Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer

Abstract

Purpose: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprising the cytotoxic agent DM1, a stable linker, and trastuzumab, has demonstrated substantial activity in human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer, raising interest in evaluating the feasibility and cardiac safety of T-DM1 in early-stage breast cancer (EBC).

Patients and methods: Patients (N = 153) with HER2-positive EBC and prechemotherapy left ventricular ejection fraction (LVEF) ≥ 55% received (neo)adjuvant doxorubicin plus cyclophosphamide or fluorouracil plus epirubicin plus cyclophosphamide followed by T-DM1 for four cycles. Patients could then receive three to four cycles of optional docetaxel with or without trastuzumab. T-DM1 was then resumed with optional radiotherapy (sequential or concurrent) for 1 year (planned) of HER2-directed therapy. The coprimary end points were rate of prespecified cardiac events and safety.

Results: Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failures were reported. Four patients (2.7%) had asymptomatic LVEF declines (≥ 10 percentage points from baseline to LVEF < 50%), leading to T-DM1 discontinuation in one patient. Of 148 patients who received ≥ one cycle of T-DM1, 82.4% completed the planned 1-year duration of HER2-directed therapy. During T-DM1 treatment, 38.5% and 2.7% of patients experienced grade 3 and 4 adverse events, respectively. Approximately 95% of patients receiving T-DM1 plus radiotherapy completed ≥ 95% of the planned radiation dose with delay ≤ 5 days.

Conclusion: Use of T-DM1 for approximately 1 year after anthracycline-based chemotherapy was feasible and generally well tolerated by patients with HER2-positive EBC, providing support for phase III trials of T-DM1 in this setting.

Trial registration: ClinicalTrials.gov NCT01196052.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.

TDM4874g study design. AC, doxorubicin plus cyclophosphamide; FEC, fluorouracil plus epirubicin plus cyclophosphamide; HER2, human epidermal growth factor receptor 2; LVEF, left ventricular ejection fraction; qw, once every week; q2w, once every 2 weeks; q3w, once every 3 weeks; RT, radiotherapy; T-DM1, trastuzumab emtansine. (*) Enrollment in adjuvant or neoadjuvant setting and choice of AC or FEC was at discretion of investigator; patients were allowed to enroll either before or after completion of AC or FEC. (†) Radiotherapy was per investigator discretion; safety was evaluated after first 20 patients had been treated with concurrent T-DM1 and RT, and additional patients were administered sequential RT with or without trastuzumab until confirmation of concurrent T-DM1 and RT safety. (‡) Dose reductions to 3.0 and 2.4 mg/kg were permitted for toxicity. (§) Maximum number of T-DM1 cycles was determined as number of cycles to complete approximately 1 year of HER2-directed therapy, including any periods of optional trastuzumab.

Fig 2.

Flow diagram of patients in TDM4874g. AC, doxorubicin plus cyclophosphamide; EBC, early-stage breast cancer; FEC, fluorouracil plus epirubicin plus cyclophosphamide; HER2, human epidermal growth factor receptor 2; RT, radiotherapy; T-DM1, trastuzumab emtansine.

Fig A1.

Algorithm for trastuzumab emtansine (T-DM1) discontinuation based on left ventricular ejection fraction (LVEF) assessments in asymptomatic patients. (*) Three intermittent holds of T-DM1 led to discontinuation. (†) Baseline refers to prechemotherapy LVEF measurement, regardless of whether patient was enrolled before or after completing chemotherapy. EF, ejection fraction.

Fig A2.

Mean left ventricular ejection fraction (LVEF) in trastuzumab emtansine (T-DM1) –treated patients over time. (*) Optional trastuzumab could have been administered between cycles four and eight.