Abstract GS1-05: 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

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.

Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. the COVID-19 pandemic breast cancer consortium

“…Patients with Stage 1 or 2, HER2 + BCs may consider ado-trastuzumab emtansine (± pertuzumab) with comparable efficacy to chemotherapy/trastuzumab-based regimens in either neoadjuvant or adjuvant settings (Priority B2) to minimize neutropenia, visits, and steroid-use [30,31]. Adjuvant trastuzumab-based therapy may be shortened from 12 to 6 months without affecting outcomes in selected patients (Priority B3) [32,33].…”

Evolving standards of care and new challenges in the management of HER2‐positive breast cancer

“…The phase 2 ATEMPT trial (ClinicalTrials.gov identifier NCT01853748) randomized approximately 500 patients with stage I, HER2‐positive BC 3:1 to receive T‐DM1 or weekly TH for 12 weeks, followed by the completion of 1 year of trastuzumab monotherapy (ie, the APT regimen) 33 . The co‐primary endpoints were 3‐year DFS in the T‐DM1 arm and a toxicity comparison between the treatment arms; it is important to note that the study was not powered for efficacy 33 . In the T‐DM1 arm, the 3‐year DFS was 97.7% (n = 383), compared with 92.8% in the TH arm (n = 114).…”

Early HER2-Positive Breast Cancer: Current Treatment and Novel Approaches

“…3 cycles of docetaxel + weekly trastuzumab (9 weeks) followed by FEC vs. doxorubicine/cyclophosphamide followed by thrice weekly docetaxel with trastuzumab followed by trastuzumab for up to 1 year stage 1 HER2-positive breast cancer were randomized to receiving T-DM1 or paclitaxel-trastuzumab at a 3: 1 ratio [45]. The 3-year DFS was 97.7% for the T-DM1 arm and 92.8% for paclitaxel/trastuzumab, but the study was not powerful enough to estimate the efficacy difference between the 2 study arms [45]. The toxicity profile incidence was similar between the 2 groups.…”

“…In the ATEMPT trial, the adjuvant T-DM1 was tested in a similar population. In that phase 2 trial, patients with stage 1 HER2-positive breast cancer were randomized to receiving T-DM1 or paclitaxel-trastuzumab at a 3:1 ratio [45]. The 3-year DFS was 97.7% for the T-DM1 arm and 92.8% for paclitaxel/trastuzumab, but the study was not powerful enough to estimate the efficacy difference between the 2 study arms [45].…”