CARDIAC SAFETY OF T-DM1

In a study reported in the Journal of Clinical Oncology, Krop et al found that ado-trastuzumab emtansine (Kadcyla) had an acceptable cardiac safety profile when used after anthracycline-based (neo)adjuvant therapy in women with early-stage HER2-positive breast cancer.

Study Details

In the study, 153 patients with a pretreatment left ventricular ejection fraction > 55% received (neo)adjuvant doxorubicin-cyclophosphamide for four cycles or fluorouracil, epirubicin, and cyclophosphamide for three or four cycles followed by ado-trastuzumab emtansine 3.6 mg/kg every 3 weeks for four cycles. Patients could then receive three or four cycles of docetaxel with or without trastuzumab (Herceptin). Ado-trastuzumab emtasine treatment was then resumed with optional sequential or concurrent radiotherapy for up to 1 year (17 cycles).

The coprimary endpoints were safety and rate of prespecified cardiac events within the first 12 weeks of ado-trastuzumab emtansine treatment. The prespecified cardiac events were death resulting from a cardiac cause or severe congestive heart failure (New York Heart Association class III or IV) accompanied by a decrease in left ventricular ejection fraction of ≥ 10% from baseline to < 50%.

Cardiac Events

Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failure was reported. Asymptomatic left ventricular ejection fraction declines of ≥ 10% from baseline to < 50% occurred in four patients (2.7%), with ado-trastuzumab emtansine being discontinued in one (0.7%). Other ado-trastuzumab emtansine–related cardiac events occurred in five patients (3.4%), including grade 4 atrial fibrillation in one (0.7%), grade 3 tricuspid valve incompetence in one (0.7%), grade 1 palpitations in four (2.7%), and grade 2 supraventricular extrasystole in one (0.7%).

Other Adverse Events

Of 148 patients who received at least one cycle of ado-trastuzumab emtansine, 82% completed the planned 1 year of treatment. The most common adverse events of any grade during ado-trastuzumab emtansine treatment were nausea (38%), headache (37%), epistaxis (32%), and asthenia (30%). Grade 3 adverse events occurred in 38.5% of patients, with the most common being thrombocytopenia (8.1%), increased aspartate transaminase (7.4%), and increased alanine transaminase (7.4%). Grade 4 adverse events occurred in 2.7% of patients (febrile neutropenia and pancytopenia, atrial fibrillation, thrombocytopenia, and hypokalemia).

At least 95% of the planned radiotherapy dose was completed with a delay ≤ 5 days in 95% of 38 patients receiving concurrent radiotherapy and 96% of 77 receiving sequential radiotherapy.

The investigators concluded: “Use of [ado-trastuzumab emtansine] for approximately 1 year after anthracycline-based chemotherapy was feasible and generally well tolerated by patients with HER2-positive [early-stage breast cancer], providing support for phase III trials of [ado-trastuzumab emtansine] in this setting.”

Ian E. Krop, MD, PhD, of Dana-Farber Cancer Institute, is the corresponding author of the Journal of Clinical Oncology article.

The study was supported by Genentech, a member of the Roche group. For full disclosures of the study authors, visit jco.ascopubs.org.