Abstract OT-03-01: Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual invasive early breast cancer after neoadjuvant therapy: A randomized, phase 3 trial (DESTINY-Breast05)

Background Preoperative chemotherapy in combination with trastuzumab and pertuzumab is a preferred regimen for treating patients (pts) with HER2-positive, invasive, early breast cancer (BC). Pts who have received such treatment but still have residual invasive disease in the breast or lymph nodes at surgery are at greater risk for disease recurrence or death than those with a pathological complete response. The antibody-drug conjugate (ADC) T-DM1 was recently approved as a postneoadjuvant treatment for pts with residual invasive disease (in the breast and/or axillary nodes) after optimal neoadjuvant chemotherapy and trastuzumab (or trastuzumab with pertuzumab). T-DXd is a potent HER2-targeted ADC with a humanized HER2 antibody attached to a membrane-permeable topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker and a drug-to-antibody ratio of ≈ 8. Recently, T-DXd was approved for the treatment of adult pts with HER2-positive, unresectable or metastatic BC who have received ≥ 2 prior anti-HER2─based regimens in the metastatic setting (US) or had prior chemotherapy and are refractory to or intolerant of standard treatments (Japan). These approvals were based on a phase 2 study in which T-DXd demonstrated an objective response rate (ORR) of 60.9% (112/184 pts) and duration of response of 14.8 months in pts with HER2-positive (IHC 3+ or ISH+), unresectable or metastatic BC previously treated with T-DM1 (Modi et al. N Engl J Med. 2020;382:610-621). Here, we describe a randomized phase 3 trial evaluating T-DXd vs T-DM1 as postneoadjuvant treatment for high-risk pts with HER2-positive primary BC who have residual invasive disease following neoadjuvant therapy. Study Description DESTINY-Breast05 is a multicenter, open-label, randomized, phase 3 trial comparing the efficacy and safety of T-DXd with those of T-DM1 in pts with HER2-positive (IHC 3+ or ISH+, centrally confirmed on pretreatment biopsy), invasive BC with pathological evidence of residual invasive disease in the breast or axillary lymph nodes after neoadjuvant therapy. Additionally, pts must be at higher risk for recurrence, having either inoperable (clinical stages T4, N0-3, M0 or T1-3, N2-3, M0) or operable BC at presentation (clinical stages T1-3, N0-1, M0) with axillary node-positive disease after optimal neoadjuvant chemotherapy and anti-HER2 treatment. The trial is recruiting pts from ≈ 400 sites globally. Approximately 1600 pts will be randomized (1:1) to T-DXd or T-DM1. Randomization is stratified by operative status, hormone receptor status, pathological nodal status following neoadjuvant therapy, and type of HER2-targeted neoadjuvant therapy (single vs dual). T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg will be administered intravenously once every 3 weeks for 14 cycles. Invasive disease-free survival based on investigator assessment is the primary efficacy endpoint; disease-free survival is the key secondary efficacy endpoint. Other secondary endpoints are overall survival, distant recurrence-free interval, and brain metastasis-free interval. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, on-study chest imaging (to screen for pneumonitis), and clinical laboratory parameters. The pharmacokinetics of T-DXd, biomarkers, and health-related quality of life will also be evaluated. Long-term follow-up will continue after the primary analysis every 6 months until death, withdrawal of consent, loss to follow-up, or trial closure. Citation Format: Charles E Geyer, Jr, Michael Untch, Aleix Prat, Priya Rastogi, Naoki Niikura, Elton Mathias, Lee Anne McLean, Yibin Wang, Sibylle Loibl. Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual invasive early breast cancer after neoadjuvant therapy: A randomized, phase 3 trial (DESTINY-Breast05) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-01.