Results of the randomized, phase II ATEMPT trial showed that the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) failed to demonstrate improved safety when compared with paclitaxel plus trastuzumab as adjuvant therapy in patients with stage 1 HER2-positive breast cancer. These results of the randomized, phase II ATEMPT trial were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS).¹ No significant differences in clinically relevant toxicities were observed between T-DM1 vs paclitaxel with trastuzumab in this patient population, but the toxicity profiles of the individual treatment arms showed some differences.

T-DM1 is an antibody-drug conjugate that links trastuzumab with emtansine, a potent cytotoxic agent. T-DM1 is approved for the treatment of metastatic HER2-positive breast cancer and treatment of residual disease after taxane plus HER2-directed neoadjuvant therapy. T-DM1 has been associated with less toxicity compared with chemotherapy plus trastuzumab in the metastatic setting.

Sara M. Tolaney, MD, MPH

“This represents the first report of patients receiving T-DM1 monotherapy as adjuvant treatment for stage I HER2-positive breast cancer. T-DM1 was associated with very few recurrences in the study population. The study did not meet its preplanned endpoint of significantly fewer toxicities with T-DM1 when compared to paclitaxel/trastuzumab,” said lead author Sara M. Tolaney, MD, MPH, of Dana-Farber Cancer Institute, Boston.

“Although there was no difference in the overall incidence of clinically relevant toxicities between the two arms, there were differences in the toxicity profiles that were seen between T-DM1 and paclitaxel plus trastuzumab. It is also important to know that not all toxicities that are significant for our patients are captured in this clinically relevant toxicity endpoint, such as alopecia, and patient-reported outcomes should be considered when assessing the tolerability of therapy,” Dr. Tolaney noted.

Patient-reported outcomes were collected in this trial and demonstrated that T-DM1–treated patients had better quality of life, less neuropathy, less hair loss, and better work productivity when compared to pac­litaxel and trastuzumab, particularly during the first 12 weeks of therapy, and some differences persisted with longer follow-up.

Phase II ATEMPT Trial

The ATEMPT investigators sought to determine whether T-DM1 would be less toxic than paclitaxel plus trastuzumab for patients with stage 1 HER2-positive breast cancer. A co-primary endpoint was to evaluate disease-free survival in patients receiving T-DM1 in this study. The combination of paclitaxel and trastuzumab is a standard regimen in this setting and is associated with a 93% 7-year disease-free survival.

“Not all toxicities that are significant for our patients are captured in this clinically relevant toxicity endpoint, such as alopecia.”

— Sara M. Tolaney, MD, MPH

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Patients enrolled on the trial were within 90 days of surgery, had node-negative disease or up to one micrometastasis, left-ventricular ejection fraction (LVEF) of 50% or greater, and no prior invasive breast cancer. A total of 512 patients were randomly assigned in a 3:1 ratio to receive treatment with either T-DM1 at 3.6 mg/kg intravenously every 3 weeks for 17 cycles or paclitaxel plus trastuzumab weekly given as paclitaxel at 80 mg/m² plus trastuzumab at 2 mg/kg intravenously for 12 weeks followed by trastuzumab at 6 mg/kg every 3 weeks for an additional 13 cycles.

The two study arms were well balanced according to tumor size and histologic grade, as well as hormone receptor status. The intention-to-treat analysis was based on 383 patients assigned to T-DM1 and 114 assigned to paclitaxel plus trastuzumab. “The study was not designed to compare disease-free survival between the two treatment arms,” Dr. Tolaney told listeners.

At SABCS, Dr. Tolaney presented disease-free survival rates, including a 3-year disease-free survival of 97.7% in the T-DM1 arm. Also among T-DM1 recipients, there were seven recurrences (two ipsilateral, three contralateral HER2-negative, and two distant) and three deaths unrelated to breast cancer.

The paclitaxel-plus-trastuzumab arm had a 3-year disease-free survival of 92.8%. There were seven events: four ipsilateral recurrences, one new contralateral primary breast cancer, and two distant recurrences.

Safety

Clinically relevant toxicities were reported in 46% of patients in each arm. Grade 3 or greater nonhematologic toxicities were similar in both arms: 10% of patients in the T-DM1 arm vs 11% of patients assigned to paclitaxel plus trastuzumab. However, twice as frequently reported grade 2 or higher neutotoxicity occurred in the paclitaxel-plus-trastuzumab arm (11% for T-DM1 and 23%, respectively).

Both arms had a similar incidence of dose delay related to toxicity: 28% and 26%, respectively. However, about three times as many patients treated with T-DM1 had toxicities requiring early treatment discontinuation (17% vs 6%, respectively).

T-DM1 was also associated with a higher incidence of grade 2 or greater thrombocytopenia (11% vs 1%, respectively), liver enzyme elevation (9% vs 4%, respectively), and increased bilirubin (5% vs 1%, respectively). Symptomatic heart failure was reported in three patients in the T-DM1 arm (0.8%) and one in the paclitaxel-plus-trastuzumab arm (0.9%). Asymptomatic declines in LVEF occurred in five and seven patients, respectively.

Cost of Treatment

During the question-and-answer session, the issue of financial toxicity was raised as an important consideration. Dr. Tolaney said that 1 year of T-DM1 costs slightly more than twice as much as paclitaxel plus trastuzumab. Although she acknowledged that financial toxicity is a key factor for some patients when making treatment decisions, she noted that the individual safety profiles of each regimen may make one or the other regimen preferable, depending on patient factors.

DISCLOSURE: The ATEMPT trial was funded by Genentech. Dr. Tolaney has received consulting fees from Novartis, Pfizer, Eli Lilly, Immunomedics, Genentech/Roche, Merck, Sanofi, Bristol-Myers Squibb, Puma, AstraZeneca, Eisai, Nektar, NanoString, and Tesaro; and has received institutional research funding from Novartis, Pfizer, Eli Lilly, Genentech/Roche, Merck, Bristol-Myers Squibb, AstraZeneca, Eisai, Exelixis, Odonate, Nektar, Cyclacel, and Immunomedics.

REFERENCE

1. Tolaney SM, Trippa L, Barry W, et al. TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT). 2019 San Antonio Breast Cancer Symposium. Abstract GS1-05. Presented December 11, 2019.