Zanidatamab Poised to Redefine First-Line Care in HER2+ Gastroesophageal Cancer

Advanced gastroesophageal adenocarcinoma (GEA) with HER2 positivity has long presented significant treatment challenges, with first-line therapies offering limited survival benefits despite advances including the addition of immune checkpoint inhibitors.

The HERIZON-GEA-01 trial (NCT05152147) was thus initiated to address the unmet need for more effective HER2-targeted treatments in this patient population, especially given the lack of approved first-line HER2 therapies for esophageal cancer. The ongoing randomized phase 3 study is evaluating zanidatamab (Ziihera), a novel HER2-directed antibody, in combination with chemotherapy with or without tislelizumab (Tevimbra) against a standard trastuzumab (Herceptin)-based regimen.¹

Interim data from the trial, toplined this past month at the 2026 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, revealed significantly extended progression-free survival (PFS) and overall survival (OS) with the zanidatamab-based regimens, topping the standard of care and marking the longest survival reported to date in this setting.²

In an interview with Targeted Oncology following the symposium, Elena Elimova, MD, staff medical oncologist at Princess Margaret Hospital and associate professor in the Department of Medicine at the University of Toronto, delved into the practice-changing results of the HERIZON-GEA-01 trial and their promise to set zanidatamab-based regimens as the new frontline standard.

Targeted Oncology: What are some of the unmet needs in this patient population that prompted the HERIZON-GEA-01 trial?

Elena Elimova, MD: For more than a decade, first-line treatment for HER2-positive advanced gastroesophageal adenocarcinoma (GEA) has relied on platinum-based chemotherapy plus trastuzumab, and more recently the addition of pembrolizumab [Keytruda] for the subset of patients with PD-L1–positive tumors. Even with these advances, outcomes have remained modest, with median [PFS] of around 8 [to] 10 months and median [OS] of approximately 17 [to] 20 months.

There is therefore an urgent unmet need for novel HER2-directed strategies to improve outcomes for all patients with HER2-positive GEA, including cancers of the stomach, gastroesophageal junction and esophagus. Currently, no HER2-targeted therapy is approved for the first-line treatment of esophageal cancer. HERIZON-GEA-01 was designed to address this gap by evaluating whether a novel HER2-targeted antibody, zanidatamab, could lead to clinically meaningful outcomes compared with the trastuzumab-based standard in the first-line setting.

What were the key efficacy/safety findings in this latest report, and what is the clinical significance of these findings?

HERIZON-GEA-01 is the first phase 3 study to demonstrate that a novel HER2-targeted antibody can significantly outperform trastuzumab in the first-line treatment of HER2-positive advanced GEA. Both zanidatamab-based combinations produced a statistically significant and clinically meaningful improvement in [PFS], with median PFS exceeding 1 year, representing more than a 4-month absolute benefit and an approximately 35% reduction in the risk of progression or death.

Zanidatamab in combination with tislelizumab and chemotherapy achieved a median OS beyond 2 years, with more than half of patients alive at 2 years and a 28% reduction in the risk of death compared with trastuzumab plus chemotherapy. This corresponds to a greater than 7-month improvement in median OS and represents the longest survival reported to date in a phase 3 trial in this setting.

The benefits were consistent across major subgroups, including across PD-L1 expression, although these analyses are hypothesis-generating. The safety profile was in line with the known profiles of HER2-targeted therapy, chemotherapy, and immunotherapy, with no new safety signals. Taken together, these phase 3 data are practice changing and support zanidatamab-based combinations as a potential new standard of care, representing the first randomized evidence of superiority over a trastuzumab-based regimen in first-line HER2-positive GEA.

Diarrhea was noted as the most common treatment-related adverse event. What would be the appropriate protocol for providers in community/frontline settings to effectively manage such toxicities?

Diarrhea is a known toxicity of both HER2-directed antibodies and fluoropyrimidine- and platinum-based chemotherapy. In HERIZON-GEA-01, diarrhea occurred early, most commonly during the first cycle, and generally resolved within about 3 weeks. Importantly, patients receiving zanidatamab received mandatory prophylaxis with loperamide, 4 mg twice daily for the first 7 days of cycle 1.

With proactive prophylaxis, early recognition, and prompt supportive care, most events were manageable and rarely led to discontinuation, even with longer treatment exposure in the zanidatamab arms. Work is ongoing to provide clear guidance to clinicians to support optimal management in routine practice.

Based on these interim data, what are you most looking forward to confirming with additional follow-up?

With longer follow-up, we are particularly interested in confirming the durability of the OS benefit, especially for the zanidatamab plus chemotherapy arm, where OS data were still immature but showed a favorable trend at the first interim analysis. An additional planned interim analysis in 2026 will be important to further define this benefit.

We also look forward to deeper characterization of long-term outcomes, including objective response rate and duration of response, to better understand the depth and durability of benefit and to further support zanidatamab-based combinations as a foundational first-line approach for patients with HER2-positive advanced GEA.

REFERENCES

1. 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 January 26, 2026. https://www.clinicaltrials.gov/study/NCT05152147

2. Elimova E, Rha SY, Shitara K, et al. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): primary analysis from HERIZON-GEA-01. J Clin Oncol. 2026, 44(suppl 4):LBA285.doi:10.1200/JCO.2026.44.2_suppl.LBA285