Gastroesophageal adenocarcinomas are challenging to treat. These cancers make up most tumors of the esophagus, stomach, and esophageal junction (where the esophagus and stomach connect). But a newly approved targeted therapy offers hope for patients with tumors that can’t be surgically removed and that also carry high levels of a protein called HER2.
The drug, called zanidatamab (Ziihera®), was approved by the U.S. Food and Drug Administration (FDA) as an additional medication for newly diagnosed patients who are getting chemotherapy. Patients may receive another drug called tislelizumab (Tevimbra®) at the same time.
“These combination treatments offer hope for patients with this aggressive disease,” says gastrointestinal medical oncologist Geoffrey Ku, MD, of Memorial Sloan Kettering Cancer Center (MSK). “For patients with HER2-positive cancers of the esophagus, gastroesophageal junction, and stomach, the combination of zanidatamab and chemotherapy — with or without the immunotherapy drug tislelizumab — improves outcomes compared with older therapies.”
Dr. Ku was senior author of the phase 2 trial of zanidatamab, published in Lancet Oncology, and served on the Steering Committee for the phase 3 trial, which resulted in the drug’s approval on August 25, 2026.
What is zanidatamab and how does it work?
Zanidatamab previously received accelerated approval to treat bile duct cancer (cholangiocarcinoma) and other cancers of the biliary tract. This approval was also based on studies led by MSK researchers.
The drug targets a protein called HER2, which is found at abnormally high levels in about 20% to 25% of gastroesophageal adenocarcinomas. This protein is also found at high levels in other cancers, including breast cancer and lung cancer. These cancer cells require HER2 to survive.
Zanidatamab belongs to a class of drugs called bispecific antibodies, and it works differently from older drugs that target HER2. Rather than attaching to the HER2 protein at a single point, it binds in two different places at the same time.
This dual grip does more than just prevent the protein from sending out the signals that cancer cells need to grow and spread: It also causes zanidatamab to bind to two different HER2 molecules, which reduces their ability to drive cancer cell growth. At the same time, this unique binding also enhances the immune system’s ability to recognize and attack the cancer cells.
What did clinical trials of zanidatamab show?
The phase 3 trial that led to zanidatamab’s approval enrolled more than 900 patients.
- About one-third received a combination of zanidatamab, tislelizumab, and platinum chemotherapy.
- Another third received zanidatamab and chemotherapy.
- The final third received chemotherapy and trastuzumab, an older drug that targets HER2.
After an average follow-up of more than two years, the study found:
- Disease progression was delayed by more than four months in patients taking either of the drug combinations that included zanidatamab — 12.4 months versus 8.1 months for those who did not take zanidatamab.
- Patients who took a combination of zanidatamab and tislelizumab lived about seven months longer — an average of 26.4 months compared with 19.2 months on standard treatment.
This study built on the findings from the phase 2 trial led by Dr. Ku, which found that the treatment was safe when combined with chemotherapy and that tumors shrank in more than three-quarters of patients.
Side effects from zanidatamab combination treatment
The most common side effect for patients in the zanidatamab clinical trials was diarrhea.
For most patients, that could be managed with anti-diarrhea medications and by lowering the dose of chemotherapy. Fewer than 5% of patients had to stop taking zanidatamab because of diarrhea.
Dr. Ku says it’s important for patients to let their medical team know when they are experiencing this or any other side effect while receiving this treatment.
HER2 testing is important for patients with gastroesophageal adenocarcinoma
Dr. Ku notes that, because zanidatamab benefits patients with HER2-positive cancer, this FDA approval reinforces the importance of doing molecular testing of patients’ tumors at the time they are diagnosed.
“Because we have had other drugs that target HER2, even prior to this approval, HER2 testing is something that we’ve been doing at MSK for more than 15 years,” he says. “Now that zanidatamab can be given to patients as a first treatment, there is even more reason that HER2 testing must be a standard part of the clinical workup right from the beginning.”
Funding and disclosures
The zanidatamab clinical trials were funded by Jazz Pharmaceuticals and Zymeworks, the companies that developed the drug.
Dr. Ku receives consulting fees as well as research support from Jazz Pharmaceuticals and Zymeworks.
Key Takeaways
- The FDA has approved zanidatamab (Ziihera®) as a first treatment for patients newly diagnosed with HER2-positive advanced cancers of the esophagus, gastroesophageal junction, and stomach.
- Zanidatamab works differently from other HER2-targeting drugs: It binds to the HER2 protein in two places at once, leading to stronger activity than older anti-HER2 treatments.
- In the phase 3 trial that led to the drug’s approval, those who received zanidatamab and tislelizumab lived an average of 26.4 months compared with 19.2 months for those on standard treatment — a difference of more than seven months.
- Diarrhea is a common side effect of zanidatamab, but it is manageable for most patients.
- Because zanidatamab only benefits patients whose tumors carry high levels of the HER2 protein, molecular testing at the time of diagnosis is essential and should be a standard part of the clinical workup.