Zanidatamab Produces Survival Benefits in HER2+ Gastroesophageal Cancer

According to an update from the phase 3 HERIZON-GEA-01 trial (NCT05152147), zanidatamab-hrii (Ziihera) plus chemotherapy with or without tislelizumab (Tevimbra) yielded promising survival benefits in patients with HER2-positive (HER2+) locally advanced or metastatic gastroesophageal adenocarcinoma (GEA), supporting potential first-line use.¹

Top-line data show that zanidatamab plus chemotherapy produced statistically significant and clinically meaningful improvements in progression-free survival (PFS) vs trastuzumab (Herceptin) and chemotherapy. With tislelizumab, the combination also demonstrated improvements in both PFS and overall survival (OS) compared with the control arm.

With or without tislelizumab, the combination also performed well in terms of secondary end points, showing improvements in objective response rate (ORR) and duration of response (DOR) vs the control arm.

Along with the encouraging efficacy findings, the safety of the combination with or without tislelizumab was consistent with the established safety profiles of each agent, with no new signals observed in either investigational combination arm.

These promising data align with findings from a previous phase 2 trial (NCT03929666) evaluating zanidatamab combined with chemotherapy in patients with HER2+ advanced GEA, in which the regimen demonstrated durable antitumor activity (confirmed ORR, 75%; 95% CI, 55.1%-89.3%; median DOR, 16.4 months; 95% CI, 1.4-19.8+) and manageable safety.^2,3 These new phase 3 results will be submitted imminently for presentation at a medical meeting in early 2026 and for publication in a peer-reviewed journal.

“The topline results from HERIZON-GEA-01 represent a true turning point for patients with HER2+ [GEA], marking real progress in an indication that has historically had limited treatment options and poor outcomes,”  Kenneth Galbraith, chair and CEO of Zymeworks, said in a news release.¹ “These data highlight the potential of zanidatamab to transform the standard of care in HER2+ 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 [Pharmaceuticals] and BeOne [Medicines] in bringing this critical therapy to patients worldwide.”

About Zanidatamab

Zanidatamab, a HER2-targeted bispecific antibody, was granted accelerated approval by the FDA in second-line HER2+ biliary tract cancer (BTC) in November 2024 after receiving priority review. This decision was supported by the phase 2b HERIZON-BTC-01 trial (NCT04466891), which showed durable and sustained responses to zanidatamab as monotherapy in a pretreated patient population. One month later, the National Comprehensive Cancer Network (NCCN) incorporated zanidatamab into its guidelines as a category 2A recommended treatment option for BTC, further establishing its position as standard of care for the indication.

With previous orphan drug and fast track designations for GEA treatment,¹ these latest results from HERIZON-GEA-01 underscore the potential of the zanidatamab combination therapy to become the next standard of care in GEA. As such, the sponsor plans to submit a supplemental biologics license application in the first half of 2026, which, if approved, would expand zanidatamab’s application to its second gastrointestinal cancer indication. As was done for BTC, the sponsor also plans to seek inclusion of these results in future updates to the NCCN guidelines.

HERIZON-GEA-01 Trial Design

The phase 3 HERIZON-GEA-01 trial is a global, randomized, multicenter study evaluating zanidatamab in combination with chemotherapy, with or without the PD-1 inhibitor tislelizumab, in untreated patients with HER2+ unresectable, locally advanced, or metastatic adenocarcinoma of the stomach, gastroesophageal junction, or esophagus.^3,4

The study’s co–primary end points are PFS and OS; secondary end points include confirmed ORR and DOR per blinded independent central review and investigator assessment, safety, changes in health-related quality of life, pharmacokinetics, and frequency and duration of anti-zanidatamab and anti-tislelizumab antibodies.

The study has enrolled 920 adult patients who have been assigned to either 1 of 2 investigational arms or a comparator arm. One investigational arm received intravenous (IV) zanidatamab plus chemotherapy with tislelizumab, while the other received the zanidatamab combination without tislelizumab. In the comparator arm, patients received IV trastuzumab plus chemotherapy.

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. November 17, 2025. Accessed November 17, 2025. https://tinyurl.com/8bj4dmnt

2. Elimova E, Ajani J, Burris H, et al. Zanidatamab plus chemotherapy as first-line treatment for patients with HER2-positive advanced gastro-oesophageal adenocarcinoma: primary results of a multicentre, single-arm, phase 2 study. Lancet Oncol. 2025;26(7):847-859. doi:10.1016/s1470-2045(25)00287-6

3. Tabernero J, Shen L, Elimova E, et al. HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma. Future Oncol. 2022;18(29):3255-3266. doi:10.2217/fon-2022-0595

4. 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://www.clinicaltrials.gov/study/NCT05152147