A Mechanism-Based Model of Tumor Quiescence and Resistance in HER2-Negative Metastatic Breast Cancer in Patients Receiving Docetaxel or Paclitaxel
Brendan C. Bender (1), Jin Jin (1), and Lena E. Friberg (2)
(1) Genentech Inc, San Francisco, CA, (2) Dept. of Pharmaceutical Biosciences, Uppsala University, Sweden
Objectives: In patients receiving docetaxel or paclitaxel, patient tumor responses exhibited variable patterns of shrinkage and quiescence, followed by drug–resistant tumor regrowth. A pharmacometric analysis was used to characterize these tumor response patterns and evaluate patient characteristics and tumor model metrics as predictors for overall survival (OS).
Methods: Tumor responses were evaluated from HER2–negative metastatic breast cancer patients receiving either docetaxel (N=185) or paclitaxel (N=242). A population kinetic/pharmacodynamic (K/PD) model was fit to tumor sum of longest diameter (SLD)–time course data. The baseline tumor size (TBSL) was parameterized as composed of a drug resistant (FNR) and drug sensitive (1-FNR) fraction. The development of drug–resistant tumor was modeled using transit compartments, and a mixture model implementation on the transit rate parameter (kdelay) was used to capture the rapid or delayed tumor resistance. Two tumor growth rates (kGrow,Sens and kGrow,Resist) described tumor growth rates for the drug–sensitive and drug–resistant tumor compartments, respectively. Patient baseline characteristics (Age, ECOG, TBSL), model parameters, and tumor metrics (tumor size ratio (TSR) at week 6; time to tumor growth (TTG)) were evaluated as predictors for OS in a parametric time–to–event (TTE) analysis. NONMEM 7.3.0 software was used for model development.
Results: The model well–described the variable patterns of longitudinal tumor data, and model fits indicated superior results when compared to the tumor growth inhibition (TGI) model (1). The typical docetaxel patient had a TBSL equal to 70mm, consisting of ~35mm drug–sensitive and ~35mm of drug–resistant tumor SLD. The kDelay parameter was bimodal, and patients had a 37% probability to develop resistance during the treatment period. For these patients, the drug–resistant tumor doubling time was calculated to be 5.8 weeks. Model results for patients receiving paclitaxel were similar. TTG and TBSL were significant predictors of survival for both docetaxel and paclitaxel treatment.
Conclusions: This tumor K/PD model successfully integrates tumor kill, tumor quiescence, and tumor drug–resistance as linked to taxane drug exposure, providing an additional modeling approach to characterize tumor response data. An increased tumor baseline–reflective of higher tumor burden, and a shorter TTG–reflective of treatment efficacy, was associated with poorer survival prognosis. In cases of tumor quiescence followed by resistance, the model provided better fits than the TGI model.
References:
[1] Claret L, Girard P, Hoff PM, Van Cutsem E, Zuideveld KP, Jorga K, Fagerberg J, Bruno R. Model-based Prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics. J Clin Oncol 2009; 27: 4103–8.