A 1-year course of trastuzumab emtansine was found to be well tolerated and safe for patients with HER2-positive early breast cancer who had undergone anthracycline-based chemotherapy in an industry-sponsored open-label phase II clinical trial.

The investigators described this as the first study to assess trastuzumab emtansine (T-DM1), a conjugate of the monoclonal antibody trastuzumab and the cytotoxic agent emtansine, in patients with early-stage rather than metastatic disease. They found that the conjugate agent was better tolerated than has been reported for trastuzumab alone in numerous studies, suggesting that it may become a less toxic alternative to the conventional chemotherapy-plus-trastuzumab approach for breast cancer.

“If validated in phase III studies, the favorable tolerability of T-DM1 may allow use of targeted cytotoxic therapy for a longer duration (e.g., 1 year) than is feasible with conventional cytotoxic agents,” wrote Dr. Ian E. Krop of breast oncology, Dana-Farber Cancer Institute, Boston, and his associates (J. Clin. Oncol 2015 Feb. 23 [doi:10.1200/JCO.2014.58.7782]).

Three randomized phase III trials are now underway – NCT01772472 (KATHERINE), NCT01966471 , and NCT02131064to confirm and extend the results of their study.

T-DM1 delivers the emtansine directly to tumor cells that overexpress HER2, inhibiting microtubule function and leading to cell death. In patients with metastatic breast cancer, the conjugate produces fewer adverse effects typically associated with chemotherapy, such as hair loss and neutropenia, presumably because it spares cells other than tumor cells. However, trastuzumab can be associated with cardiotoxicity, particularly in patients who also receive anthracycline-based regimens.

To assess the safety and tolerability of T-DM1 in early-stage breast cancer, Dr. Krop and his associates examined it in this single-arm trial involving 153 patients with HER2-positive early breast cancer whose left ventricular ejection fraction was 55% or greater at baseline. The patients were treated at 35 sites during a 1-year period and followed for a median of 25 months (range, 0.2-29.0 months).

They received four cycles of (neo)adjuvant doxorubicin plus cyclophosphamide or three to four cycles of fluorouracil plus epirubicin plus cyclophosphamide, then were given four cycles of T-DM1. They could then opt to receive three to four cycles of docetaxel, with or without trastuzumab, at their physician’s discretion. Sequential or concurrent radiotherapy could then be provided, and T-DM1 was resumed for a planned year of treatment.

Of the 148 patients who received at least 1 cycle of T-DM1, 122 (82%) completed the planned duration of therapy – a median of 14 cycles. “Only 17.6% of patients who initiated treatment with T-DM1 did not complete the planned therapy duration,” the investigators wrote, adding that by comparison, 31% of patients in a joint analysis of the NSABP and NCCTG trials discontinued trastuzumab alone before completing 1 year of treatment .

None of the study participants developed a cardiac event or symptomatic heart failure. By comparison, previous trials of adjuvant trastuzumab alone showed 2%-4% rates of CHF after anthracycline-based chemotherapy.

In this study, 2.7% of patients had asymptomatic declines in LVEF. By comparison, rates of LVEF decline ranged from 7% to 34% in previous trials of single-agent trastuzumab. Of the four women in this study who had LVEF decreases, one discontinued T-DM1 when her LVEF dipped to 45%; it subsequently recovered to baseline level.

Other adverse events included nausea (38% of patients) and headache (37%). The most common adverse events of grade 3 and above were thrombocytopenia (8.1%), increased ALT (7.4%), and increased AST (7.4%).

T-DM1 is marketed by Genentech as Kadcyla.Genentech supported the study. Dr. Krop is an employee of Vertex Pharmaceuticals and has received funding from Genentech. His associates reported ties to numerous industry sources