For patients diagnosed with human epidermal growth factor receptor 2 (HER2)-overexpressing Gastroesophageal Adenocarcinoma or GEA, trastuzumab in combination with chemotherapy is the only approved targeted therapy. Following disease progression, patients have limited treatment options.
GEA is the fifth most common cancer worldwide and approximately 20 percent of patients diagnosed with this form of cancer are HER2-positive. HER2-positive GEA has high morbidity and mortality and patients are urgently in need of new treatment options.
In phase 2 trials zanidatamab, a HER2-targeted bispecific antibody that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding, has demonstrated potential benefit in a range of HER2-expressing cancers, including first-line GEA, with durable anti-tumor activity with good tolerability response rates that compare favorably to both current standard of care and emerging treatments.
Zanidatamab’s unique binding properties result in multiple mechanisms of action including HER2-receptor clustering, internalization, and downregulation; inhibition of growth factor-dependent and -independent tumor cell proliferation; antibody-dependent cellular cytotoxicity and phagocytosis; and complement-dependent cytotoxicity.
Zanidatama is being developed by Zymeworks and is based on the company’s Azymetric™ platform technology.
Phase 2 Study Results
In September 2021, Zymeworks presented data at the European Society for Medical Oncology (ESMO) Annual Meeting from a Phase 2 clinical study of 36 patients with HER2-expressing GEA who received zanidatamab in combination with either CAPOX (capecitabine/oxaliplatin; n=14), FP (5FU/cisplatin; n=2) or mFOLFOX6 (5FU/leucovorin/oxaliplatin; n=20). None of the patients had received prior HER2-targeted therapies.
In 28 response-evaluable patients with metastatic HER2-positive GEA, zanidatamab plus chemotherapy resulted in a confirmed objective response rate (cORR) of 75% and disease control rate (DCR) of 89% overall, with a cORR of 93% and DCR of 100% in the proposed Phase 3 regimen of zanidatamab and CAPOX/FP. All patients except one experienced a decrease in their tumor size. Across all treatment regimens, the median duration of response is 16.4 months and the median progression-free survival is 12.0 months, with 61% of patients still on the study at the time of data cutoff.
In addition, the data demonstrate that zanidatamab plus chemotherapy is generally well tolerated, with the majority of treatment-related adverse events (TRAEs) considered mild to moderate in severity (Grade 1 or 2). The most common grade ≥ 3 TRAE was diarrhea, which was manageable in the outpatient setting; the introduction of prophylactic loperamide reduced the incidence in cycle 1 from 44% to 18%. No severe (grade ≥ 3) infusion-related reactions or cardiac events were observed.
Based on the outcomes of these early studies, Zymeworks launched the HERIZON-GEA-01 study, a global Phase 3 study with zanidatamab in first-line HER2-Positive GEA. The study will evaluate zanidatamab and chemotherapy with or without tislelizumab, a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages being developed by BeiGene and Novartis, versus standard of care. The study design enables a potential supplemental biologics license application (BLA) for zanidatamab in first-line HER2-positive GEA as early as 2024.
“We are incredibly excited to launch our second pivotal, and the first Phase 3 clinical trial for zanidatamab, HERIZON-GEA-01,” said Ali Tehrani, Ph.D., Zymeworks’ President, and Chief Executive Officer.
“Gastrointestinal cancers have a significant unmet patient need and we have the opportunity to help a large and growing patient population. With two potential Biologics License Applications over the next 3 years, we believe zanidatamab has the potential to achieve blockbuster status and position Zymeworks as the leader in the treatment of HER2-positive GI cancers,” Tehrani noted.
The primary objective of the HERIZON-GEA-01 study is to evaluate the efficacy and safety of zanidatamab in combination with physician’s choice chemotherapy [CAPOX (capecitabine/oxaliplatin) or FP (5FU/cisplatin)] with or without tislelizumab compared to trastuzumab plus physician’s choice chemotherapy in subjects with advanced or metastatic HER2-positive GEA. Primary endpoints are progression-free survival by RECIST 1.1, assessed by blinded independent central review, and overall survival.
Open for enrollment
The HERIZON-GEA-01 study seeks to enroll approximately 700 patients at approximately 300 sites across 38 countries. BeiGene will oversee trial sites in Asia (excluding Japan), Australia and New Zealand, and Zymeworks will oversee trial sites in the rest of the world, including North and South America, Japan, Europe, Middle East, and Africa.
“We are pleased the HERIZON-GEA-01 study has begun enrollment and our aim is to establish zanidatamab as the foundational agent of a new standard of care with tislelizumab for the first-line treatment of HER2-positive GEA,” said Neil Josephson, M.D., Zymeworks’ Chief Medical Officer.
“Based on the study design, we expect to have progression-free survival data as soon as 2024, which could enable submission of a supplemental Biologics License Application that same year,” Josephson added.
“The encouraging zanidatamab Phase 2 data support its further investigation with tislelizumab in this Phase 3 HERIZON-GEA-01 trial in first-line HER2-positive gastroesophageal adenocarcinomas,” said Yong (Ben) Ben, M.D., Chief Medical Officer, Solid Tumors, at BeiGene.
“We are excited to continue our collaboration with Zymeworks as we strive to address the unmet medical needs in this patient population by accelerating the development of zanidatamab,” Ben further noted.
The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified biliary tract cancer (BTC), and two Fast Track designations to zanidatamab, one as monotherapy for refractory BTC and one in combination with standard of care chemotherapy for first-line gastroesophageal adenocarcinoma (GEA). These designations mean zanidatamab is eligible for Accelerated Approval, Priority Review, and Rolling Review, as well as intensive FDA guidance on an efficient drug development program. Zanidatamab has also received Orphan Drug designations from the FDA as well as the European Medicines Agency (EMA) for the treatment of biliary tract and gastric cancers.
Trial of ZW25 (Zanidatamab) in Patients With Advanced HER2-expressing Cancers NCT02892123
A Phase 2 Single-Arm Open-Label Pilot Trial Evaluating Zanidatamab (ZW25) in Patients With Early Stage HER2/Neu Positive (HER2+) Breast Cancer (BC) – NCT05035836
A Safety and Efficacy Study of ZW25 (Zanidatamab) Plus Combination Chemotherapy in HER2-expressing Gastrointestinal Cancers, Including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer – NCT03929666
A Study of ZW25 (Zanidatamab) in Subjects With Advanced or Metastatic HER2-Amplified Biliary Tract Cancers (HERizon-BTC-01) – NCT04466891
Highlights of Prescribing Information
Trastuzumab (Herceptin®; Genentech/Roche)[Prescribing Information]
Capecitabine (Xeloda®; Genentech/Roche)[Prescribing Information]
Oxaliplatin (Eloxatin®; Sanofi Genzyme)[Perscription Information]
 Ku G, Elimova E, Denlinger CS, Mehta R, Lee KW, Iqbal S, Kang YK, Oh DY, Rha SY, et al. Phase (Ph) 2 Study of Zanidatamab + Chemotherapy in First-line (1L) HER2-expressing Gastroesophageal Adenocarcinoma (GEA). Abstract: 3678/ Poster 1380P; Presented at the European Society for Medical Oncology (ESMO21), held September 16 – September 21, 2021. [Poster][Presentation]
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