The U.S. Food and Drug Administration (FDA) approved two new first-line treatment regimens incorporating the HER2-targeted antibody zanidatamab-hrii (Ziihera) for adults with previously untreated, unresectable locally advanced or metastatic HER2-positive adenocarcinoma of the stomach, gastroesophageal junction, or esophagus. Announced on August 25, 2026, the approvals provide critical alternatives for patients whose tumors cannot be removed surgically or have spread throughout the body.
FDA Approves Zanidatamab Combinations for Advanced HER2-Positive Gastrointestinal Cancers
The regulatory action establishes two distinct treatment protocols based on the level of HER2 expression in the tumor. The first approval authorizes a four-drug combination consisting of zanidatamab-hrii, the PD-1 inhibitor immunotherapy tislelizumab-jsgr (Tevimbra), a fluoropyrimidine-based chemotherapy, and a platinum-based chemotherapy. This regimen is cleared for patients whose tumors test HER2-positive as either IHC 3+ or IHC 2+/ISH+ using an FDA-approved test.
The second approval clears zanidatamab paired solely with fluoropyrimidine- and platinum-containing chemotherapy—omitting tislelizumab—specifically for patients whose tumors fall into the highest HER2-expression category of IHC 3+. HER2 is a protein that drives cancer cell proliferation, making its identification essential for selecting targeted therapies.
Clinical Trial Results Show Extended Survival and Delayed Disease Progression
The approvals stem from data gathered in the phase 3 HERIZON-GEA-01 clinical trial, which evaluated patients diagnosed with HER2-positive advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma. Investigators compared the four-drug regimen containing zanidatamab, tislelizumab, and chemotherapy against the historical standard of care, which combined trastuzumab with chemotherapy.
Patients receiving the zanidatamab, tislelizumab, and chemotherapy combination achieved a median overall survival of 26.4 months, compared to 19.2 months for those treated with trastuzumab and chemotherapy. The four-drug combination also delayed cancer growth and spread, yielding a median progression-free survival of 12.4 months versus 8.1 months for the control arm.
For patients restricted to the two-drug zanidatamab and chemotherapy regimen due to IHC 3+ tumor status, median progression-free survival reached 14.2 months, compared with 7.6 months for trastuzumab plus chemotherapy. However, overall survival results for this specific two-treatment approach did not reach statistical significance at the time of the primary analysis.
Pharmacology, Dosing Schedules, and Administration Protocols
Zanidatamab functions as a HER2-targeted monoclonal antibody administered intravenously to bind directly to HER2 receptors on cancer cells. Tislelizumab operates as an intravenous PD-1 inhibitor designed to release immune system brakes so that T-cells can recognize and destroy malignant cells.
The chemotherapy backbone typically incorporates a fluoropyrimidine—such as capecitabine or fluorouracil—paired with a platinum drug like oxaliplatin. Treatment intervals vary according to patient body weight and the specific regimen chosen. Zanidatamab administration occurs every two or three weeks, while tislelizumab infusions may be scheduled every two, three, four, or six weeks.
Boxed Warnings, Immune-Related Toxicities, and Patient Monitoring
Selecting an appropriate oncology regimen requires evaluating individual tumor characteristics, overall health status, prior treatments, and personal care goals. Zanidatamab carries a boxed warning flagging risks of severe diarrhea and potential fetal harm during pregnancy. Other notable adverse events associated with zanidatamab include left ventricular dysfunction impacting heart function and infusion-related reactions.
Tislelizumab carries risks for immune-related adverse reactions, wherein an activated immune system attacks healthy tissues across the lungs, intestines, liver, endocrine glands, skin, and kidneys. It can also cause infusion reactions and fetal harm. The oncology care team advises patients to report new or worsening symptoms immediately, including persistent diarrhea, chest discomfort, shortness of breath, fever, skin rashes, abdominal pain, yellowing of the skin or eyes, unexplained fatigue, or sudden changes in bowel habits.
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