Trastuzumab emtansine plus pertuzumab in Japanese patients with HER2-positive metastatic breast cancer: a phase Ib study.

PURPOSE: To investigate the safety, pharmacokinetics, and efficacy of trastuzumab emtansine (T-DM1) in combination with pertuzumab in Japanese patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. PATIENTS AND METHODS: Patients with HER2-positive advanced or recurrent breast cancer who had received trastuzumab and chemotherapy-containing therapies were eligible. Patients received T-DM1 (3.6 mg/kg) with full-dose pertuzumab (a loading dose of 840 mg and then 420 mg) intravenously every 3 weeks. This study was registered at the Japan Pharmaceutical Information Center-Clinical Trials Information (JapicCTI-101234). RESULTS: Six patients enrolled in this study. The median duration of treatment was 11 (range 1-32) cycles. The most common treatment-emergent adverse event (TEAE) for any grade was diarrhea. Grade 3 or greater TEAEs included aspartate aminotransferase increased, left ventricular ejection fraction (LVEF) decreased, and neutrophil count decreased. The dose-limiting toxicity of grade 3 LVEF decreased was observed in one patient during cycle 1; however, it resolved within 30 days. The pharmacokinetic parameters of T-DM1 and pertuzumab were not affected by co-administration of the drugs. The best overall response included a partial response (PR) in 3 patients (50%) and stable disease (SD) in 2 patients (33%). CONCLUSIONS: The combination of T-DM1 and pertuzumab was tolerated and showed exploratory efficacy in Japanese patients with HER2-positive metastatic breast cancer.

Ethnic sensitivity assessment of the antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer.

PURPOSE: Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities. METHODS: Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy. RESULTS: NCA pharmacokinetic parameters (T-DM1, total trastuzumab, DM1) were comparable across ethnic groups; mean cycle 1 T-DM1 AUCinf was 475, 442, and 518 day µg/mL for white (n = 461), Asian (n = 68), and others (n = 57), respectively. PopPK analysis showed that ethnicity (white, Asian, and others) was not a significant covariate for T-DM1 pharmacokinetics (n = 671). Additionally, visual predictive check plots indicated that observed pharmacokinetic profiles in Japanese patients (n = 42) were within the prediction interval generated from the final PopPK model. Exposure-response analyses showed that ethnicity was not a significant covariate impacting efficacy or hepatotoxicity risk, but there was a trend of greater thrombocytopenia risk among Asians versus non-Asians, which could not be explained by similar exposure between the ethnic groups. Most Asians with thrombocytopenia were able to continue T-DM1 using dose-adjustment rules recommended for the global population. CONCLUSIONS: These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.