New FDA-Approved Treatment Offers Longer Survival for HER2-Positive Advanced Stomach and Esophageal Cancers

“Notably, comparable outcomes were observed among patients with both PD-L1-positive and PD-L1-negative tumors, indicating that this treatment approach may benefit a broad patient population,” Dr. Dayyani tells SurvivorNet.

“These findings also reinforce the longstanding importance of HER2 testing at diagnosis in patients with advanced or metastatic gastroesophageal adenocarcinoma, as the results can play a critical role in determining the most appropriate treatment strategy,” Dr. Dayyani continued.

For patients who have advanced gastric (stomach) cancer and are HER2-positive, this approval means that instead of first relying on trastuzumab (Herceptin) plus chemotherapy, which had been the standard first treatment for years for HER2-positive advanced gastric cancer, oncologists now have another option to consider from the very start.

Unlike some immunotherapy combinations that only work well in patients with high PD-L1 expression — a protein that helps cancer cells evade the immune system, and one doctors often test for to predict how well immunotherapy will work — this regimen was approved for all HER2-positive patients regardless of PD-L1 status.

Jazz Pharmaceuticals, the drug manufacturer behind Ziihera, says, “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.”

The Trial Behind the New Approved Treatment

The HERIZON-GEA-01 results include the longest median overall survival reported in a Phase 3 trial in this setting, at 26.4 months.

Details published in the New England Journal of Medicine on the HERIZON-GEA-01 trial showed that the triplet regimen achieved a median overall survival of 26.4 months versus 19.2 months with trastuzumab (Herceptin) plus chemotherapy—the longest median OS reported in a Phase 3 trial in this setting.

The median progression-free survival (the length of time a patient lives with cancer without it growing or spreading) was 12.4 months, and both zanidatamab-based regimens significantly improved outcomes compared with trastuzumab, which had been the prior standard of care.

The FDA also approved two companion diagnostic devices — the PATHWAY anti-HER2/neu (4B5) antibody test and the VENTANA HER2 Dual ISH DNA Probe Cocktail — to help identify HER2-positive (IHC3+ or IHC2+/ISH+) patients eligible for this treatment.

Patients receiving the treatment reported diarrhea as the most common side effect.

“Zanidatamab does have a higher incidence of diarrhea, which requires proactive prophylaxis and management,” said Dr. Lakshmi Balasubramanian, Clinical Associate Professor of GI Medical Oncology, Medical Director of GI Regional Therapies, and Physician Director for the Quality Division of Hematology Oncology at UF Health.

Loperamide, commonly known as Imodium, is used to help manage this side effect. Other things patients on this treatment should watch for include infusion reactions and decreased heart function, which typically require periodic heart monitoring during treatment.

“For tumors that are both HER2 and PD-L1–positive, this regimen provides an additional treatment option. However, I would not interpret the 26.4-month OS in HERIZON-GEA-01 versus 20.0 months in KEYNOTE-811 as evidence of superiority, since addition of zanidatamab/tislelizumab to chemotherapy vs trastuzumab/pembrolizumab with chemotherapy have not been compared head-to-head and the outcomes of their respective control arms also somewhat differed,” Dr Balasubramanian tells SurvivorNet.

Better Understanding Stomach and Esophageal Cancers

For patients and families processing a new diagnosis or trying to understand where this treatment fits in, here’s a closer look at how stomach and esophageal cancers develop, present, and are treated.

Esophageal cancer starts in the inner lining of the esophagus, the muscular tube that moves food from the throat to the stomach. Since it can spread outward through the esophageal wall, catching it early is critical.

WATCH: Esophageal Cancer Early Detection 

Common Esophageal Cancer Symptoms to Watch For

Because early signs can mimic everyday discomforts, it’s important to take persistent symptoms seriously. Known indicators include:

• Pain or difficulty swallowing
• Unexplained weight loss
• Pain behind the breastbone
• Persistent hoarseness or cough
• Indigestion or heartburn
• A lump under the skin (often near lymph nodes)

“Symptoms include things like … they’re losing weight, they’re having some burning in their esophagus or their chest, they’re having trouble or pain with swallowing,” explained Dr. Sofya Pintova, a hematologist and oncologist at Mount Sinai Cancer Center.

“It’s one of the cancers with some of the lowest cure rates out there, but like many cancers, if we find it early, we can often treat it effectively either with surgery, with surgery and chemotherapy, or with chemotherapy and radiation,” Dr. Brendon Stiles, a thoracic surgeon at Montefiore Medical Center, explained to SurvivorNet.

Chemotherapy plays a vital role in treating esophageal cancer, whether it’s adenocarcinoma (a type of esophageal cancer) or squamous cell carcinoma (a type of esophageal cancer). The specific drugs used depend on the cancer type and individual patient factors.

The goals of chemotherapy include:

• Shrinking tumor size
• Reducing the number of cancer cells in the body
• Lowering the risk of cancer spreading
• Easing current symptoms

Navigating Stomach Cancer Diagnosis

Gastric cancer originates in the stomach. The most common type of stomach cancer is adenocarcinoma, which begins in the stomach’s inner lining.

