Background: The APT trial previously demonstrated that adjuvant TH is associated with favorable outcomes in patients (pts) with small HER2-positive BC. The ATEMPT trial sought to determine if adjuvant T-DM1 is associated with less toxicity than TH, and if it is associated with a clinically acceptable disease-free-survival (DFS) in pts with Stage I HER2+ BC.

Methods: ATEMPT is an investigator-initiated, randomized, multicenter, phase II adjuvant study of T-DM1 vs TH. Pts with Stage I centrally confirmed HER2+ BC (IHC 3 + and/or FISH > 2.0) were eligible. Pts were randomized 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks (w) for 17 cycles or T 80 mg/m2 IV with H qw x 12w (4 mg/kg load →2 mg/kg), followed by H x 39w (6 mg/kg q 3w). The co-primary endpoints were to compare the incidence of clinically relevant toxicities (CRT) in pts treated with T-DM1 vs TH and to evaluate the DFS in pts receiving T-DM1. CRT included grade ≥3 non-hematologic toxicity, grade ≥2 neurotoxicity, grade ≥4 hematologic toxicity, febrile neutropenia, and any toxicity requiring dose delay or discontinuation of protocol therapy. DFS events included invasive local, regional or distant recurrence, contralateral invasive breast cancer or death from any cause. With 375 and 125 pts randomized to T-DM1 and TH, respectively, there was 81% power to detect a 40% relative reduction in CRT between T-DM1 and TH. An interim analysis for comparison of CRT was performed when two-thirds of pts had completed therapy. For evaluation of DFS, the study was sized to have 95% power to distinguish between 3-year failure rates of 9% vs. 5% based on the total patient-years of follow-up (PYFU). Planned interim analyses were designed to stop early for futility at 186, 486, 861, and 1236 PYFU, and T-DM1 would be deemed worthy of further study with <39 DFS events after 1600 PYFU. All pts who began protocol therapy were included in the analyses.

Results: 512 pts with HER2+ tumors were enrolled and 497 began protocol therapy (383 T-DM1, 114 TH). 73% had hormone-receptor positive tumors. 11% of tumors were T1a; 31% T1b; 57% T1c. After interim analyses and continued review of safety, the Data Safety Monitoring Board approved release of study results. CRT were experienced by 25% of pts receiving T-DM1 and 36% of patients receiving TH; the difference was statistically significant (p=.03) but the relative reduction was < 40% (p=0.95). 2% (9/383) of pts receiving T-DM1 experienced g3/4 neurotoxicity compared to 7% (8/114) of pts receiving TH; 17% of pts discontinued T-DM1 early due to adverse events. With 1562 PYFU and a median follow-up of 3.0 years, a total of 11 DFS events in the T-DM1 arm (1 distant recurrence, 3 local recurrences, 3 contralateral breast cancers, 1 death due to recurrent breast cancer, 3 deaths from other causes) and 6 events in the TH arm (2 distant recurrences, 3 local recurrences, and 1 contralateral breast cancer) have occurred. The 3 yr DFS for pts receiving T-DM1 was 97.5% (95% CI:95.9%-99.3%) and for TH was 93.2% (95%CI: 88.1%-98.7%).

Conclusion: This represents the first report of pts receiving T-DM1 monotherapy as adjuvant treatment for Stage I HER2+ BC. The regimen was associated with very few recurrences in the study population. T-DM1 was associated with significantly fewer CRT than TH, but did not meet the preplanned 40% relative reduction in toxicity. Updated efficacy data will be presented.

Citation Format: Sara M Tolaney, Lorenzo Trippa, William Barry, Jiani Hu, Chau Dang, Denise Yardley, Steven Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Frederick Briccetti, Bryan Schneider, Merrill Garrett, Kelly Marcom, Kathy Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel Jankowitz, Michelle Demeo, Ann Partridge, Harold Burstein, Eric P. Winer, Ian Krop. TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-05.