Abstract OT-03-09: Trastuzumab deruxtecan (T-DXd; DS-8201) vs investigator’s choice of chemotherapy in patients with hormone receptor-positive (HR+), HER2 low metastatic breast cancer whose disease has progressed on endocrine therapy in the metastatic setting: A randomized, global phase 3 trial (DESTINY-Breast06)
Authors: Bardia Aditya , Barrios Carlos , Dent Rebecca , Hu Xichun , O’Shaughnessy Joyce , Yonemori Kan , Darilay Annie , Boston Sarice , Liu Yufan , Patel Gargi , Curigliano Giuseppe 
Published: February 2021

Abstract
Background: HER2 directed therapies have substantially improved clinical outcomes in patients with HER2 positive (immunohistochemistry [IHC] 3+ or in situ hybridization [ISH] positive) metastatic breast cancer. However, no HER2 directed therapies are currently available for breast cancer with lower HER2 expression (IHC 2+/ISH− or IHC 1+). Patients with HER2 low and HR+ breast cancer typically receive initial treatment with endocrine therapy ± targeted therapies (CDK4/6, PI3K, or mTOR inhibitors). After disease progression, patients are treated with chemotherapy, which has shown limited clinical benefit. There is an unmet need for treatments that provide a superior risk-benefit profile compared with standard chemotherapy. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane permeable topoisomerase I inhibitor payload. Results from a phase 1 study demonstrated promising antitumor activity with a confirmed objective response rate (ORR) of 37.0% (20 of 54) per independent central review (ICR) and a median progression-free survival (PFS) of 11.1 months in patients with heavily pretreated (median 7.5 prior regimens) HER2 low metastatic breast cancer. Among patients with HR+ disease, the ORR was 40.4% (19 of 47) per ICR (Modi S, et al. J Clin Oncol. 2020;38:1887-1896). Here, we describe a phase 3 trial evaluating the efficacy and safety of T-DXd vs chemotherapy in patients with HR+, HER2 low metastatic breast cancer that has progressed on prior endocrine therapy. In addition to the primary population of patients with HER2 low disease being studied, this trial will also study the efficacy and safety of T-DXd in an IHC &gt; 0 &lt; 1+ (detectable HER2 staining &lt; 1+) population. Study Description: DESTINY-Breast06 is a global, randomized, multicenter, open-label, phase 3 trial designed to demonstrate superiority of T-DXd vs investigator’s choice of chemotherapy in patients with HR+, HER2 low metastatic breast cancer who had prior progression on endocrine therapy. Approximately 850 patients (HER2 low, n = 700; IHC &gt; 0 &lt; 1+, n = 150) from ≈ 300 centers globally will be randomized 1:1 to receive T-DXd 5.4 mg/kg every 3 weeks or investigator’s choice of chemotherapy (paclitaxel, nab-paclitaxel, or capecitabine) until disease progression, discontinuation due to intolerable toxicity, or death. Patients must have progression on ≥ 2 prior lines of endocrine therapy and cannot have received prior chemotherapy or any anti-HER2 therapy for metastatic disease. Randomization will be stratified by prior CDK4/6 inhibitor use (yes vs no), HER2 IHC expression (IHC2 +/ISH− vs IHC 1+ vs IHC &gt; 0 &lt; 1+), and prior taxane use in the non-metastatic setting (yes vs no). The primary endpoint is PFS per blinded ICR (BICR) in the HER2 low population. Key secondary endpoints are overall survival in the HER2 low and intent-to-treat (ITT; HER2 low and HER2 IHC &gt; 0 &lt; 1+) populations and PFS by BICR in the ITT population. Primary and key secondary endpoints will be tested in a hierarchical order. Other secondary endpoints are ORR by BICR and investigator assessment (according to RECIST 1.1), duration of response by BICR and investigator, time to second progression or death per investigator, time to first subsequent treatment or death, and time to second subsequent treatment or death (all in the HER2 low and ITT populations); PFS per investigator assessment in the HER2 low population; and safety, pharmacokinetics, patient-reported outcomes, and immunogenicity.
Citation Format: Aditya Bardia, Carlos Barrios, Rebecca Dent, Xichun Hu, Joyce O’Shaughnessy, Kan Yonemori, Annie Darilay, Sarice Boston, Yufan Liu, Gargi Patel, Giuseppe Curigliano. Trastuzumab deruxtecan (T-DXd; DS-8201) vs investigator’s choice of chemotherapy in patients with hormone receptor-positive (HR+), HER2 low metastatic breast cancer whose disease has progressed on endocrine therapy in the metastatic setting: A randomized, global phase 3 trial (DESTINY-Breast06) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-09.