Data presented at the 2021 congress of the European Society for Medical Oncology (ESMO) for a clinical study of 36 patients with HER2-expressing Gastroesophageal Adenocarcinoma (GEA) who received zanidatamab (ZW25), a HER2‐targeted bispecific antibody being developed by Zymeworks, in combination with either CAPOX (capecitabine/oxaliplatin; n=14), FP (5FU/cisplatin; n=2), or mFOLFOX6 (5FU/leucovorin/oxaliplatin; n=20), demonstrated promising results.

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 + CAPOX/FP. All patients except one experienced a decrease in their tumor size. The results also showed a median duration of response (mDOR) of 16.4 months and median progression-free survival (mPFS) of 12 months.

None of the patients had received prior HER2-targeted therapies.

Based on the results of the investigators believe that the data support the use of zanidatamab + chemotherapy as the foundation of a potential new standard of care in first-line HER2-positive GEA

Well tolerated
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.

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“Despite recent advances, metastatic HER2-expressing GEA has high morbidity and mortality, and new treatment options are desperately needed,” said the principal investigator on the trial, Geoffrey Ku, M.D., a Medical Oncologist at Memorial Sloan Kettering Cancer Center (MSK) in New York.

“The data presented today at ESMO demonstrate the potential of zanidatamab in the first-line setting, highlighted by response rates and durability that compare favorably to the current standard of care as well as to emerging treatment options,” Ku added.

“These data support further evaluation of zanidatamab plus chemotherapy in a randomized pivotal trial in first-line HER2-positive GEA,” he concluded.

Current Standard of Care
HER2 is overexpressed in approximately 20% of GEA patients. For these patients, trastuzumab (Herceptin®; Genentech/Roche) is the only approved HER2‐targeted therapy in first-line treatment, and therapeutic options are currently limited if disease progression occurs.

Bispecific approach
Zanidatamab’s bispecific approach simultaneously binds two non-overlapping epitopes of HER2, ECD2, and ECD4, resulting in multiple mechanisms of action that provide potential therapeutic benefits beyond the combination of two monoclonal antibodies.

“Herceptin and chemotherapy have been the standard of care in first-line HER2-positive GEA for over 10 years. The data presented today give us the confidence that we have developed a next-generation HER2-targeted agent that has the potential to provide patients with an improved option in this setting,” said Neil Josephson, M.D., Zymeworks’ Interim Chief Medical Officer.

“Based on these data, we will pursue a randomized, Phase 3 trial with the aim of establishing zanidatamab as the foundational agent of a new standard of care in first-line HER2-positive GEA.”

Other studies
In addition to the Phase 2 study presented today, Zymeworks and its partner BeiGene are conducting a parallel open-label Phase 2 clinical trial evaluating zanidatamab and chemotherapy in combination with the PD-1 inhibitor, tislelizumab, in first-line HER2-positive metastatic GEA. The results of this study are expected to be presented at a future medical conference.

Together with BeiGene, Zymeworks plans to launch a randomized, global Phase 3 study, called HERizon-GEA-01) in the fourth quarter of 2021. The study will also evaluate zanidatamab plus chemotherapy (CAPOX or FP) with or without tislelizumab, versus standard of care (trastuzumab plus chemotherapy), for first-line treatment of locally advanced, unresectable, or metastatic HER2-positive GEA.

“Our long-standing vision for zanidatamab has been for it to become a best-in-class HER2-targeted therapeutic that could address the needs of a broad spectrum of patients with HER2-expressing cancers,” said Ali Tehrani, Ph.D., Zymeworks’ President & CEO.

“Over the years we have shared data that have showcased the promising anti-tumor activity and safety profile of zanidatamab. That said, the data shared today stand out as they represent the first clinical validation of zanidatamab in a front-line setting. As we embark on our second pivotal trial and prepare for commercialization, these data represent a landmark moment for zanidatamab and for Zymeworks,” Tehrani concluded.

Clinical trials
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
Trial of ZW25 (Zanidatamab) in Patients With Advanced HER2-expressing Cancers – NCT02892123
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]

[1] 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]

Featured Image: Zymeworks’ detailed understanding of protein dynamics helps the company’s research scientists to profile protein hotspots and refine protein engineering approaches. Photo Courtesy:  © 2016 – 2021 Zymeworks. Used with permission.


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