LAUSR

PurposeIn 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.MethodsExposure–response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (Cmin) 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.ResultsAn 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 Cmin, OS and PFS hazard ratios for T-DM1-treated patients in the lowest exposure quartile (Q1) versus control were < 1 after adjusting for baseline risk factors (e.g., ECOG status, tumor burden, measurable disease, and number of disease sites). No meaningful exposure–response relationship was observed for any safety endpoints.ConclusionExposure–response relationships for efficacy were inconsistent across exposure metrics; model-predicted cycle 1 Cmin showed the strongest exposure–response trend. The Q1 subgroup based on model-predicted cycle 1 Cmin had numerically similar or better OS and PFS versus control following covariate adjustment. The approved T-DM1 dose (3.6 mg/kg every 3 weeks) has a positive benefit–risk ratio versus control, even for the T-DM1 Q1 subgroup.