Abstract P2-15-03: Cardiac safety of trastuzumab emtansine (T-DM1) following anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) early-stage breast cancer (EBC): Final data from TDM4874g
Authors: Krop IE , Suter TM , Dirix L , Romieu G , Zamagni C , Citron ML , Campone M , Dang CT , Xu N , Smitt M , Gianni L 
Published: August 2014

Abstract
Background
T-DM1 is an antibody-drug conjugate comprising the cytotoxic agent DM1 and trastuzumab, bound together with a stable linker. T-DM1 has demonstrated substantial activity in patients (pts) with HER2+ metastatic breast cancer (MBC) in the first-line and trastuzumab-refractory settings and was recently approved by the FDA for pts with HER2+ MBC previously treated with trastuzumab and a taxane. These findings have raised interest in evaluating T-DM1 in adjuvant studies. This phase 2 study assessed the safety and feasibility of approximately 1 year of T-DM1 therapy following anthracycline-based chemotherapy in the adjuvant or neoadjuvant setting for HER2+ EBC.
Methods
TDM4874g (NCT01196052) is a phase 2, single-arm, open-label study of T-DM1 (3.6 mg/kg q3w IV; up to 17 cycles) following completion of doxorubicin/cyclophosphamide (AC; q2w or q3w for 4 cycles), or 5-fluorouracil/epirubicin (100 mg/m2)/cyclophosphamide (FEC; q3w for 3-4 cycles) chemotherapy in pts with HER2+ EBC. Radiation therapy (RT) was administered after the first 4 cycles of T-DM1 to pts in whom it was indicated. Four cycles of trastuzumab/docetaxel (given after the first 4 cycles of T-DM1) were optional. Co-primary end points were safety and rate of prespecified cardiac events. Prechemotherapy LVEF by MUGA/ECHO ≥55% was required for enrollment. LVEF was evaluated at baseline, at the end of anthracycline treatment, after cycles 2 and 4 of T-DM1, and every 4 cycles of T-DM1 thereafter, as well as before and after the start of a new treatment (eg, optional docetaxel or RT).
Results
As of April 22, 2013, a total of 148 pts had received T-DM1. No prespecified cardiac events occurred (95% CI: 0.00%-2.45%), and there were no reports of symptomatic left ventricular systolic dysfunction or heart failure. One pt discontinued T-DM1 due to asymptomatic LVEF decline. Overall, 123 (83.1%) pts completed the planned course of T-DM1 treatment; 119 (80.4%) without dose reduction. Twenty pts (13.5%) had adverse events (AEs) leading to T-DM1 discontinuation. Eleven of these were laboratory abnormalities requiring discontinuation (none were grade 4), and 9 were due to symptomatic AEs (2 grade 3 [fatigue, joint crepitation]; no grade 4). Of the 148 pts, 32.4% had grade 3 T-DM1-related AEs and 2.7% had grade 4 T-DM1-related AEs (1 pt each: febrile neutropenia and pancytopenia; atrial fibrillation; decreased platelet count; hypokalemia); no deaths occurred. Of the 116 pts receiving RT, 39 received it concurrently with T-DM1 and 77 received it sequentially. The percentage of pts who completed the planned RT dose without delays was similar with concurrent or sequential treatment (90% and 92% respectively). Fifty pts (stage I, 8%; stage II, 56%; stage III, 36%) received neoadjuvant T-DM1 and underwent surgery. The pCR rate was 56.0% (95% CI, 41.3%-69.6%).
Conclusions
T-DM1 following anthracycline-based chemotherapy was feasible and was generally well tolerated in pts with HER2+ EBC. No symptomatic left ventricular dysfunction was observed. This favorable safety profile provides support for randomized trials of T-DM1 in pts with HER2+ EBC.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-15-03.