FDA Approves Ziihera Combinations for First-Line Treatment of HER2-Positive Gastroesophageal Cancer

The U.S. Food and Drug Administration (FDA) has approved two treatment combinations containing Ziihera (zanidatamab-hrii) for adults with unresectable, locally advanced or metastatic HER2-positive gastroesophageal adenocarcinoma (GEA).

The approval includes Ziihera in combination with Tevimbra (tislelizumab-jsgr) and chemotherapy for certain patients with HER2-positive disease, as well as Ziihera plus chemotherapy for patients whose tumors are strongly HER2-positive.

Gastroesophageal adenocarcinoma includes cancers that start in the stomach, the area where the stomach and esophagus meet, or the esophagus. About 20% of people with these cancers have tumors that are HER2-positive, meaning their cancer cells have higher-than-normal levels of a protein called HER2 that can help cancer cells grow.

What Does the Ziihera Approval Mean for Patients?

The FDA approval gives people with advanced HER2-positive gastroesophageal cancer additional options for their initial, or first-line, treatment.

The Ziihera, Tevimbra and chemotherapy combination is approved for patients with HER2-positive tumors regardless of their PD-L1 status. PD-L1 is another protein that can affect how a cancer responds to immunotherapy.

The approval was based on results from the phase 3 HERIZON-GEA-01 clinical trial. Researchers found that the benefits of the Ziihera-containing treatments were generally seen across different groups of patients, including those with different PD-L1 levels.

How Well Did Ziihera Work?

In the HERIZON-GEA-01 trial, both Ziihera-containing treatment combinations helped patients go longer without their cancer getting worse compared with trastuzumab plus chemotherapy.

The risk of cancer progression or death was reduced by 35%. Patients receiving the Ziihera-containing treatments had a median progression-free survival of 12.4 months, compared with 8.1 months for those receiving trastuzumab plus chemotherapy.

Progression-free survival refers to the amount of time patients live without their cancer getting worse.

Researchers also found an overall survival benefit for patients who received Ziihera, Tevimbra and chemotherapy. The risk of death was reduced by 28% compared with trastuzumab plus chemotherapy. Median overall survival was 26.4 months with the Ziihera combination compared with 19.2 months with trastuzumab and chemotherapy.

Overall survival refers to how long patients live after entering a clinical trial or starting treatment.

How Does Ziihera Work?

Ziihera is a targeted treatment that works against HER2, a protein found at higher levels on some cancer cells.

Ziihera is a type of treatment called a bispecific antibody. It attaches to two different areas of HER2, which can help reduce the amount of HER2 on the surface of cancer cells. It can also activate the immune system in ways that may help destroy cancer cells.

The FDA's new approval covers adults with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma, including cancers of the stomach, gastroesophageal junction and esophagus.

Ziihera was previously approved in the United States for certain adults with previously treated HER2-positive biliary tract cancer.

What Are the Side Effects of Ziihera?

Like all cancer treatments, Ziihera can cause side effects. The most common side effect reported with these combinations was diarrhea. The prescribing information for Ziihera includes boxed warnings for severe diarrhea and potential harm to an unborn baby.

When Ziihera was given with chemotherapy and Tevimbra, diarrhea occurred in 85% of patients in clinical studies. Grade 3 diarrhea occurred in 24% of patients, while Grade 4 diarrhea occurred in 2.1%. Fatal outcomes related to diarrhea occurred in 1.5% of patients.

Other common side effects with Ziihera, chemotherapy and Tevimbra included nausea, decreased appetite, vomiting, low potassium levels, fatigue, rash, nerve-related symptoms known as peripheral neuropathy and infusion-related reactions.

Ziihera can also affect the heart by lowering the left ventricular ejection fraction, which is a measure of how well the heart pumps blood. Doctors should check heart function before treatment and regularly during treatment.

Because Ziihera may harm a developing fetus, people who can become pregnant should talk with their health care team about pregnancy risks and effective birth control during treatment.

Why Is This Approval Important?

For people living with advanced HER2-positive gastroesophageal cancer, this FDA approval provides additional first-line treatment options.

The results from HERIZON-GEA-01 showed that the Ziihera, Tevimbra and chemotherapy combination helped patients live longer and delayed the time before their cancer progressed compared with trastuzumab and chemotherapy. The benefits were also generally consistent among patients with different PD-L1 statuses.

Because HER2 status can help determine which treatments may be appropriate, patients with advanced or metastatic gastroesophageal adenocarcinoma should talk with their health care team about HER2 testing and how the results may affect their treatment options.

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