Doctors can use advanced endoscopic techniques — a thin, lighted tube with a tiny camera — that is inserted into the body through the mouth and views the throat, esophagus, stomach, and more. If patients manage to catch stomach cancer early, treatment is much easier to endure.

WATCH: Understanding stomach cancer risk factors

Symptoms for stomach cancer vary depending on how advanced the cancer is. For early-stage stomach cancer, symptoms may include:

• Bloating after eating
• Indigestion and upset stomach
• Nausea
• Loss of appetite

Symptoms for more advanced stomach cancer may include:

• Unexplained weight loss
• Stomach pain
• Bloody stool
• Vomiting
• Jaundice (yellowing of the skin and eyes)
• Difficulty swallowing

While experiencing any of these symptoms does not always mean stomach cancer, if you find yourself dealing with these issues more frequently, contact your doctor for some follow-up tests.

WATCH: How is stomach cancer staged?

“If a physician is suspecting stomach cancer … one of the first simple tests to do is blood work,” says Dr. Pintova.

“In the blood work, we are looking for several specific things. We’re looking at organ function, such as liver function and kidney function, but we’re also looking at the level of red blood cells in the blood,” she explains.

“So, if the level of red blood cells is low, that is called anemia. And when someone has a new anemia that cannot be explained for other reasons, obvious reasons like a recent bleeding from the nose, for example, or other type of bleeding, then that warrants an evaluation by a gastroenterologist.”

Patients may also present with signs or symptoms of distant metastatic (spread) disease. The most common sites of metastatic disease are the liver, the peritoneal surfaces, and the lymph nodes.

Besides blood exams to evaluate anemia, nutritional status, and overall biochemistry, the most important exam is the upper gastrointestinal endoscopy.

“If a cancer is found in the stomach, the next step for us as oncologists or surgeons would be staging. And what staging means is we ask ourselves: is the tumor, the cancer still confined only to the stomach or has it spread to other organs,” Dr. Pintova explains. “So, several tests that we usually do to identify that are what’s called radiology tests or imaging that could take the form of computerized tomography scans, PET scans, sometimes MRIs.”

Treating Stomach Cancer

Surgery is often the most critical part of the treatment process for gastric cancer, especially in cases where the disease is localized and has not spread extensively beyond the stomach.

The goal of surgery is to remove the cancer, along with part or all of the stomach, depending on how much the cancer has spread. Surgeons aim to ensure that no cancer cells are left behind, which gives patients the best chance at long-term survival.

RELATED: Surgery for Gastric Cancer: What You Need to Know

WATCH: When is chemo given before surgery?

For patients whose cancer is at an earlier stage, surgery can often be curative. Surgery may still be an option even for patients with more advanced cancer.

Systemic therapies, such as chemotherapy, targeted therapies, and immunotherapy, may also be used. Eligibility for these treatment approaches will depend on several factors, including the stage of the cancer, the patient’s overall health, and the results of biomarker testing.

Stomach cancer patients who are eligible for chemotherapy may receive neoadjuvant chemotherapy, which means chemo before surgery.  This approach aims to shrink the tumor and improve the chances that it can be completely removed during surgery. By targeting cancer cells in advance, the treatment may help make surgery more effective and reduce the risk of cancer returning.

RELATED: What are the Treatment Options for Advanced Gastric Cancer?

“We notice that it’s easier for patients to receive chemotherapy before surgery [rather than after]. So some cancer centers around the U.S. try to offer more chemotherapy before surgery,” Dr. Alan Lima Pereira, a medical oncologist at Moffitt Cancer Center in Tampa, Florida, tells SurvivorNet.

The neoadjuvant chemotherapy may involve getting chemo every other week four to six times before surgery, followed by additional chemotherapy after surgery.

RELATED: How to Deal With the Side Effects of Chemotherapy

Chemotherapy can cause side effects, including fatigue, nausea, and hair loss. However, these side effects can often be managed.

The side effects experienced from these two chemo approaches varied slightly:

• FLOT Regimen: Patients experienced higher rates of side effects such as low white blood cell counts (which can increase infection risk), diarrhea, infections, and numbness or tingling in the hands and feet.
• Standard Therapy (epirubicin, cisplatin, and fluorouracil – ECF): Patients had higher rates of nausea, vomiting, and blood clots.

Looking Ahead

For patients and families navigating a stomach, GEJ, or esophageal cancer diagnosis, treatment options continue to expand — and this newly approved regimen adds another tool for oncologists treating HER2-positive advanced disease, regardless of PD-L1 status. As Dr. Balasubramanian’s caution illustrates, more options don’t always mean a clear “best” choice; treatment decisions still depend on individual factors such as biomarker testing, overall health, and how a patient’s cancer has progressed.

Whether facing a new diagnosis or weighing next steps in an existing treatment plan, patients are encouraged to discuss the full range of available therapies — including newer approvals like this one — with their care team. SurvivorNet’s Clinical Trial Finder and “My Health Questions” tool can also help patients explore current options and get answers to specific questions about their diagnosis and treatment.

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