Abstract PO2-19-06: An Open-label, Interventional, Multicenter Study of Trastuzumab Deruxtecan Monotherapy in Patients With Unresectable and/or Metastatic HER2-Low or HER2 Immunohistochemistry 0 Breast Cancer: DESTINY-Breast15
Authors: Modi Shanu , Salgado Roberto , Guarneri Valentina , Alagappan Divi , Dennis Natalie , Newell Amy Hanlon , Boran Aislyn , Morsli Ouzna , Llombart-Cussac Antonio 
Published: May 2024

Abstract
Background
Approximately 50% of all breast cancer (BC) tumors express low levels of HER2, defined by HER2 immunohistochemistry (IHC) scores of 1+ or IHC 2+/in situ hybridization negative (ISH−), and are referred to as HER2-low BC. Trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate, has been approved in the United States, European Union, and other countries for the treatment of adult patients with unresectable or metastatic HER2-low BC (IHC 1+ or IHC 2+/ISH−), regardless of hormone receptor (HR) status, who previously received chemotherapy in the metastatic setting or who have developed disease recurrence within 6 months of completing adjuvant chemotherapy. The DESTINY-Breast04 trial that formed the basis of T-DXd approval in HER2-low BC included only 63 patients who were HR–negative and patients with HER2 IHC 0 status were not enrolled. However, the phase 2 DAISY trial demonstrated clinically meaningful activity of T-DXd in patients with HER2 IHC 0 BC. Along with HER2 status, HR–positive or HR-negative tumor status could confer variation in prognosis and sensitivity to systemic therapy. Few targeted agents are available for patients with HR-negative, HER2 IHC 0 metastatic BC, particularly for patients without pathogenic BC gene mutations or programmed cell death ligand 1 expression. Therefore, there is an unmet medical need for therapeutic treatment options in this patient population.
Study Description
DESTINY-Breast15 is a multicenter, open-label, single-arm, phase 3b trial designed to evaluate the efficacy and safety of T-DXd in patients with HR-positive or HR-negative unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH−) or HER2 IHC 0 BC who received 1 or 2 lines of prior therapy in the metastatic setting, including (but not limited to) targeted agents or endocrine therapy per cohort. Patients must have an ECOG PS score of 0 or 1, have never previously been HER2-positive (IHC 3+ or IHC 2+/ISH+), and have never previously received anti-HER2 therapy in the metastatic setting. At least 250 patients will be enrolled from approximately 80 sites in Belgium, Brazil, China, Ireland, Italy, Netherlands, Portugal, Spain, and the United States to receive T-DXd and will be assigned to 1 of 4 cohorts according to their HR and HER2 status (tested per local practice in accordance with ASCO/CAP 2018 guidelines). The 4 cohorts are cohort 1, HR-negative, HER2-low (n ≈ 100); cohort 2, HR-negative, HER2 IHC 0 (n ≈ 50); cohort 3, HR-positive, HER2-low (n ≈ 50); and cohort 4, HR-positive, HER2 IHC 0 (n ≈ 50). Cohort 3 will specifically recruit patients with rapid disease progression, defined as recurrent disease &lt; 2 years from starting adjuvant endocrine therapy, progression within 12 months of completing adjuvant CDK4/6 inhibitor, or progression within 12 months of starting CDK4/6 inhibitor therapy in the metastatic setting. T-DXd will be administered at a dose of 5.4 mg/kg intravenously once every 3 weeks until disease progression, unacceptable toxicity, or 2 years after the first dose of T-DXd. The primary end point is time from the start of T-DXd treatment to initiation of subsequent anticancer treatment or death. Secondary end points are real-world progression-free survival (defined as time from the date of first administration of T-DXd to date of first observed instance of disease progression per RECIST version 1.1 or death from any cause), time to treatment discontinuation or death, objective response rate per RECIST version 1.1, safety, and patient-reported quality-of-life–related outcomes. Time-to-event endpoints will be evaluated using Kaplan-Meier methods.
Citation Format: Shanu Modi, Roberto Salgado, Valentina Guarneri, Divi Alagappan, Natalie Dennis, Amy Hanlon Newell, Aislyn Boran, Ouzna Morsli, Antonio Llombart-Cussac. An Open-label, Interventional, Multicenter Study of Trastuzumab Deruxtecan Monotherapy in Patients With Unresectable and/or Metastatic HER2-Low or HER2 Immunohistochemistry 0 Breast Cancer: DESTINY-Breast15 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-06.