Abstract OT1-13-01: HER2CLIMB-04: phase 2 trial of tucatinib + trastuzumab deruxtecan in patients with HER2+ locally advanced or metastatic breast cancer with and without brain metastases (trial in progress)
Authors: Hamilton Erika , Carey Lisa , Ramos Jorge , Chen Yiyi , Krop Ian 
Published: March 2022

Abstract
Background Tucatinib is an oral, reversible, small-molecule tyrosine kinase inhibitor highly selective for HER2 with minimal inhibition of the human epidermal growth factor receptor. Tucatinib is approved in the US for use in combination with trastuzumab and capecitabine in patients with HER2+ metastatic breast cancer, with and without brain metastases, who have received 1 or more 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 approved in the US for patients with HER2+ metastatic breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. In HER2+ breast cancer 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). Abstract P1-18-09. Proceedings of San Antonio Breast Cancer Symposium, December 10-14, 2019). While significant advances have been made in the treatment of patients with HER2+ breast cancer, treatment of metastatic disease remains a clinical challenge for which options are limited, particularly in patients with brain metastases. The HER2CLIMB-04 study is evaluating the efficacy and safety of tucatinib in combination with T-DXd in patients with HER2+ metastatic breast cancer following progression on 2 or more HER2-directed regimens in the metastatic setting. Trial Design HER2CLIMB-04 (NCT04539938) is a single-arm, open-label, multicenter, phase 2 study of tucatinib in combination with T-DXd in previously treated patients aged ≥18 years with unresectable, locally advanced, or metastatic HER2+ breast cancer. Patients with brain metastases, including active brain metastases, may be enrolled. A safety lead-in portion of the study will enroll 10 patients who will be followed for at least 1 cycle. If tucatinib combined with T-DXd has a manageable safety profile, the trial will enroll approximately 60 response-evaluable patients (including the 10 patients from the safety lead-in), approximately evenly distributed between patients with and without brain metastases. The primary endpoint is confirmed objective response rate (cORR) by investigator assessment per Response Evaluation Criteria in Solid Tumors (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, OS, 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 using the European Quality of Life 5-Dimension 5-Level instrument. Efficacy and safety will be summarized with descriptive endpoints to describe continuous variables. For response rates, the 2-sided exact confidence interval using the Clopper-Pearson method will be calculated. Enrollment began in late 2020 at approximately 30 study sites in the US.
Citation Format: Erika Hamilton, Lisa Carey, Jorge Ramos, Yiyi Chen, Ian Krop. HER2CLIMB-04: phase 2 trial of tucatinib + trastuzumab deruxtecan in patients with HER2+ locally advanced or metastatic breast cancer with and without brain metastases (trial in progress) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-13-01.