Zanidatamab: Evolving GEA Treatment Paradigm

Zanidatamab, a next-generation bispecific HER2 antibody, is showing meaningful first-line efficacy in HER2-positive gastroesophageal adenocarcinoma, with deeper disease control when combined with chemotherapy and immunotherapy.  “For more than a decade we’ve relied on trastuzumab-based therapy in this disease,” said Manish Shah, MD, head of the Solid Tumor Service at Weill Cornell Medicine. “Zanidatamab represents a more precise way to target HER2, with encouraging gains in progression-free survival.”

  • A new HER2 approach: Zanidatamab is a bispecific antibody that targets two HER2 domains, delivering deeper pathway inhibition and immune activation than trastuzumab.

  • First-line signal: In untreated metastatic HER2-positive disease, zanidatamab-based regimens improved progression-free survival, with the strongest benefit seen in combination with immunotherapy.

  • Benefits vs. risks: The triplet regimen of zanidatamab, tislelizumab and chemotherapy achieved the longest disease control but adds immune-related toxicities and zanidatamab-associated diarrhea, requiring careful monitoring.

  • Quality-of-life focus: As outcomes improve, treatment decisions increasingly center on managing side effects and preserving quality of life rather than avoiding effective therapy.

HER2 targeted treatment is now a factor in gastroesophageal adenocarcinoma. That’s a big deal. Now the field is learning how to use these drugs, when to use them, and how to educate providers on the IHC testing required.

“For about 15 years now, the standard treatment for HER2-positive  gastroesophageal adenocarcinoma has been the use of trastuzumab plus chemotherapy,” explains Manish Shah, MD, director of the GI Oncology Research Program at Weill Cornell Medicine. Patients would often saw responses, but not lasting ones. Over time, the standard of care for tumors that were PD-L1 positive, treatment expanded to include immunotherapy.  But while immunotherapy helped some patients, it didn’t solve the core problem of durability in treatment.

Trastuzumab targeted HER2, but the responses it produced often didn’t last. In a solid tumor like esophageal and gastric cancer— HER2 expression can vary from one area of the tumor to another—and Trastuzumab proved ineffective in suppressing growth over time. As a result, many patients experienced only temporary benefit before the disease found a way to progress again.

“But it’s very important to target HER2 because this is a validated pathway,” Dr Shah explained.  HER2 targeting has been successful across other solid tumors, most notably in breast cancer, and more recently in biliary tract cancer, where zanidatamab received FDA approval—giving clinicians real-world experience with both its effectiveness and side-effect profile.

After years of success using HER2-directed therapies in those settings, researchers began to recognize an opportunity to approach the pathway differently in gastroesophageal cancer, where responses to earlier HER2 drugs were often short-lived. That shift in thinking opened the door to a more potent strategy

“So zanidatamab is a bispecific drug that targets two portions of the HER2 protein, the second and the fourth motif,” Shah explained. “By doing that, it may inhibit the signaling of HER2 better, but it also may activate an immune response against the cancer cells better.”

Instead of hitting HER2 in one place, the HERIZON-GEA-01 trial tested whether a stronger, more complete way of targeting the pathway  could translate into deeper and more durable disease control.

A Bispecific Strategy to Deepen HER2 Blockade

 Unlike trastuzumab, which binds a single epitope on the HER2 receptor, zanidatamab is a bispecific antibody designed to engage two distinct parts of the HER2 protein—the second and fourth motifs.

“Zanidatamab is a single-molecule antibody, but it has two different portions to it,” says Shah. “One portion binds to the second motif like trastuzumab does, and the other binds to the fourth motif, similar to what pertuzumab does.” By simultaneously binding both regions, zanidatamab delivers more comprehensive HER2 inhibition.

This dual binding produces two complementary effects. “By doing that, it may inhibit HER2 signaling better, but it also may activate an immune response against the cancer cells better,” Shah added, ” it both blocks the downstream signaling, and activates an immune response.”

The HERIZON-GEA-01 Trial

Zanidatamab’s activity in gastroesophageal cancer was evaluated in the HERIZON-GEA-01 clinical trial, a first-line study in patients with untreated metastatic HER2-positive disease. The trial included three arms:

  • Chemotherapy plus trastuzumab (standard of care at the time)

  • Chemotherapy plus zanidatamab

  • Chemotherapy plus zanidatamab plus teslelizumab, a PD-1 inhibitor

“The clinical trial was really comparing zanidatamab versus trastuzumab as the HER2-targeting agent,” Shah said. The third arm was designed to evaluate the added effect of immunotherapy on top of enhanced HER2 blockade.

Efficacy Signals Across All Arms

Progression Free Survival: “The median progression-free survival with trastuzumab and chemotherapy was 8.1 months,” Shah said. “But when you substituted zanidatamab for trastuzumab and added tislelizumab, the progression-free survival improved to 12.4 months.”

The hazard ratio for progression-free survival was 0.63, representing a 37% reduction in the risk of disease progression or death compared with standard therapy.

2 Year Outcomes:  At two years, only 15.6% of patients treated with chemotherapy and trastuzumab remained progression-free. In contrast, 38% of patients receiving zanidatamab, teslelizumab, and chemotherapy had not progressed—more than double the rate seen with standard care.

Managing Potency and Toxicity

However the most effective regimen- the triplet  also carries the greatest complexity and risks. “The most potent regimen on the HERIZON study was the triplet combination,” Shah noted. Adding a PD-1 inhibitor introduces known immune-related toxicities, including colitis and pneumonitis, while zanidatamab itself is associated with diarrhea. “Someone who has ulcerative colitis or Crohn’s disease might be more prone to colitis.”

“It wasn’t overwhelming compared to what you expect with other PD-1 inhibitors,” Shah added- emphasizing that most toxicities were manageable. Hypersensitivity reactions during infusion are another consideration, but overall comfort with the drug is growing, particularly given prior experience in biliary tract cancer.   “I think it’s better to try it and manage the toxicity as best you can as opposed to avoiding it altogether,” he said. “On balance, the risk–benefit ratio is really quite in favor of the new treatment regimen.”

NOTE:  The study findings are limited by timing. Pembrolizumab had not been approved in this setting when the trial was designed, the control arm does not reflect the current U.S. standard of care – for HER2 positive and GEA patients that are also PD-L1 positiv – which now includes trastuzumab, chemotherapy, and pembrolizumab.  The trial does not offer a direct comparison with today’s frontline regimen.