Abstract OT1-12-04: A phase 3, open-label trial of neoadjuvant trastuzumab deruxtecan (T-DXd) monotherapy or T-DXd followed by THP compared with ddAC-THP in patients with high-risk HER2-positive early-stage breast cancer (DESTINY-Breast11)

Abstract Background: The current standard of care (SOC) for neoadjuvant treatment of human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer (EBC) consists of trastuzumab + pertuzumab and polychemotherapy. These multiagent regimens expose patients to short- and long-term toxicities, and many patients, particularly those with locally advanced or inflammatory disease, still experience relapse and/or death. In the phase 2 DESTINY-Breast01 study, T-DXd monotherapy demonstrated efficacy, with a confirmed objective response rate of 61.4% (complete response, 6.5%), median time to response of 1.6 months, and median progression-free survival of 19.4 months in patients with previously treated HER2-positive unresectable/metastatic breast cancer (Modi et al. SABCS 2020. Abstract PD3-06). Given the efficacy of T-DXd monotherapy, it is anticipated that replacing all or part of these SOC regimens with T-DXd could benefit patients with high-risk HER2-positive EBC. Here, we describe a phase 3 trial evaluating the efficacy, safety, and tolerability of T-DXd monotherapy or T-DXd followed by paclitaxel + trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) in patients with high-risk HER2-positive EBC. Methods: DESTINY-Breast11 is a phase 3, global, open-label, multicenter trial to determine the efficacy and safety of T-DXd monotherapy or T-DXd followed by THP as neoadjuvant treatment vs ddAC-THP in patients with high-risk (T stage ≥3 and/or node positive or inflammatory) HER2-positive EBC. Approximately 624 patients will be randomized 1:1:1 into 3 arms (arm A: T-DXd monotherapy every 3 weeks [q3w] for eight 3-week cycles; arm B: T-DXd [q3w for four 3-week cycles] followed by THP [paclitaxel every week + trastuzumab + pertuzumab q3w for four 3-week cycles]; arm C: ddAC-THP [ddAC every 2 weeks for four 2-week cycles followed by THP for four 3-week cycles]), stratified by hormone receptor status (positive vs negative) and central HER2 immunohistochemical score (IHC; IHC 3+ vs other). Patients should undergo breast or axillary surgery 3 to 6 weeks after administration of the last cycle of assigned treatment. After surgery, patients will receive treatment per local clinical standards. For patients who achieve a pathological complete response (pCR), adjuvant HER2-directed therapy for up to 1 year is recommended. For patients who do not achieve a pCR, therapy with up to 14 cycles of trastuzumab emtansine is recommended. Radiotherapy and endocrine therapy should be administered per local clinical standards. After the last dose of study treatment, patients will be assessed for survival and recurrence every 3 months for the first 3 years and every 6 months in years 4 and 5. The primary endpoint is pCR (ypT0/Tis ypN0) (defined as absence of invasive cancer in the breast and sampled regional lymph nodes) by central review. Secondary endpoints include pCR (ypT0 ypN0) (defined as absence of invasive and in situ cancer in the breast and sampled regional lymph nodes) by central review as well as 3-year event-free survival, 3-year invasive disease-free survival, overall survival, patient-reported tolerability, physical functioning, immunogenicity, pharmacokinetics, and safety. Exploratory endpoints include 3-year distant metastasis-free survival, objective response rate, rate of breast-conserving surgery, biomarkers, patient-reported outcomes, and healthcare resource utilization. Citation Format: Nadia Harbeck, Jean-François Boileau, Shanu Modi, Catherine M Kelly, Shinji Ohno, Jiong Wu, Mark Brekenridge, Pia Herbolsheimer, Tinghui Yu, Lajos Pusztai. A phase 3, open-label trial of neoadjuvant trastuzumab deruxtecan (T-DXd) monotherapy or T-DXd followed by THP compared with ddAC-THP in patients with high-risk HER2-positive early-stage breast cancer (DESTINY-Breast11) [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 OT1-12-04.

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