Abstract
PurposeTo characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure–response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure–efficacy and –safety relationships and support the approved SC dosing regimen.MethodsPopulation pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression.ResultsSC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest.ConclusionThe approved PH FDC SC dose [loading: 1200/600 mg pertuzumab/trastuzumab (15 mL); maintenance: 600 mg pertuzumab/trastuzumab (10 mL) and 2000 U/mL recombinant human hyaluronidase every 3 weeks] provides a positive benefit–risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab.
Highlights
A two-compartment model with first-order absorption for SC administration and first-order elimination from the central compartment was utilized as a starting point for the modeling using NONMEM version 7.4.3 (ICON Development Solutions, Ellicott City, Maryland, USA) with the first-order conditional estimation with interaction method. Evaluated covariates included those from previous pertuzumab IV models (LBW, albumin), standard demographic variables, standard baseline laboratory variables, stratification factors in the study design [hormone receptor status, clinical stage (II–IIIA or IIIB–IIIC), and chemotherapy regimen (4 cycles of ddAC every 2 weeks followed by paclitaxel once weekly for 12 weeks, or 4 cycles of AC every 3 weeks followed by 4 cycles of docetaxel every 3 weeks)], standard disease-related variables (ECOG), or covariates of specific interest (Asian region)
Significant covariates on pertuzumab exposure included lean body weight (LBW), race, and albumin; their effects were relatively small compared with the overall interindividual variability of the population and the effects were not considered clinically relevant
Cycle 7 was selected for pertuzumab exposure metrics, as this was when the majority of patients reached steady state
Summary
The approved SC formulation of trastuzumab has been shown to have non-inferior serum trough concentrations (Ctrough) and pathologic complete response (pCR) rates to IV trastuzumab, along with consistent long-term efficacy and a comparable safety profile [17,18,19,20,21,22,23,24,25,26]. The PH FDC SC is given as a loading dose of 1200 mg pertuzumab and 600 mg trastuzumab in 15 mL, and 600 mg pertuzumab and trastuzumab maintenance doses in 10 mL, along with 2000 U/mL rHuPH20 every 3 weeks This dose was assessed clinically in the FeDeriCa study (NCT03493854), which showed that PH FDC SC was non-inferior to P + H IV, based on cycle 7 pertuzumab serum Ctrough concentrations, and that PH FDC SC and P + H IV demonstrated comparable efficacy (total pathologic complete response) and safety profiles [30]. A pertuzumab ER analysis in the PH FDC SC arm, which aimed to evaluate the pertuzumab exposure–efficacy and –safety relationships and, confirm the dosing regimen and support the label for this new formulation
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