Abstract OT1-07-01: [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) vs ado-trastuzumab emtansine (T-DM1) in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received trastuzumab and a taxane: A phase 3, randomized trial (DESTINY-Breast03)
Authors: Cortés Javier , Shahidi Javad , Lee Caleb , Zhang Yufen , Verma Sunil 
Published: March 2020

Abstract
Background: Ado-trastuzumab emtansine (T-DM1), a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC), is approved for subjects with HER2-positive metastatic breast cancer (BC) after disease progression on a trastuzumab-based regimen. Approval of T-DM1 was based on the EMILIA trial, in which T-DM1 demonstrated an objective response rate (ORR) of 43.6%, a median progression-free survival (PFS) of 9.6 months, and an overall survival (OS) of 30.9 months (Verma et al, N Engl J Med, 2012). [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is a novel HER2-targeted ADC with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker and a high drug-to-antibody ratio of 7 to 8. In an ongoing, phase 1 study, T-DXd showed promising antitumor activity in subjects with HER2-positive BC previously treated with T-DM1, with a confirmed ORR of 59.5% (Tamura et al, Lancet Oncol, 2019). Results from the pivotal, phase 2 study of subjects with HER2-positive BC previously treated with T-DM1 (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-positive, unresectable and/or metastatic BC who previously received trastuzumab and a taxane. Study Description: DESTINY-Breast03 is a multicenter, open-label, phase 3 trial that will assess the efficacy and safety of T-DXd vs T-DM1 in subjects with centrally confirmed HER2-positive (immunohistochemistry [IHC] 3+ or in situ hybridization [ISH]+), unresectable and/or metastatic BC previously treated with trastuzumab and a taxane. The trial started in July 2018 and is recruiting subjects from ≈ 160 sites in North and South America, Europe, and Asia. Subjects who previously received a HER2-targeted ADC are excluded. Approximately 500 eligible subjects will be randomized (1:1) to receive T-DXd (5.4 mg/kg) or T-DM1 (3.6 mg/kg) intravenously once every 3 weeks. Randomization will be stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. For subjects randomized to T-DM1, the treatment will be in accordance with the approved label. The primary efficacy endpoint is PFS based on blinded, independent central review using RECIST v1.1 criteria. Secondary efficacy endpoints include OS, ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health-related quality of life will also be measured. Long-term follow-up will continue every 3 months until death, withdrawal of consent, loss to follow-up, or trial closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥ 1 dose of trial treatment. For further information on this trial, visit ClinicalTrials.gov (NCT03529110).
Citation Format: Javier Cortés, Javad Shahidi, Caleb Lee, Yufen Zhang, Sunil Verma. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) vs ado-trastuzumab emtansine (T-DM1) in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received trastuzumab and a taxane: A phase 3, randomized trial (DESTINY-Breast03) [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 OT1-07-01.