Abstract OT1-02-03: 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 is 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. T-DXd is approved globally 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 or had prior chemotherapy and are refractory to or intolerant of standard treatments. These approvals have been supported by results from DESTINY-Breast01, an open-label, international, multicenter, phase 2 study of T-DXd in patients with HER2-positive metastatic BC. In an updated data cutoff (June 8, 2020), T-DXd demonstrated an objective response rate (ORR) of 61.4% (113/184 pts) and a duration of response of 20.8 months in pts with HER2-positive (IHC 3+ or ISH+), unresectable or metastatic BC previously treated with T-DM1 (Modi et al. Cancer Res. 2021;81[4 suppl]:PD3-06). Yet, further unmet need exists in patients who do not achieve pathologic complete response to neoadjuvant treatment, as these patients have increased risk of recurrence. 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 pathologic evidence of residual invasive disease in the breast or axillary lymph nodes after neoadjuvant therapy. Additionally, pts must have a higher residual risk for recurrence, following standard T-DM1, defined as either presenting with inoperable disease (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 neoadjuvant chemotherapy and anti-HER2 treatment. Approximately 1600 pts will be randomly assigned (1:1) to T-DXd or T-DM1 from ≈ 400 sites globally. Randomization is stratified by operative status at presentation, hormone receptor status, pathologic 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. Secondary endpoints are overall survival, disease-free survival, distant recurrence-free interval, and brain metastasis-free interval. The pharmacokinetics of T-DXd, biomarkers, and health-related quality of life will also be evaluated (NCT04622319). 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 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-03.