Breast cancer is the most common malignancy diagnosed in women in the United States and the second leading cause of death from cancer. The HER2-positive patient subset includes 15-20% of all breast cancer cases. And while HER2-targeted therapies have markedly improved survival for patients with HER2-positive breast cancer and treatment options available today have increased the median overall survival, after progression with other available HER2–targeted therapies, the treatment for patients with advanced HER2–positive breast cancer is generally a regimen comprised of a HER2–targeted antibody (e.g., trastuzumab) combined with a single chemotherapeutic agent. 
Based on the results of ongoing clinical studies with previously treated patients (1–3 prior therapies) the overall response rate with such therapy is < 25% with median progression–free survival (PFS) < 6 months, and the median overall survival for these patients is < 2 years  Furthermore, for patients with metastatic treatment-naïve HER2-positive breast cancer to almost 5 years, metastatic HER2-positive disease remains incurable with an ongoing need to expand our available anti-HER2 therapies. To address the unmet medical needs, novel therapeutic agents are currently in development.
Among these novel agents is the HER2-targeted bispecific antibody, zanidatamab (ZW25, Zymeworks), an investigational drug that has shown to be effective and well-tolerated in patients with a variety of HER2-positive cancers.
Clinical data for zanidatamab in heavily pretreated, HER2-positive breast cancer was presented at the San Antonio Breast Cancer Symposium (SABCS) taking place in San Antonio, Texas, and virtually, December 7-10, 2021.
Zanidatamab is a HER2-targeted bispecific humanized, antibody directed against the juxtamembrane domain (ECD4) and the dimerization domain (ECD2) of HER2. The drug is developed using Zymeworks proprietary Azymetric™ platform. The drug simultaneously binds two distinct sites on HER2, a protein expressed on many types of cancer cells. This unique design results in multiple mechanisms of action, including dual HER2 signal blockade, increased antibody binding, receptor clustering, and removal of HER2 from the cell surface, and potent effector function.
The data presented are results from a clinical study of 24 patients with heavily pretreated
HER2-positive metastatic breast cancer who received zanidatamab in combination with either vinorelbine (Navelbine®, GSK; n=12), capecitabine, (Xeloda®, Roche/Genentech; n=8), or paclitaxel (Taxol®, Bristol-Myers Squibb; n=4).
Patients received multiple prior regimens containing HER2-targeted agents including trastuzumab (Herceptin®, Roche/Genentech; 96%), pertuzumab (Perjeta®, Roche/Genentech; 96%), and ado-trastuzumab emtansine/T-DM1 (Kadcyla®, Roche/Genetech; 96%), and many also received a tyrosine kinase inhibitor.
In 22 efficacy-evaluable patients, treatment with zanidatamab and chemotherapy resulted in a complete Objective Response Rate (cORR) of 36.4% and DCR of 86.4%, and the majority of patients experienced a decrease in their tumor size. The median Progression-Free Survival (mPFS) is 7.3 months across all treatment regimens with 42% of patients still on study at the time of data cutoff.
The study results demonstrated that zanidatamab in combination with single-agent chemotherapy was well tolerated, with the majority of treatment-related adverse events considered mild to moderate in severity (Grade 1 or 2).
“Zanidatamab together with chemotherapy shows encouraging antitumor activity and a manageable safety profile in patients with HER2-positive breast cancer that has progressed after treatment with multiple HER2-targeted agents,” explained Neil Josephson, M.D., Chief Medical Officer at Zymeworks.
“We were impressed by the activity and durability of disease control with
zanidatamab, with over half of patients experiencing a confirmed response or stable disease lasting over 6 months. These results, together with data presented earlier this year in both HER2-expressing biliary tract cancer and gastroesophageal adenocarcinoma, build on our belief that zanidatamab has the potential to be a foundational therapy across multiple HER2-expressing solid tumor indications,” Josephson added.
“Zanidatamab continues to generate clinical data that differentiate it from existing and emerging HER2-targeted standards of care,” said James Priour, Chief Commercial Officer at Zymeworks.
“Expanding on our commitment to complete ongoing pivotal trials in biliary tract and gastric cancers, we see breast cancer as the next indication to pursue a potential label. As we await additional data in early lines of breast cancer, these data in late-line present an additional registrational opportunity. With the majority of HER2-positive breast cancer patients benefitting from new therapies and surviving longer than ever before, there is a significant commercial opportunity in the third- and fourth-line setting. We believe the data presented today demonstrate that zanidatamab and chemotherapy could be a new
Zymeworks is expected to share additional data with zanidatamab in HER2-positive breast cancer from other ongoing trials in the first half of 2022, including in combination with Ibrance and fulvestrant in late-line hormone receptor-positive disease as well as in combination with docetaxel in the first-line setting.
 Bedard PL, Im SA, Elimova E, Rha SY, Goodwin R, Ferrario C, Lee KW, Hanna D, et al. Zanidatamab (ZW25), a HER2-targeted Bispecific Antibody, in Combination with Chemotherapy (chemo) for HER2-positive Breast Cancer (BC): Results from a Phase 1 Trial. Presented by Philippe L. Bedard, M.D., Princess Margaret Cancer Center, Toronto, ON Canada (Abstract: #93; Program Number: P2-13-07)[Poster]
 Hurvitz SA, Chaves J, Brufsky A, Montero AJ, Fang B, Yeung K, Patel MR, Parajuli R, et al. Zanidatamab (ZW25) in Combination with Evorpacept (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) Presented by Sara A. Hurvitz, M.D., University of California, Los Angeles; Jonsson Comprehensive Cancer Center, Los Angeles, CA, US (Abstract: #182; Program Number: OT1-14-01)[Poster]
Highlights of Prescription Information
Vinorelbine (Navelbine®, GSK) (Prescribing Information)
Capecitabine (Xeloda®, Roche/Genentech) (Prescribing Information)
Paclitaxel (Taxol®, Bristol-Myers Squibb) (Prescribing information)
Trastuzumab (Herceptin®, Roche/Genentech) (Prescribing Information)
Pertuzumab (Perjeta®, Roche/Genentech) (Prescription information)
Ado-trastuzumab emtansine/T-DM1 (Kadcyla®, Roche/Genetech) (Prescribing Information)
 Martínez-Sáez O, Prat A. Current and Future Management of HER2-Positive Metastatic Breast Cancer. JCO Oncol Pract. 2021 Oct;17(10):594-604. doi: 10.1200/OP.21.00172. Epub 2021 Jun 2. PMID: 34077236.
 Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, et al.Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. doi: 10.1001/jamaoncol.2020.7932. PMID: 33480963; PMCID: PMC7823434.
 ZW25 Effective in HER2-Positive Cancers. Cancer Discov. 2019 Jan;9(1):8. doi: 10.1158/2159-8290.CD-NB2018-162. Epub 2018 Nov 30. PMID: 30504239.
Featured Image: General Views of the SABCS 2018. Photo Courtesey: © 2018 – 2021 SABCS/AACR. Used with permission.