EGFR status and daily dose: Effect on tumor growth inhibition in cancer patients treated with dacomitinib (PF-00299804).

Abstract

e18093 Background: Dacomitinib (D) is a highly selective, irreversible small molecule pan-human epidermal growth factor (EGFR/HER) inhibitor. The effect of mean D daily dose (exposure) on tumor growth dynamics was analyzed using a longitudinal exposure-response tumor growth inhibition model. Methods: Estimated parameters included tumor shrinkage rate (KD), which changes over time as resistance to therapy develops according to an exponential decay function where λ = slope of the dynamic shrinkage rate change; and tumor growth rate constant (KL). eDose, the effect of mean D daily dose changes on tumor shrinkage rate, was tested in the base model to establish the best relationship between tumor shrinkage and drug exposure. Model parameters were estimated using a population (pop) approach. Pop pharmacodynamic analyses included data from 4 clinical trials (3 phase I and 1 phase II) of D (15–45 mg QD) in patients (pts) with advanced solid tumors. Multiple tumor size (SLD) measurements were collected from each pt. Data analysis used nonlinear mixed effects modeling (NONMEM, v 7.1.2). After visual inspection of relationships between covariates (weight, age, creatinine clearance, bilirubin, ALT, baseline ECOG PS, race, sex, EGFR status) and individual parameter estimates of KD; subpopulation analysis was carried out in pts with confirmed EGFR status (mutation [mu] or wild type [WT]) to quantify the potential effect of EGFR status on KD. Results: SLD values over time were collected from 200 pts (47% male). For a typical pt, KL = 0.63 year-1; KD = 1.6 year-1; developed therapy resistance over time (λ) = 13.7 year-1; and eDose = 0.45. Drug-specific parameters affecting tumor shrinkage (KD, λ, eDose) and the disease-specific KL were well estimated with low relative standard errors. Visual inspection of relationships between covariates and individual parameter estimates showed a higher shrinkage rate (KD) for pts with EGFR mu vs those with WT EGFR. Conclusions: D mean daily dose affected tumor growth dynamics. Tumor shrinkage rate at an averaged daily dose below 45 mg QD was lower vs 45 mg QD. EGFR status was a significant covariate affecting tumor shrinkage rate (83% less shrinkage in pts with EGFR WT vs. pts with EGFR mut).