Abstract OT2-16-02: Open-label, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with advanced/metastatic human epidermal growth factor receptor 2–positive breast cancer: DESTINY-Breast12
Authors: Lin Nancy U. , Ciruelos Eva , Jerusalem Guy , Müller Volkmar , Niikura Naoki , Viale Giuseppe , Oscroft Emma , Anand Shawn , Prahladan Manoj , Harbeck Nadia 
Published: March 2023

Abstract
Background: Patients (pts) with human epidermal growth factor receptor 2–positive breast cancer (HER2+ BC) have a high incidence (up to 50%) of brain metastasis (BM) despite advances in treatment (Zimmer AS et al. Cancer Rep (Hoboken). 2020;e1274; Hurvitz SA et al. Clin Cancer Res. 2019;25:2433-2441). Although several agents have been studied in pts with HER2+ BC with BM, an unmet medical need remains. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a pt subgroup with stable BM (n=24), with a confirmed objective response rate (ORR) of 61.4%, an extracranial confirmed ORR by independent central review (ICR) of 58.3%, respectively, and median progression-free survival (PFS) of 19.4 and 18.1 months, respectively (Modi S et al. Cancer Res. 2021. Abst PD3-06; Jerusalem G et al. Ann Oncol. 2020. Abst 138O). T-DXd also demonstrated preliminary efficacy in a subgroup of pts with BM in the DESTINY-Breast03 trial, with an extracranial ORR of 67.4%, intracranial ORR of 63.9%, and median PFS of 15.0 months (Hurvitz S et al. SABCS 2021. Abst GS3-01). However, both trials excluded pts with active/progressive BM. Here we describe a trial evaluating T-DXd in a real-world setting in pts with stable or active BM and pts without BM with previously treated advanced/metastatic HER2+ BC. The data generated by this study will complement previous and ongoing studies, providing a more robust understanding of T-DXd treatment in patients with and without BM. Trial design: DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (91 sites in the US, Europe, Australia, Canada, and Japan), phase 3b/4 study assessing the efficacy and safety of T-DXd 5.4 mg/kg every 3 weeks in pts with HER2+ BC ± BM. As part of prescreening, all pts will provide informed consent for tumor tissue samples (archival tumor tissue or fresh biopsy) to be collected and tested for HER2 status. Pts will be enrolled in 1 of 2 cohorts (250 pts each): cohort 1 (no BM at baseline) and cohort 2 (BM at baseline). Pts must have previously treated HER2-positive BC that has progressed on or after ≥1 prior anti-HER2–based regimen (including disease progression ≤6 months after adjuvant treatment with HER2-targeted therapies) and received ≤2 lines of therapy in the metastatic setting (excluding pts with prior tucatinib). Cohort 1 will be limited to include ≤25% third-line pts. Pts with BM must have untreated BM not needing immediate local therapy or previously treated stable or progressing BM. Primary endpoints are ORR in cohort 1 and PFS in cohort 2 (both by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 per ICR). Secondary endpoints in both cohorts are overall survival, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and quality of life. Incidence of new symptomatic central nervous system (CNS) metastasis is a secondary endpoint in cohort 1, and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNS metastasis are secondary endpoints in cohort 2.
Citation Format: Nancy U. Lin, Eva Ciruelos, Guy Jerusalem, Volkmar Müller, Naoki Niikura, Giuseppe Viale, Emma Oscroft, Shawn Anand, Manoj Prahladan, Nadia Harbeck. Open-label, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with advanced/metastatic human epidermal growth factor receptor 2–positive breast cancer: DESTINY-Breast12 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-02.