HERIZON-GEA-01 Results Indicate Potential 1L Use of Zanidatamab for Gastroesophageal Adenocarcinoma

From among the 3 experimental arms in the phase 3 HERIZON-GEA-01 trial (NCT05152147) for patients fighting HER2-positive advanced or metastatic gastric and esophageal adenocarcinoma (mGEA), the 2 arms containing zanidatamab continue to post superior first-line results vs the comparator arm containing trastuzumab. This is according to the first trial results being presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.¹

“Despite recent advances, many patients with metastatic gastroesophageal adenocarcinoma still experience disease progression within a year of treatment,” said Rachna Shroff, MD, MS, FASCO, associate director of clinical investigations and coleader of the gastrointestinal clinical research team, University of Arizona Cancer Center, in a statement.² “These are practice-changing results that offer a new treatment option for patients with HER2-positive upper GI cancers.”

HERIZON-GEA-01 is an international randomized, multicenter, open-label phase 3 study comparing the safety and effectiveness of the bispecific monoclonal antibody zanidatamab plus physician’s choice of chemotherapy, with and without the immune checkpoint inhibitor tislelizumab, against the HER2 inhibitor trastuzumab plus physician’s choice of chemotherapy.³ The 4 chemotherapies are capecitabine plus oxaliplatin (CAPOX) and 5-fluorouracil (5-FU) plus cisplatin (FP). The primary outcomes are progression-free survival (PFS) by blinded independent central review, as measured by time from randomization to date of documented disease progression or any-cause death, and overall survival (OS), as measured by time from randomization to any-cause death. The 14 secondary outcomes of interest include confirmed objective response rate, duration of response per investigator assessment, incidence of adverse events, health-related quality of life, and serum concentration of zanidatamab and tislelizumab.

Between December 2021 and February 2025, patients were randomized 1:1:1 to receive zanidatamab 1800 mg (if weighing < 70 kg) or 2400 mg (≥ 70 kg) plus tislelizumab 200 mg, both administered intravenously every 3 weeks, plus CAPOX or FP (n = 302); zanidatamab plus CAPOX or FP (n = 304); or trastuzumab plus CAPOX or FP (n = 308). The median follow-up was 26 months. To qualify for inclusion, patients had to be 18 years or older; have unresectable, locally advanced, or metastatic GEA; be HER2-positive via immunohistochemistry; have an Eastern Cooperative Oncology Group performance status of 0 or 1; be treatment naive for locally advanced/metastatic disease; and be treatment naive for HER2-targeted treatment and immunotherapy.

Median PFS (mPFS) was 53% longer in both zanidatamab arms compared with the trastuzumab arm, and 18-month PFS was 82% and 110% longer with and without tislelizumab, respectively:

• Zanidatamab with tislelizumab and chemo:
  • mPFS: 12.4 months (95% CI, 9.8-18.5), for a 37% reduced risk of disease progression or death (HR, 0.63; 95% CI, 0.51-0.78; P < .0001)
  • 18-month PFS: 43.9%
• Zanidatamab and chemo:
  • mPFS: 12.4 months (95% CI, 9.8-14.5), for a 35% reduced risk of disease progression or death (HR, 0.65; 95% CI, 0.52-0.81; P < .0001)
  • 18-month PFS: 38.0%
• Trastuzumab and chemo:
  • mPFS: 8.1 months (95% CI, 7.0-8.9)
  • 18-month PFS: 20.9%

Median OS (mOS) was also superior in both zanidatamab arms, by 37.5% and 27.1%, compared with the trastuzumab arm, as was 24-month OS, by 39.9% and 29.6%:

• Zanidatamab with tislelizumab and chemo:
  • mOS: 26.4 months (95% CI, 21.5-30.3), for a 28% lessened risk (HR, 0.72; 95% CI, 0.57-0.90; P = .0043)
  • 24-month OS: 54.3%
• Zanidatamab and chemo:
  • mOS: 24.4 months (95% CI, 20.4-30.0), for a 20% lessened risk (HR, 0.80; 95% CI, 0.64-1.01; P = .0564)
  • 24-month OS: 50.3%
• Trastuzumab and chemo:
  • mOS: 19.2 months (95% CI, 16.8-21.8)
  • 24-month OS: 38.8%

Partial and complete response rates, indicating antitumor activity, were as follows⁴:

• Zanidatamab with tislelizumab and chemo: 51.1% and 19.6%, respectively
• Zanidatamab and chemo: 52.5% and 17.1%
• Trastuzumab and chemo: 54.8% and 11.0%

HERIZON-GEA-01 is the first phase 3 study to evaluate first-line zanidatamab, and approximately 20% of people who have mGEA also have HER2-positive disease, making these results especially significant.² These patients’ survival is also dismal, with only 5% to 7% surviving out to 5 years after diagnosis. Phase 2 studies have already shown the potential of zanidatamab with and without tislelizumab plus chemo to slow the progression of mGEA.²

Overall, grade 3 and higher adverse events (AEs) were seen more often in the zanidatamab/tislelizumab/chemo arm vs the trastuzumab arm (71.8% vs 59.5%), while in the zanidatamab/chemo arm, the rate was slightly lower (59.0%).¹ The most common AEs in the zanidatamab arms were diarrhea, hypokalemia, and anemia, and in the trastuzumab arm, diarrhea, anemia, decreased neutrophil count, and decreased platelet count. Treatment discontinuation rates were slightly higher in the zanidatamab arms vs the trastuzumab arm (11.9%, with tislelizumab; 8.5%, without tislelizumab; 2.3%, tislelizumab).

“This is the first phase 3 trial to demonstrate a benefit for a novel HER2-targeted therapy compared to trastuzumab as part of a combination regimen in HER2-positive first-line treatment for these patients,” said lead study author Elena Elimova, MD, of Princess Margaret Cancer Centre in Toronto, Canada.

Zanidatamab is currently approved by the FDA under its accelerated approval pathway for adults with previously treated, unresectable or metastatic HER2-positive biliary tract cancer.⁵

References

1. 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. Presented at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 8-10, 2026; San Francisco, CA. Abstract LBA285.
2. Zanidatamab and chemotherapy can slow cancer growth, extend survival in some people with gastroesophageal adenocarcinoma. News release. American Society of Clinical Oncology. January 6, 2026. Accessed January 7, 2026. https://www.asco.org/about-asco/press-center/news-releases/zanidatamab-and-chemotherapy-can-slow-cancer-growth
3. 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 December 17, 2025. Accessed January 7, 2026. https://www.clinicaltrials.gov/study/NCT05152147
4. 2026 ASCO Gastrointestinal Cancers Symposium embargoed pre-meeting press briefing. ASCO. January 5, 2026. Accessed January 7, 2026. https://asco1.sharefile.com/share/view/94250e3840db49f4/fod93314-94ef-46b1-8f14-723c8103f6b1
5. Santoro C. FDA approves zanidatamab-hrii for HER2+ biliary tract cancer. AJMC^®. November 21, 2024. Accessed January 7, 2026. https://www.ajmc.com/view/fda-approves-zanidatamab-hrii-for-her2-biliary-tract-cancer