FDA Approves Zanidatamab Combinations for First-Line HER2+ Advanced GEA

The FDA has approved zanidatamab-hrii (Ziihera) plus tislelizumab-jsgr (Tevimbra) and chemotherapy, as well as zanidatamab-hrii plus chemotherapy alone, for the first-line treatment of adults with unresectable locally advanced or metastatic HER2-positive gastroesophageal adenocarcinoma (GEA), regardless of PD-L1 status.^1,2The approval is based on results from the phase 3 HERIZON-GEA-01 trial (NCT05152147), which showed a median overall survival (OS) of 26.4 months with the triplet regimen vs 19.2 months with trastuzumab (Herceptin) plus chemotherapy—the longest median OS reported in a phase 3 trial in this setting.

Both zanidatamab-containing regimens significantly improved progression-free survival (PFS) in the overall HER2-positive population, reducing the risk of disease progression or death by 35% and extending median PFS to 12.4 months vs 8.1 months with trastuzumab plus chemotherapy. The triplet combination also reduced the risk of death by 28% compared with the control arm. PFS and OS benefits were generally consistent across major prespecified subgroups, including geographic region and PD-L1 status.

HERIZON-GEA-01 Design and Regulatory History

HERIZON-GEA-01 is a global, randomized, open-label phase 3 trial that compared zanidatamab plus chemotherapy, with or without tislelizumab, against trastuzumab plus chemotherapy as first-line treatment for adults with HER2-positive locally advanced or metastatic GEA, including cancers of the stomach, gastroesophageal junction, and esophagus. Patients were randomized 1:1:1 and enrolled regardless of PD-L1 status; HER2 positivity (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) was confirmed centrally. Results were first presented at the 2026 Gastrointestinal Cancers Symposium and later published in The New England Journal of Medicine.³

The FDA accepted the supplemental biologics license application under its Real-Time Oncology Review program and granted priority review in April 2026, setting a Prescription Drug User Fee Act target action date of August 25, 2026.⁴ Zanidatamab previously received accelerated approval in November 2024 for adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer, making today's decision the drug's second FDA approval in under 2 years.⁵ The agent has also received 3 FDA breakthrough therapy designations, 2 fast track designations, and multiple orphan drug designations across its development program.¹

"This approval is a major step forward for people with HER2+ advanced GEA. [Zanidatamab] is now the first and only bispecific HER2-targeted antibody combined with a PD-1 inhibitor and chemotherapy approved for all HER2+ advanced GEA patients, regardless of PD-L1 status, establishing a new standard of care in first-line treatment,” saidRob Iannone, MD, MSCE, executive vice president, global head of research and development, and chief medical officer, Jazz Pharmaceuticals, in a news release.²

"Similar outcomes were seen in patients whose tumors were PD-L1 positive or PD-L1 negative, suggesting that this regimen has the potential to benefit a broad range of patients. It further underscores what we have known for more than 15 years: HER2 testing at the time of diagnosis for advanced or metastatic gastroesophageal adenocarcinoma is critical to optimally guide treatment selection,” added Geoffrey Ku, MD, HERIZON-GEA-01 study co-author and associate attending physician, Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, in a news release.

Safety Profile

The prescribing information carries boxed warnings for diarrhea and embryo-fetal toxicity. In the triplet arm, diarrhea occurred in 83% of patients (grade 3, 24%; grade 4, 2.1%), leading to permanent discontinuation in 3.9% of patients; in the doublet arm, diarrhea occurred in 79% of patients (grade 3, 20%; grade 4, 1.3%), with discontinuation in 1.8%. Loperamide prophylaxis is required during cycle 1 for patients receiving zanidatamab with chemotherapy, with or without tislelizumab.¹

Decreases in left ventricular ejection fraction occurred in 9% of patients in the triplet arm and 5% in the doublet arm; infusion-related reactions occurred in 22% and 24% of patients, respectively. The most common adverse reactions (≥20%) with the triplet regimen were diarrhea, nausea, decreased appetite, vomiting, hypokalemia, fatigue, rash, peripheral neuropathy, and infusion-related reactions.

REFERENCES

1. FDA approves zanidatamab-hrii and tislelizumab-jsgr for HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma. News release. US FDA. August 25, 2026. Accessed August 25, 2026. https://tinyurl.com/2hceyypc

2. Jazz Pharmaceuticals plc announces FDA approval of Ziihera (zanidatamab-hrii) with and without tislelizumab plus chemotherapy in first-line HER2+ advanced gastroesophageal adenocarcinoma. News release. Jazz Pharmaceuticals. August 25, 2026. Accessed August 25, 2026. https://tinyurl.com/2p8xajtz

3. Shitara K, Elimova E, Liu T, et al. Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. N Engl J Med. 2026;394(20):2002-2014. doi:10.1056/NEJMoa2517729

4. Jazz Pharmaceuticals announces FDA acceptance and priority review of supplemental biologics license application for Ziihera (zanidatamab-hrii) combinations in first-line HER2+ locally advanced or metastatic GEA. News release. Jazz Pharmaceuticals. April 27, 2026. Accessed August 25, 2026. https://tinyurl.com/3pp29pnk

5. Jazz Pharmaceuticals announces U.S. FDA approval of Ziihera (zanidatamab-hrii) for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC). News release. Jazz Pharmaceuticals. November 20, 2024. Accessed August 25, 2026. https://tinyurl.com/na4a2mz7