Abstract Background HER2-targeted therapies have substantially improved survival in patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization-positive) advanced or metastatic breast cancer. Despite significant advancements, patients ultimately develop resistance to standard-of-care HER2-targeted therapies. Therefore, a need remains for regimens that prolong disease control and survival in these patients. T-DXd is a HER2-targeted antibody-drug conjugate containing a linker selectively cleaved in tumor cells and a topoisomerase I inhibitor payload with high cell-membrane permeability. T-DXd has been approved by the FDA for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥ 2 prior anti-HER2-based regimens in the metastatic setting and by Japan’s Ministry of Health, Labour and Welfare for use in patients with HER2-positive unresectable or recurrent breast cancer after prior chemotherapy (use limited to patients refractory to or intolerant of standard treatments). Results from the phase 2 DESTINY-Breast01 trial demonstrated an objective response rate (ORR) of 60.9% per independent central review and a median progression-free survival (PFS) of 16.4 months in a heavily pretreated population (median of 6 prior lines of therapy) of patients with HER2-positive advanced or metastatic breast cancer treated with T-DXd (Modi S, et al. N Engl J Med. 2020;382:610-621). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd combinations in patients with HER2-positive advanced or metastatic breast cancer. Study Description DESTINY-Breast07 is a global, multicenter, open-label, phase 1b/2 dose-finding and dose-expansion trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd in combination with other therapies in patients with HER2-positive advanced or metastatic breast cancer. Patients will be enrolled globally at ≈ 110 sites in ≈ 10 countries. The study will initially consist of 4 combination modules, each with 2 parts: dose finding (part 1) and dose expansion (part 2), and a T-DXd monotherapy module (part 2 only). The 4 combination modules will enroll patients for treatment with (1) T-DXd + durvalumab, (2) T-DXd + pertuzumab, (3) T-DXd + paclitaxel, or (4) T-DXd + durvalumab + paclitaxel. New combination treatment modules may be added via protocol amendment. Part 1 of each combination module will enroll patients who have had disease progression on ≥ 1 prior line of therapy in the metastatic setting. In part 2, patients who have received no prior therapy for metastatic disease will be randomized to receive a combination regimen or T-DXd monotherapy. Antitumor activity will be evaluated based on investigator assessment according to RECIST 1.1. The primary endpoint is to assess the safety and tolerability of T-DXd combinations and determine the recommended phase 2 doses. Secondary endpoints include ORR, PFS, duration of response, overall survival, pharmacokinetics, and immunogenicity. Citation Format: Fabrice Andre, Erika Hamilton, Sherene Loi, Peter Schmid, Tinghui Yu, Shiyao Lu, Sarice Boston, Celina D'Cruz, Pia Herbolsheimer, Komal Jhaveri. Trastuzumab deruxtecan (T-DXd; DS-8201) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2 open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07) [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-03-04.