Pharmacokinetic and exploratory exposure-response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study.

Purpose: To characterize the pharmacokinetics (PK) of, and perform an exploratory exposure-response (E-R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within the APHINITY study (NCT01358877, BIG 4-11/BO25126/TOC4939G).
Methods: A previously developed pertuzumab two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation to examine appropriateness for describing pertuzumab concentrations from the APHINITY study. Pharmacokinetic drug-drug interactions (DDIs) between pertuzumab, trastuzumab, and chemotherapy were assessed by comparing observed serum or plasma C _max , C _min , and AUC _last geometric mean ratios with 90% CIs. Predictions of pertuzumab C _max,ss , C _min,ss , and AUC _ss were derived from individual parameter estimates and used in an exploratory E-R analysis.
Results: Using data from 72 patients, based on goodness-of-fit, the popPK model was deemed appropriate for predictions of individual exposures for subsequent comparisons to historical data, assessment of DDIs, and E-R analyses. No evidence of DDIs for pertuzumab on trastuzumab, trastuzumab on pertuzumab, or pertuzumab on chemotherapy PK was observed. Analyses of differences in exposure between patients with and without invasive disease-free survival events did not indicate improved efficacy with increased exposure. Overall Grade ≥ 3 diarrhea prevalence was higher with pertuzumab versus placebo, but was not greater with increasing pertuzumab exposure. No apparent E-R relationship was suggested with respect to other grade ≥ 3 AEs.
Conclusion: Overall, the limited available data from this exploratory study suggest that no dose adjustments are needed for pertuzumab when administered in combination with trastuzumab and an EBC chemotherapy regimen.