Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer

Abstract

PurposeTrastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate.MethodsMultiple analytes—T-DM1, total trastuzumab (TT), DM1, and key metabolites—were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays.ResultsPK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w.ConclusionsThe PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.

Absorption, Distribution, Metabolism, and Excretion Considerations for the Development of Antibody-Drug Conjugates

“…The unconjugated drug in blood usually displays formationlimited kinetics and has an apparent terminal half-life similar to or slightly shorter than that of the ADCs. The molar concentrations of the unconjugated drugs are often 100-to 1000-fold lower than those of the ADCs (Younes et al, 2010;Girish et al, 2012). Shown in Fig.…”

“…consistent with their half-life estimates. The plasma unconjugated DM1 levels after ado-trastuzumab emtansine administration were generally below the limit of quantification, and the T max was close to the end of infusion (Girish et al, 2012;CDER, 2013). Plasma unconjugated MMAE had a delayed time to reach the maximum plasma concentration (T max ) of 2 to 3 days compared with that of DM1 (CDER, 2011).…”

ADME of Antibody–Maytansinoid Conjugates

“…1), and thus is less susceptible to cleavage via thiol-disulfide exchange (11,12). One factor influencing the outcome of such assessments is the effect of linker choice on the pharmacokinetics of the conjugates in vivo (6,(13)(14)(15)(16). Another factor is the safety profile: for example, in preclinical rodent models, the trastuzumab-maytansinoid conjugate made with the uncleavable SMCC linker was found to be better tolerated than trastuzumab-SPP-DM1 (17,18), while, across several antibodies studied, Ab-SPP-DM1 and Ab-SPDB-DM4 were found to have similar tolerability (16).…”

“…The results are not unique to T-DM1 as other Ab-SMCC-DM1 conjugates have similarly shown slightly faster clearance of conjugate versus total antibody in preclinical studies (11,21). The preclinical observations with T-DM1 appear to translate to the clinic: analysis of data from four clinical studies of single agent T-DM1 administered at 3.6 mg/kg every 3 weeks have shown that the clearance rate of T-DM1 and total trastuzumab in patients ranged from 7 to 13 and 3 to 6 mL/kg/day, respectively, with half-lives of about 4 and 9-11 days for T-DM1 and for total trastuzumab, respectively (13). The mechanism for the faster clearance of T-DM1 as compared to the total trastuzumab is unclear.…”

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

“…The pharmacokinetics and pharmacology, toxicology, and bioanalytical strategies used for these ADCs have been reviewed (17)(18)(19)(20)(21)(22). Immunogenicity support strategies (and the resulting data) for these approved ADCs form the knowledge base on what is an expanding field (Table I illustrates the examples of published ADC immunogenicity information).…”