice and may guide future investigation to improve therapy.
References:
[1] Claret L. et al. J.Clin.Oncol. (2009). 27:4103-4108.
[2] Wang Y. et al. Clin.Pharmacol.Ther. (2009). 86:167-174.
Reference: PAGE 21 () Abstr 2390 [www.page-meeting.org/?abstract=2390]
Poster: Oncology