Abstract OT1-14-01: Zanidatamab in combination with ALX148 in advanced human epidermal growth factor receptor 2 (HER2)-expressing cancers, including breast cancer: A phase 1b/2, multicenter, open-label, dose-finding and cohort-expansion study (ZWI-ZW25-204)
Authors: Hurvitz Sara A. , Chaves Jorge , Brufsky Adam , Montero Alberto J. , Fang Bruno , Yeung Kay , Patel Manish R. , Parajuli Ritesh , Omidpanah Adam , Gartner Elaina , Fong Abraham , Randolph Sophia , Meric-Bernstam Funda 
Published: March 2022

Abstract
Background: HER2-targeted therapies have led to marked improvements in survival for patients with HER2-positive breast cancer. Despite the gains obtained with current HER2-targeted therapies, an unmet medical need remains for patients with HER2-expressing (high or low expression) advanced breast cancer that has progressed after prior treatments. Zanidatamab is a novel HER2-targeted bispecific antibody that has multiple mechanisms of action, including immune clearance of HER2-expressing tumor cells through antibody-dependent cellular phagocytosis. Zanidatamab has been shown to be well-tolerated and has demonstrated antitumor activity, both as monotherapy and in combination with chemotherapy, across HER2-expressing solid tumors in a Phase 1 study. ALX148 is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of anticancer therapies, including antibodies, with minimal added hematologic toxicity. Treatment with zanidatamab in combination with ALX148 has the potential to augment the immune clearance of HER2-expressing cancer cells by blocking the CD47-SIRPa interaction that inhibits phagocytosis of the same cancer cells. In a Phase 1 study, ALX148 demonstrated antitumor activity when combined with trastuzumab in patients whose disease had progressed on prior HER2-targeted therapies. Here, we describe a Phase 1b/2 study to investigate the safety and antitumor activity of a chemotherapy-free combination of zanidatamab plus ALX148 in advanced HER2-expressing cancers, including breast cancer. Methods: ZWI-ZW25-204 is a Phase 1b/2, 2-part, open-label, multicenter study to evaluate the safety and antitumor activity of zanidatamab administered in combination with ALX148 in patients with locally advanced/inoperable and/or metastatic HER2-expressing cancer. Part 1 of this study will evaluate safety and tolerability and will establish the recommended doses (RDs) of zanidatamab plus ALX148. It will include patients with either HER2-positive (defined per ASCO/CAP guidelines) or HER2-low (defined as immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization (ISH) negative) breast cancer. Part 2 will evaluate the antitumor activity of zanidatamab plus ALX148 (at their combination therapy RDs) in 3 expansion cohorts: HER2-positive breast cancer (Cohort 1), HER2-low breast cancer (Cohort 2) and other HER2-overexpressing advanced malignancies (Cohort 3). Other key eligibility criteria include: prior use of approved agents known to confer clinical benefit, disease progression on or after the most recent systemic therapy, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Patients will receive zanidatamab and ALX148, each administered intravenously once every 2 weeks in a 28-day treatment cycle. Response assessments will be performed every 8 weeks. Primary endpoints include safety and tolerability assessments (Part 1) and confirmed objective response rate per RECIST 1.1 (Part 2). Secondary endpoints in Part 2 include disease control rate, clinical benefit rate, duration of response, progression-free survival, overall survival, safety, pharmacokinetics, and immunogenicity assessments. The study is currently open for enrollment in the United States and may enroll up to 93 patients (NCT: 05027139).
Citation Format: Sara A. Hurvitz, Jorge Chaves, Adam Brufsky, Alberto J. Montero, Bruno Fang, Kay Yeung, Manish R. Patel, Ritesh Parajuli, Adam Omidpanah, Elaina Gartner, Abraham Fong, Sophia Randolph, Funda Meric-Bernstam. Zanidatamab in combination with ALX148 in advanced human epidermal growth factor receptor 2 (HER2)-expressing cancers, including breast cancer: A phase 1b/2, multicenter, open-label, dose-finding and cohort-expansion study (ZWI-ZW25-204) [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 OT1-14-01.