Clinical data for the HER2‑targeted bispecific antibody zanidatamab in combination with docetaxel (Taxotere®; Sanofi) shows a 90.5% confirmed Objective Response Rate (cORR) in first-line treatment of advanced HER2-positive breast cancer. Furthermore, in combination with chemotherapy and tislelizumab (BGB-A317; BeiGene), zanidatamab (ZW25; Zymeworks) demonstrated a 75.8% cORR and 100% disease control rate (DCR) in first-line treatment of advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma. [1][2]

This data was being presented in two separate poster sessions at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 3-7, 2022 in Chicago, IL.

Zanidatamab is a bispecific antibody, based on Zymeworks’ Azymetric™ technology platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding, and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients.

Clinical development
“These encouraging new data sets presented at ASCO provide further validation of zanidatamab’s potential in the treatment of advanced HER2-positive cancers and follow the release of other promising data in gastroesophageal and breast cancer in 2021,” noted Neil Josephson, M.D., Chief Medical Officer at Zymeworks.

Port Worthy

“These new data continue to demonstrate the potential for zanidatamab to be an important advancement in the treatment of a wide range of HER2-expressing cancers, including in first-line treatment regimens,” Josephson added.

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Gastric cancer
Over one million patients are diagnosed with gastric cancer every year worldwide, and it is the fourth most common cause of cancer-related deaths. [3]

Human epidermal growth factor receptor 2 (HER2)-positive disease accounts for 15–25% of gastric cancers. [4] For these patients, trastuzumab (Herceptin®; Genentech/Roche) in combination with chemotherapy is the global standard of care treatment but with an expected overall survival of less than 18 months, there remains a significant unmet need.

In a clinical study, 33 response-evaluable patients with advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma treated with zanidatamab and tislelizumab in combination with oxaliplatin (Eloxatin®; Sanofi) and capecitabine (Xeloda®; Genentech/Roche),  a chemotherapy combination known as CAPOX (or XELOX) the cORR was 75.8% (25/33). The DCR was 100% (33/33) and duration of response (DOR) ranged from 2.1+ to 18.2+ months. Twenty patients (61%) remain on study at the time of data cut-off.

In addition, the data demonstrate that zanidatamab and tislelizumab in combination with the CAPOX 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; introduction of prophylactic loperamide reduced the incidence from 33% to 21%. Immune mediated adverse events occurred in 27% of patients, including ≥ Grade 3 events in 21% of patients and resulted in discontinuation of tislelizumab in 3 patients (9%). This manageable safety profile compares favorably to the current standard of care as well as to emerging treatments and is consistent with previous reports.[5]

This new data set further supports the launch of Zymeworks’ global Phase 3 study (HERIZON-GEA-01; NCT05152147), which is investigating zanidatamab in combination with chemotherapy with or without tislelizumab for first-line treatment of locally advanced, unresectable, or metastatic HER2-positive gastroesophageal adenocarcinoma.

Zymeworks, along with its Asia-Pacific partner BeiGene, plan to enroll 714 patients at approximately 300 sites across 38 countries. Enrollment is expected to be completed by the end of 2023. The study design will be presented in a Trials in Progress poster (Poster ID: P-26) at the European Society of Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer taking place in Barcelona, Spain from June 29-July 2, 2022.

Breast cancer
Preliminary results from a Phase 1b/2 study shows that zanidatamab in combination with docetaxel (Taxotere®; Sanofi) also demonstrated positive results as first-line therapy for patients with advanced HER2-positive breast cancer.

Worldwide, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in women, with over 650,000 deaths in 20201.[6] HER2-positive breast cancer accounts for approximately 20% of all breast cancers. [7][8][9] Though HER2-targeted agents have improved outcomes in HER2-positive breast cancer, most patients treated for advanced disease eventually relapse and develop resistant disease. [10][11]

in one clinical study, in 21 response-evaluable patients with advanced HER2-positive breast cancer treated with zanidatamab and docetaxel the cORR was 90.5%, with 15 patients (78.9%) having an ongoing response at the time of the data cut. The median follow-up was 7.0 months (range 1.1-17.4 months) and the six-month progression-free survival rate was 95.2%.

The combination of zanidatamab and docetaxel had a manageable safety profile with the incidence of TRAEs consistent with standard of care therapy. The most common TRAEs were neutrophil count decreased (13 patients; 54.2%), diarrhea (13 patients; 54.2%), and anemia (nine patients; 37.5%), and the most common ≥ Grade 3 TRAEs were neutrophil count decreased (12 patients; 50.0%), diarrhea (3 patients; 12.5%), and white blood cell count decreased (2 patients; 8.3%).

“We will continue to support ongoing R&D efforts to generate and report robust data highlighting and reinforcing the potential applications of our therapeutics and technology platforms in the treatment of a wide range of diseases,” said Kenneth Galbraith, Chair and Chief executive officer of Zymeworks.

