Abstract CT289: A phase II study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in patients with HER2-positive metastatic solid tumors and metastases to brain (TUCATEMEB)

Abstract Background: HER2 overexpression or amplification is a validated prognostic and predictive biomarker for treatments in several tumor types. The development of brain metastases is an unfortunate and common complication in patients with metastatic cancer and the incidence of brain metastases continues to grow as advances in cancer treatment extend the survival. Unfortunately many of the clinical trials still exclude patients with brain metastases. Tucatinib is a selective small molecule HER2 inibitor that has shown intracranial activity and it is approved with trastuzumab and capecitabine for treatment of patients with breast cancer including with active brain metastases. Tucatinib showed significant preclinical and clinical antitumor activity in combination with other HER2-targeted therapies, including T-DM1 in breast and other cancers. We hypothesize that the combination of tucatinib and T-DM1 will be a safe and effective treatment in HER2-positive (+) metastatic solid tumors that have metastasized to the brain. To test this hypothesis, we are conducting a Phase II Study of Tucatinib and T-DM1 in Patients with HER2+ Metastatic Solid Tumors and Metastases to Brain (TUCATEMEB). Methods: Eligible adult patients with HER2-positive solid tumors and active brain metastases (with at least one untreated brain lesion ≥0. 5 cm and 3. 0 cm) will be enrolled in the study. HER2 positivity is defined as HER2 overexpression by immunohistochemistry 3+ or 2+ and fluorescence in situ hybridization positive and/or HER2 amplification by in situ hybridization or next-generation sequencing and/or activating ERBB2 mutation. Patients will receive the study treatment in 21-day cycles: Tucatinib 300 mg orally twice daily; T-DM1 3. 6 mg/kg intravenously on Day 1. The primary objective is to determine the intracranial antitumor activity of the tucatinib and T-DM1 combination per the modified RECIST in patients with HER2+ metastatic solid tumors and brain metastases. The secondary objectives are to determine the intracranial antitumor activity per the RANO-BM criteria; to evaluate the safety and tolerability, the duration of intracranial response, the overall survival, the progression free survival, the systemic antitumor activity and clinical benefit rate in patients with HER2+ metastatic solid tumors and brain metastases. Exploratory objectives are to assess predictive and pharmacodynamic markers of response and to corelate them with clinical and molecular characteristics. The efficacy endpoint will be monitored using the Bayesian optimal phase 2 BOP2 design and safety and tolerability will be monitored based on Bayesian posterior probability. Restaging brain MRI and systemic scans will be performed every 6 weeks for the first 12 weeks, and every 9 weeks thereafter. The trial opened in May 2023 and is enrolling patients (NCT05673928). Citation Format: Ecaterina E. Dumbrava, Amber M. Kennon, Rashmi K. Murthy, Emma J. Montazari, Hussein Tawbi, Jing Li, Frederick F. Lang, Gisela Sanchez, Jianbo Wang, Isabella C. Glitza, Barbara J. O'Brien, Thomas Beckham, Todd Swanson, Martin C. Tom, Uyen M. Vu, Tanisha T. Darko, Tiantian Cai, Komal Shah, Funda Meric-Bernstam, Jordi Rodon. A phase II study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in patients with HER2-positive metastatic solid tumors and metastases to brain (TUCATEMEB) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT289.