Zanidatamab-Based Regimens Exhibit Improved PFS in Gastroesophageal Cancers

Zanidatamab plus chemotherapy with or without tislelizumab displayed a significant improvement in the key secondary end points of objective response rate and duration of response vs trastuzumab/chemotherapy in this patient group.

The addition of zanidatamab-hrii (Ziihera) to chemotherapy with or without tislelizumab (Tevimbra) exhibited significantly improved survival outcomes, including progression-free survival (PFS) and overall survival (OS), compared with chemotherapy and trastuzumab (Herceptin) as a frontline treatment for patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma, encompassing cancers of the stomach, gastroesophageal junction, and esophagus, in the phase 3 HERIZON-GEA-01 trial (NCT05152147), according to a news release from the developer, Zymeworks Inc.1

Additionally, findings revealed that a PFS and OS benefit was observed with the investigational combination among PD-L1–positive and PD-L1–negative subgroups. Moreover, zanidatamab plus chemotherapy with or without tislelizumab displayed a significant improvement in the key secondary end points of objective response rate (ORR) and duration of response (DOR) vs trastuzumab/chemotherapy in this patient group.

Furthermore, zanidatamab plus chemotherapy with or without tislelizumab exhibited clinically meaningful and statistically significant improvements in OS, as well as a statistically significant and clinically meaningful improvement in PFS compared with the control arm. An interim analysis for OS assessing zanidatamab and chemotherapy is planned for mid-2026.

“The topline results from HERIZON-GEA-01 represent a true turning point for patients with [HER2-positive] gastroesophageal adenocarcinoma, marking real progress in an indication that has historically had limited treatment options and poor outcomes,” Kenneth Galbraith, chair and chief executive officer of Zymeworks, stated in the news release.1 “These data highlight the potential of zanidatamab to transform the standard of care in [HER2-positive] indications, demonstrate the strength of our Azymetric™ platform to engineer novel and differentiated multifunctional biologics, and reinforce the strategic value of our partnership strategy with Jazz and BeOne in bringing this critical therapy to patients worldwide.”

Patients 18 years and older enrolled in the phase 3 trial had HER2-positive, metastatic disease and were ineligible for treatment with surgery or chemoradiation.2 Patients in the experimental arms were treated with intravenous zanidatamab and chemotherapy, consisting of capecitabine and oxaliplatin (CAPOX) or a fluoropyrimidine-based chemotherapy with 5-fluorouracil and cisplatin (FP), with or without intravenous tislelizumab. Those in the comparator arms received chemotherapy consisting of FP or CAPOX and intravenous trastuzumab.

The primary end points of the trial included PFS per blinded independent review committee and OS. Secondary end points included ORR, DOR, PFS per investigator, safety, and health-related quality of life.

Warnings and precautions in the prescribing information for zanidatamab included left ventricular dysfunction, infusion-related reactions, and diarrhea.3 The most common adverse effects occurring in 20% or more of patients included diarrhea, infusion-related reactions, abdominal pain, and fatigue. Additionally, the recommended dose of the agent is listed as 20 mg/kg intravenously once every 2 weeks.

Jazz Pharmaceuticals, with whom Zymeworks has a strategic partnership, is planning to submit a supplemental biologics license application for zanidatamab plus chemotherapy with or without tislelizumab as a frontline treatment in this patient population in the first half of 2026. Additionally, zanidatamab is currently approved as a second-line monotherapy among patients with biliary tract cancer (BTC) in the US, EU, and China.

Furthermore, the FDA has previously granted breakthrough therapy designation for zanidatamab as a treatment for patients with HER2 amplified BTC, fast track designation for the therapy as a single agent in refractory BTC, and as a combination therapy with chemotherapy for first-line gastroesophageal adenocarcinoma, and orphan drug designation to zanidatamab for the treatment of BTC and gastroesophageal adenocarcinoma. Additionally, zanidatamab previously received orphan drug designation from the European Medicines Agency for the treatment of BTC and gastric cancer.

References

1. Zymeworks announces positive HERIZON-GEA-01 phase 3 results supporting Ziihera® (zanidatamab-hrii) as HER2-targeted agent-of-choice and new standard of care in first-line HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma. News release. Zymeworks Inc. November 17, 2025. Accessed November 17, 2025. https://tinyurl.com/mp2kttre
2. 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). ClinicalTrials.gov. Updated October 22, 2025. Accessed November 17, 2025. https://tinyurl.com/yn39r4wx
3. Ziihera. Prescribing information. Jazz Pharmaceuticals; 2024. Accessed November 17, 2025. https://tinyurl.com/mr3kecp7