P1-12-07: Pharmacokinetics (PK) of Trastuzumab Emtansine and Paclitaxel or Docetaxel in Patients with HER2−Positive MBC Previously Treated with a Trastuzumab-Containing Regimen.

Abstract

Abstract Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab, DM1 (a potent cytotoxic tubulin polymerization inhibitor), and the stable MCC linker. Based on in vitro and preclinical data suggesting synergy in tumor cell cytotoxicity with T-DM1 + taxanes, these combinations are being tested in phase Ib studies. The assessment of risk for PK-based drug interaction (PK-DI) with these combinations is important. T-DM1 is expected to undergo proteolytic degradation with no significant involvement of cytochrome P450 isoenzymes (CYPs), and DM1 is metabolized mainly by CYP3A4 (and to a lesser extent by CYP3A5). Paclitaxel (P) and docetaxel (D) are metabolized primarily by CYP2C8 and CYP3A4, respectively. None of these drugs inhibits or induces CYPs at clinically relevant concentrations. Since DM1 and D are both metabolized by CYP3A4, PK-DI may occur. This is less likely with DM1 and P since they are primarily metabolized by different CYPs. Methods: The tolerability, PK, and dose-limiting toxicities of T-DM1 + P or D were investigated in 2 studies (TDM4652g and BP22572) of patients with HER2−positive MBC previously treated with a trastuzumab-containing regimen. For PK-DI analysis, both studies used a staggered dosing design in the first cycle, with same-day dosing in subsequent cycles. Study BP22572 was later amended to give both drugs on the same day in all cycles. Either P (65 mg/m2, n=11; 80 mg/m2, n=6) or D (60 mg/m2, n=12; 75 mg/m2, n=6) was combined with T-DM1 at various doses (2 mg/kg or 2.4 mg/kg q3w or 1.2 mg/kg qw for TDM4652g; 2.4 mg/kg or 3.6 mg/kg q3w for BP22572). PK of T-DM1, total trastuzumab (conjugated + unconjugated trastuzumab), DM1, P, and D were evaluated and compared with historical singleagent data and across cycles within the study, using population analysis and/or noncompartmental analysis (NCA), as data allowed. Preliminary safety and efficacy data for the historical T-DM1 singleagent studies were reported previously (Krop JCO 2010; Burris JCO 2010; Krop ESMO 2010). Results: The PK of P and D were similar from cycle 1 to cycle 2 for maximum concentration (Cmax), area under the concentration-time curve, halflife, clearance (CL) and steady-state volume of distribution, and were also similar to historical single-agent data. The Cmax of DM1 was <8 ng/mL in both studies, and the average Cmax values were similar to historical single-agent data. T-DM1 PK parameters for the combination studies are within the range of historical single-agent data (Table). Data from additional patients and doses in the combination studies will be presented. Conclusion: The risk of clinically relevant PK-DI between T-DM1 and P or D appears to be low. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-07.