Abstract P3-14-06: Pharmacokinetic (PK) Interaction Potential of Trastuzumab-DM1 (T-DM1) and Pertuzumab (P) in Pts with HER2-Positive, Locally Advanced or MBC: Results from a Phase 1b/2 Study
Authors: Burris III HA , Lu D , Dees EC , Cortes J , Yi J-H , Shih T , Girish S. 
Published: April 2011

Abstract
Introduction
T-DM1 is an antibody-drug conjugate (ADC) composed of the cytotoxic DM1 conjugated to trastuzumab and retaining its antitumor properties. P is a HER2-directed monoclonal antibody that inhibits HER2 dimerization and subsequent signaling. The combination of T-DM1 and P has demonstrated synergistic antitumor activity in HER2-positive xenograft models. T-DM1 and P are expected to undergo proteolytic degradation with no significant involvement of cytochrome P450 isoenzymes. In contrast, DM1 is metabolized mainly by CYP3A4 and to a limited extent by CYP3A5. Therefore, a key component in evaluating this combination clinically is determining whether a PK-based drug interaction potential exists when these drugs are administered together. Assessment of PK-based therapeutic protein-ADC interaction potential is novel, as antibodies have typically been combined with chemotherapy in clinical studies. Methods
This 3+3 dose escalation, open-label, phase 1b/2 study evaluated the safety, tolerability, PK, and efficacy of T-DM1 (3.0 mg/kg q3w or 3.6 mg/kg q3w [established phase 2 dose]) in combination with P (840 mg loading dose; 420 mg q3w thereafter) in pts with HER2-positive locally advanced or MBC. Because of the half-life of both agents, staggered dosing was not a practical approach to assess the PK interaction. Thus, both drugs were administered sequentially on Day 1 of each cycle. All pts receiving study treatment were evaluated for serum concentrations of T-DM1, total trastuzumab (conjugated and unconjugated to DM1), and plasma concentrations of DM1, at pre-specified time points. To avoid the interference of P with the quantification of total trastuzumab, a new assay that allows capturing trastuzumab in the presence of P was developed and validated. PK of T-DM1 and related analytes were compared with historical single agent data by population and/or noncompartmental analyses. Whether combination with P was a significant covariate of T-DM1 clearance and central volume of distribution (V1) was tested. The confidence intervals (CIs) of the ratios of clearance and V1 of combination to monotherapy were estimated. A CI containing 1 is indicative of comparable parameters. Results
PK data were available for 63 pts. Combination with P was not a significant covariate of T-DM1 clearance and V1 (P&gt;0.05 by the log likelihood ratio test). The combination to monotherapy ratios for clearance and V1 had a 95% CI of [0.90-1.04] and [0.95-1.06], respectively, indicating comparable clearance and V1 of combination and monotherapy. The average post-hoc Bayesian estimates of T-DM1 clearance and V1 in the presence of P were 0.69±0.14 L/day and 3.3±0.41 L, which were comparable with historical measures of 0.73±0.19 L/day and 3.4±0.57 L with monotherapy. The average maximal concentration of total trastuzumab in cycle 1 was 101±29 μg/ml in the 3.0 mg/kg TDM1 dose (n=3) and 98±32 μg/ml for the 3.6 mg/kg dose (n=60). The maximum DM1 level was &lt;17 ng/mL at both T-DM1 doses. The PK of total trastuzumab and DM1 were also comparable with monotherapy (data not shown).
Conclusions
This assessment suggests that P does not alter the PK of T-DM1 when these drugs are administered together.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-06.