“We remain focused on exploring potential research and collaboration opportunities that can lead to a broader portfolio of innovative therapies for patients in need around the world with difficult-to-treat cancers.”

Regulatory development
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).

Zanidatamab received also two Fast Track designations, one as a single agent 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.

In Europe zanidatamab has received Orphan Drug designations for the treatment of biliary tract, gastric and ovarian cancers, from the European Medicines Agency. In addition, zanidatamab received Orphan Drug designation for the treatment of gastric cancer from the European Medicines Agency.

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Clinical trials
A Study of Zanidatamab in Combination With Chemotherapy Plus or Minus Tislelizumab in Patients With HER2-positive Advanced or Metastatic Gastric and Esophageal Cancers (HERIZON-GEA-01) – NCT05152147
Anti-HER2 Bispecific Antibody ZW25 Activity in Combination With Chemotherapy With/Without Tislelizumab – NCT04276493
Trial of ZW25 (Zanidatamab) in Patients With Advanced HER2-expressing Cancers – NCT02892123
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.

Highlights of prescribing information
Docetaxel (Taxotere®; Sanofi)[Prescribing Information]
Trastuzumab (Herceptin®; Genentech/Roche)[Prescribing Information]
Oxaliplatin (Eloxatin®; Sanofi)[Perscription Information]
Capecitabine (Xeloda®; Genentech/Roche) [Prescribing information]

Reference
[1] Lee KS, Wang X, Im YH, Zeng X, Li H, Wang K, Li H, Zhou P, Bao Y, Jiang Z. Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with docetaxel as first-line (1L) therapy for patients (pts) with advanced HER2-positive breast cancer: Preliminary results from a phase 1b/2 study. J Clin Oncol 40, 2022 (suppl 16; abstr 1031) | DOI 10.1200/JCO.2022.40.16_suppl.1031
[2] Lee KW, Bai LY, Jung M, Ying J, Hyuck Im YH, Oh DY, Cho JY, Oh SC, Chao Y, Li H, Zhou P, Bao Y, Kang YK. Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) and tislelizumab (TIS) as first-line (1L) therapy for patients (pts) with advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma (G/GEJC): Preliminary results from a phase 1b/2 study. J Clin Oncol 40, 2022 (suppl 16; abstr 4032) | DOI 10.1200/JCO.2022.40.16_suppl.4032
[3] Globocan 2020. Online Last accesses on June 5, 2022
[4] Nakamura Y, Kawazoe A, Lordick F, Janjigian YY, Shitara K. Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nat Rev Clin Oncol. 2021 Aug;18(8):473-487. doi: 10.1038/s41571-021-00492-2. Epub 2021 Mar 31. PMID: 33790428.
[5] Ku G, Elimova E, Denlinger CS, Mehta R, Lee K-W, Iqbal S, Kang YK, et al. Phase (Ph) II study of zanidatamab + chemotherapy (chemo) in first-line (1L) HER2 expressing gastroesophageal adenocarcinoma (GEA) (Abstract: 1380P) DOI 10.1016/j.annonc.2021.08.1489
[6] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. Erratum in: CA Cancer J Clin. 2020 Jul;70(4):313. PMID: 30207593.
[7] Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr; American Society of Clinical Oncology. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007 Nov 20;25(33):5287-312. doi: 10.1200/JCO.2007.14.2364. Epub 2007 Oct 22. PMID: 17954709.
[8] Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF; American Society of Clinical Oncology/College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131(1):18-43. doi: 10.5858/2007-131-18-ASOCCO. PMID: 19548375.
[9] Giordano SH, Temin S, Kirshner JJ, Chandarlapaty S, Crews JR, Davidson NE, Esteva FJ, Gonzalez-Angulo AM, Krop I, Levinson J, Lin NU, Modi S, Patt DA, Perez EA, Perlmutter J, Ramakrishna N, Winer EP; American Society of Clinical Oncology. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014 Jul 1;32(19):2078-99. doi: 10.1200/JCO.2013.54.0948. Epub 2014 May 5. PMID: 24799465; PMCID: PMC6076031.
[10] Ayoub NM, Al-Shami KM, Yaghan RJ. Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches. Breast Cancer (Dove Med Press). 2019 Jan 17;11:53-69. doi: 10.2147/BCTT.S175360. PMID: 30697064; PMCID: PMC6340364.
[11] Rier HN, Levin MD, van Rosmalen J, Bos MMEM, Drooger JC, de Jong P, Portielje JEA, Elsten EMP, Ten Tije AJ, Sleijfer S, Jager A. First-Line Palliative HER2-Targeted Therapy in HER2-Positive Metastatic Breast Cancer Is Less Effective After Previous Adjuvant Trastuzumab-Based Therapy. Oncologist. 2017 Aug;22(8):901-909. doi: 10.1634/theoncologist.2016-0448. Epub 2017 May 22. PMID: 28533475; PMCID: PMC5553959.

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: © 2017 – 2022 Zymeworks. Used with permission.

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