Abstract OT1-07-02: A phase 3, multicenter, randomized, open-label trial of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) vs investigator’s choice in HER2-low breast cancer (DESTINY-Breast04)
Authors: Modi Shanu , Ohtani Shoichiro , Lee Caleb , Wang Yibin , Saxena Kapil , Cameron David A. 
Published: March 2020

Abstract
Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have greatly improved survival in subjects with HER2-positive breast cancer (BC). However, there are many more subjects with BC with HER2-low expression (immunohistochemistry [IHC] 1+ or 2+/in situ hybridization negative), for whom no HER2-targeted therapies are approved. [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a humanized HER2 antibody, peptide-based cleavable linker, and topoisomerase I inhibitor payload. It has a drug-to-antibody ratio of 7 to 8, and the membrane permeability of the cleaved payload induces a cytotoxic bystander effect. In an ongoing, phase 1 study, T-DXd demonstrated an objective response rate (ORR) of 44.2% (19/43) with a manageable safety profile in heavily pretreated, advanced HER2-low BC (Modi et al, SABCS 2018). Results from the pivotal, phase 2 study of subjects with HER2-positive BC previously treated with [ado-] trastuzumab emtansine (DESTINY-Breast01) confirmed the activity observed in the phase 1 trial and will be presented at the meeting (Krop, et al). Here, we describe the phase 3 trial evaluating T-DXd in subjects with HER2-low BC. Study Description: DESTINY-Breast04 is a randomized, phase 3, 2-arm, open-label, multicenter trial comparing the efficacy and safety of T-DXd with investigator’s choice of treatment in HER2-low (IHC1+ or IHC2+/ISH−), unresectable and/or metastatic BC. The trial started in December 2018 and is recruiting subjects from 223 sites in North America, Europe, and Asia. Approximately 540 subjects (480 hormone receptor [HR]+ and 60 HR-) will be randomized (2:1) to T-DXd (5.4 mg/kg intravenously every 3 weeks) or investigator’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Randomization will be stratified by HER2 IHC status, number of prior treatments, and prior CDK4/6 inhibitor therapy/HR status. HER2 IHC will be assessed and confirmed by central testing based on archival samples. The primary efficacy endpoint is progression-free survival (PFS) per RECIST v1.1, determined by blinded independent central review. Secondary efficacy endpoints include investigator-assessed PFS, overall survival, ORR, and duration of response. Safety endpoints include treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest (including interstitial lung disease/pneumonitis, cardiotoxicity, and infusion-related reactions). For further information about this trial, visit ClinicalTrials.gov (NCT03734029).
Citation Format: Shanu Modi, Shoichiro Ohtani, Caleb Lee, Yibin Wang, Kapil Saxena, David A. Cameron. A phase 3, multicenter, randomized, open-label trial of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) vs investigator’s choice in HER2-low breast cancer (DESTINY-Breast04) [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 OT1-07-02.