Background: Tucatinib is an oral reversible small-molecule tyrosine kinase inhibitor highly selective for human epidermal growth factor receptor 2 (HER2). Tucatinib is approved in the US for use in combination with trastuzumab and capecitabine in adult patients with HER2+ metastatic breast cancer (MBC), with and without brain metastases, who have received ≥1 prior anti–HER2-based regimens in the metastatic setting. Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC) comprising a HER2-directed monoclonal antibody conjugated to a topoisomerase I inhibitor payload, is also approved in the US for patients with HER2+ MBC. In HER2+ breast cancer (BC) xenograft models, tucatinib increased the antitumor activity of a HER2-directed ADC comprising a HER2-directed monoclonal antibody conjugated with 8 exatecan moieties (T-Ex) when compared to T-Ex alone (Kulukian et al 2019). While significant advances have been made in the treatment of patients with HER2+ BC, treatment of metastatic disease remains a clinical challenge due to limited treatment options. Methods: HER2CLIMB-04 (NCT04539938) is a single-arm, open-label, multicenter, phase 2 study evaluating the efficacy and safety of tucatinib plus T-DXd in previously treated patients aged ≥18 years with unresectable, locally advanced, or metastatic (LA/M) HER2+ BC. Patients must have prior treatment with a taxane and trastuzumab (with or without pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without pertuzumab). Patients with brain metastases, including active brain metastases, may be enrolled. A safety lead-in portion of the study with 10 patients who were followed for at least 1 cycle has been completed. This portion of the study demonstrated a manageable safety profile so the trial will enroll approximately 60 response-evaluable patients (including the 10 patients from the safety lead-in), evenly distributed between patients with and without brain metastases. The primary endpoint is confirmed objective response rate (cORR) by investigator assessment per RECIST 1.1. Secondary endpoints are progression-free survival (PFS), duration of response (DOR), disease control rate (DCR) by investigator assessment per RECIST 1.1, overall survival, and safety. Exploratory endpoints will include cORR, PFS, DCR, and DOR by independent central review per RECIST 1.1, pharmacokinetic analyses, biomarker analyses, and changes in patient-reported outcomes. Efficacy and safety will be summarized with descriptive statistics. Enrollment in the US began in late 2020. Clinical trial information: NCT04539938.