HER2-Targeted Antibody ZW25 Earns FDA Fast Track Designation in GEA

The novel bispecific antibody ZW25 has been granted a fast track designation by the FDA for the treatment of patients with HER2-overexpressing gastroesophageal adenocarcinoma to be used in combination with standard-of-care chemotherapy.

The novel bispecific antibody ZW25 has been granted a fast track designation by the FDA for the treatment of patients with HER2-overexpressing gastroesophageal adenocarcinoma (GEA) to be used in combination with standard-of-care chemotherapy.1

The FDA grants this designation to agents with superior efficacy over what is available or that will serve a patient population for which there are no approved therapies, thereby fulfilling an unmet need. The goal is to accelerate patient access to life-changing disease treatments.

“While major advances have been made in the treatment of HER2-positive breast cancer, patients with HER2-positive gastroesophageal adenocarcinomas still have limited options,” Diana Hausman, MD, chief medical officer of Zymeworks, the company developing ZW25, said in a statement. “Based on the encouraging single-agent, antitumor activity we observed in patients with gastroesophageal adenocarcinomas in our phase I study, we believe that ZW25 has the potential to address this need, and we are excited to be starting this first-line trial.”

ZW25 is currently being investigated in a multicenter, open-label phase II clinical trial to study the safety, tolerability, and antitumor activity of the agent added to chemotherapy in the frontline setting for patients with HER2-positive unresectable, locally advanced, recurrent, or metastatic GEA (NCT03929666). Physician’s choice of combination chemotherapy will include capecitabine and cisplatin; fluorouracil (5-FU), leucovorin, and cisplatin; or 5-FU, leucovorin, and oxaliplatin (mFOLFOX6) in 1 of 3 arms.

Patients in the trial are enrolled into 2 parts with HER2-expressing patients in the first part, which will test varying doses of ZW25 with a focus on dose-limiting toxicities and safety to determine the maximum-tolerated dose. Patients with HER2-high GEA in phase 2 will be given the recommended dose and the primary endpoint of the phase is objective response rate.

The agent was designed using the Azymetric bispecific platform, which transforms monospecific antibodies into bispecific antibodies. The ZW25 antibody is biparatopic, or capable of binding 2 HER2 epitopes: ECD4, the trastuzumab (Herceptin) binding domain, and ECD2, the pertuzumab (Perjeta) binding domain. The unique binding of ZW25 allows additional mechanisms of action such as increased tumor-cell binding and HER2 receptor clustering.2

Results of a phase I study of ZW25 were presented at the American Society of Clinical Oncology 2018 Annual Meeting, in which patients with HER2-expressing cancer that progressed after standard-of-care therapies—including trastuzumab, pertuzumab, and T-DM1 (trastuzumab emtansine; Kadcyla) in breast cancer and trastuzumab in gastroesophageal cancer—were evaluated to determine the agent’s maximum-tolerated dose, overall safety, and tolerability.

Based on 22 patients assessed with a 3+3 dose escalation, it was determined that 10 mg/kg weekly or 20 mg/kg every 2 weeks would be explored. There were no dose-limiting toxicities.

At the data cutoff of April 18, 2018, there were 42 patients enrolled on the trial. Thirteen of those had gastroesophageal cancer with a median of 4 prior systemic therapy regimens including trastuzumab in all patients.

Responses to single-agent ZW25 were most promising in gastroesophageal cancers over other cancers evaluated in the cohort, with a partial response observed in 4 patients (44%) and stable disease in 1 (12%), for a disease-control rate of 56%. Four patients (44%) experienced progressive disease.

The most common treatment-emergent adverse events (TRAEs) in the entire cohort were infusion reaction (55%), fatigue (38%), diarrhea (52%), and nausea (26%). TRAEs were all grade 1/2 except for in 1 patient who had reversible grade 3 hypophosphatemia, arthralgia, and fatigue. There were no serious AEs or discontinuations related to treatment.


  1. Zymeworks’ lead asset, ZW25, granted Fast Track designation from the FDA [news release]. Vancouver, BC; Zymeworks Inc.: May 29, 2019. https://bit.ly/2Mt6iJQ. Accessed May 30, 2019.
  2. Meric-Bernstam F, Beeram M, Mayordomo JI, et al. Single agent activity of ZW25, a HER2-targeted bispecific antibody, in heavily pretreated HER2-expressing cancers.J Clin Oncol. 2018; 36(suppl 15;abstr 2500). doi: 10.1200/JCO.2018.36.15_suppl.2500.