title: Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancer.
abstract: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1-related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this study and historical single-agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15-30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-agent study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. danlu@gene.com
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.forename: Javier
authors.initials: J
authors.lastname: Cortes
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
authors.forename: Manish
authors.initials: M
authors.lastname: Gupta
authors.forename: Joo-Hee
authors.initials: JH
authors.lastname: Yi
authors.forename: Yu-Waye
authors.initials: YW
authors.lastname: Chu
authors.forename: Ted
authors.initials: T
authors.lastname: Shih
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004347:Drug Interactions / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D000068878:Trastuzumab
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab