Exposure–response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane

• Published in: Cancer chemotherapy and pharmacology 2017-12, Vol.80 (6), p.1079-1090
• Main Authors: Li, Chunze, Wang, Bei, Chen, Shang-Chiung, Wada, Russell, Lu, Dan, Wang, Xin, Polhamus, Daniel, French, Jonathan, Vadhavkar, Shweta, Strasak, Alexander, Smitt, Melanie, Joshi, Amita, Samant, Meghna, Quartino, Angelica, Jin, Jin, Girish, Sandhya
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Immunological - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Bridged-Ring Compounds - therapeutic use; Cancer; Cancer Research; Effectiveness; Epidermal growth factor; ErbB-2 protein; Exposure; Female; Hepatotoxicity; Humans; Immunotherapy; Maytansine - analogs & derivatives; Maytansine - therapeutic use; Medicine; Medicine & Public Health; Middle Aged; Monoclonal antibodies; Numerical prediction; Oncology; Original Article; Patients; Pharmacology/Toxicology; Quality; Receptor, ErbB-2 - metabolism; Risk analysis; Risk factors; Risk management; Survival; Targeted cancer therapy; Taxanes; Taxoids - therapeutic use; Thrombocytopenia; Trastuzumab; Trastuzumab - therapeutic use; Trends
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-017-3440-4

Purpose In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure–response relationship. Methods Exposure–response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration ( C min ) and area under the concentration–time curve from time zero to day 21 of T-DM1 at cycle 1] and multiple efficacy (OS, PFS, objective response rate) and safety (grade ≥ 3 adverse events, grade ≥ 3 thrombocytopenia, grade ≥ 3 hepatotoxicity) endpoints. Results An apparent exposure–response trend was observed between model-predicted exposure metrics and efficacy; trends for observed exposure metrics were shallower and often not significant. Although median OS and PFS were numerically longer in patients with higher versus lower model-predicted cycle 1 C min , OS and PFS hazard ratios for T-DM1-treated patients in the lowest exposure quartile ( Q 1) versus control were