A phase 1 study of weekly dosing of trastuzumab emtansine (T‐DM1) in patients with advanced human epidermal growth factor 2–positive breast cancer

Abstract

BACKGROUND:We conducted a phase 1, multicenter, open-label, dose-escalation study (TDM3569g) to assess the safety, tolerability, and pharmacokinetics of single-agent trastuzumab emtansine (T-DM1) administered weekly and once every 3 weeks in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab. The weekly dose results are described here. METHODS: Patients were administered escalating doses of T-DM1 weekly, starting at 1.2 mg/kg. Additional patients were enrolled at the maximum tolerated dose (MTD) to better characterize tolerability and pharmacokinetics. RESULTS: Twenty-eight patients received weekly T-DM1, and the MTD was determined to be 2.4 mg/kg. In general, T-DM1 was well tolerated, requiring few dose modifications or discontinuations because of adverse events (AEs). Grade !3 AEs were reported in 19 patients (67.9%); treatment-related AEs occurred in 25 (89.3%) patients. Exposure to weekly T-DM1 was dose-proportional at !1.2 mg/kg, and accumulation of T-DM1 and total trastuzumab was observed. Objective partial tumor responses were reported in 13 (46.4%) patients; the median duration of response was 18.6 months, and the 6-month clinical benefit rate was 57.1%. CONCLUSION: The results suggest that a weekly dose of T-DM1 2.4 mg/ kg has antitumor activity and is well tolerated in patients with HER2-positive metastatic breast cancer. Cancer 2012;118:5733-40.

A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of B-cell malignancies

“…47 For example, the maximum tolerated dose of ado-trastuzumab emtansine is 3.6 mg/kg given every 3 weeks, or 2.4 mg/kg weekly. 48,49 Therefore, the tolerability of antibody-maytansinoid conjugates offers the prospect of using functional antibody attributes of an ADC candidate, as done here. This concept provides the potential of targeting actively dividing malignant cells via the maytansinoid component acting on microtubules and targeting nondividing malignant cells via antibodymediated mechanisms.…”

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“…The overall survival (OS) of kadcyla or lapatinib plus capecitabine were 6.4 months and 25.1 months. [53][54][55] On July 25, 2013, genentech/roche announced that a Phase 3 trial comparing Kadcyla to the physician's choice of treatment in patients with HER2-positive BC who have already been treated with an HER2-targeted therapy, met its coprimary endpoint of progression-free survival. The other endpoint is OS [ Figures 9 and 10], but these data are not yet mature.…”

Trastuzumab Emtansine: A Novel Antibody–Drug Conjugate for HER2-Positive Breast Cancer

“…In the 9 patients with measurable disease treated at the MTD, the objective response rate (ORR) was 44% (10). In the weekly schedule, the MTD was 2.4 mg/kg and the ORR in the 15 response-evaluable patients treated at the MTD was 40% (11). Although both schedules were clearly active, the every-3-week schedule was used in almost all subsequent studies, largely because of the convenience for patients of less frequent dosing.…”