056: Population Pharmacokinetic Analysis of Tucatinib in Healthy Subjects & Subjects With HER2+ Metastatic Breast Cancer or Metastatic Colorectal Cancer

Statement of Purpose: Tucatinib is a potent and selective HER2-directed TKI approved for patients with HER2+ metastatic breast cancer (mBC) who have received one or more prior anti-HER2 therapies, or RAS WT HER2+ metastatic colorectal cancer (mCRC) that has progressed following treatment with fluoropyrimidine- oxaliplatin- and irinotecan-based chemotherapy (US only). A population pharmacokinetic (PPK) model was developed to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in subjects with HER2+ mBC or mCRC.

Description of Methods & Materials: Plasma concentration-time data were analyzed using a nonlinear mixed-effects modeling approach (NONMEM v7.3.0 and 7.4.3) and R (v4.0.4) was used for simulations. First order conditional estimation method with interaction was used for estimation. Subsequently, effects of selected covariates (body weight, sex, race, tumor type, creatinine clearance, age, National Cancer Institute liver dysfunction category, albumin and ECOG performance status) were evaluated. Model goodness-of fit and performance (including visual predictive check and nonparametric bootstrapping) were also assessed.

Data & Results: The tucatinib PPK dataset was constructed using data from four Phase 1 studies conducted in healthy volunteers, two Phase 1b studies in subjects with HER2+ mBC (ONT-380-004, ONT-380-005) and a Phase 2 study in subjects with HER2+ mCRC (SGNTUC-017), comprised of 3942 quantifiable observations from 283 subjects. PK data included four tucatinib doses (50, 150, 300 and 350 mg BID) administered as single or multiple doses. The final model for tucatinib was a 2-compartment model with linear elimination, first-order absorption with lag time, with covariate effects of mBC and mCRC on CL/F, and mCRC on Frel (relative bioavailability). A CL/F of 112 L/h was estimated for healthy subjects. Relative to healthy subjects, the model estimated a 51.9% lower CL (and thus CL/F) in subjects with HER2+ mBC and a 70.5% lower CL with 63.7% lower Frel, resulting in an 18.7% lower CL/F in subjects with HER2+ mCRC. Model-predicted geometric mean (CV%) AUCs were 5,620 (43) and 3,370 (49) ng*h/mL for subjects with HER2+ mBC and mCRC, respectively, who received 300 mg BID. Effective half-life estimates were 11.9h (mBC) and 16.4h (mCRC).

Interpretation, Conclusion or Significance: Tumor types (mCRC and mBC) were identified as significant covariates on tucatinib PK parameters, resulting in 1.22- and 2.10-fold increase of tucatinib steady-state exposure (AUC) compared to healthy subjects. This difference is within the observed PK variability and is not considered to have any clinically meaningful impact. No other covariates were identified to impact tucatinib PK. No starting dose adjustments are recommended for subjects with HER2+ mBC or mCRC.

Disclosures: Daping Zhang, Christopher Endres and Ariel Topletz-Erickson are employees and stock holders of Seagen Inc.