ASCO Updates Guideline to Broaden First-Line Treatment for HER2-Positive Gastroesophageal Cancer

Patients with HER2-positive gastroesophageal cancer, cancer of the stomach or the area where the esophagus meets the stomach, now have more treatment options to start with, according to an updated guideline from the American Society of Clinical Oncology (ASCO). The update was published Aug. 17, 2026, in the Journal of Clinical Oncology.

HER2 is a protein that, when found in high amounts on cancer cells, can help those cells grow. Cancers with high levels of this protein are called HER2-positive, and drugs that target HER2 are a key part of treatment for these patients. ASCO's guideline is a living document, meaning it gets updated as new research becomes available, and this version broadens the first treatment patients may be offered.

What Changed in the Updated Guideline?

Under the new guideline, patients whose HER2-positive cancer has certain features, described as mismatch repair-proficient and microsatellite-stable, should be offered a HER2-targeting antibody, a lab-made protein designed to attach to HER2 and block cancer growth, together with two types of chemotherapy. For patients whose tumors also test positive for a protein called PD-L1 at a level of 1% or higher, doctors should now add immunotherapy, a treatment that helps a patient's own immune system attack cancer cells, to that combination.

This is a change from the previous guideline, which named one specific HER2-targeting antibody. The updated version instead allows doctors to choose from more than one antibody in this class, giving patients and their care teams more flexibility.

What Data Support the ASCO Guideline Update?

The change is based on results from a large, phase 3 study called HERIZON-GEA-01. In this study, patients treated with the antibody Ziihera (zanidatamab-hrii) plus the immunotherapy drug Tevimbra (tislelizumab) and chemotherapy lived a median of 26.4 months, compared with 19.2 months for patients treated with the antibody Herceptin (trastuzumab) plus chemotherapy. This difference was considered statistically meaningful, meaning it was unlikely to be due to chance.

Patients on the three-drug combination also went longer without their cancer growing or spreading, a measure called progression-free survival, at 12.4 months compared with 8.1 months for those on Herceptin.

A separate group of patients received Ziihera and chemotherapy without the immunotherapy drug. They lived a median of 24.4 months, though this result was not considered statistically different from the Herceptin group. Their progression-free survival was 12.4 months.

Researchers also looked at how patients responded based on their PD-L1 levels. Both Ziihera-based combinations helped slow cancer growth compared with Herceptin, whether PD-L1 levels were low or high. The three-drug combination showed a clear survival benefit in patients with lower PD-L1 levels, but not in those with higher levels.

What Were the Trial Details Behind the Guideline Change?

HERIZON-GEA-01 enrolled 914 patients with HER2-positive advanced gastroesophageal cancer who had not yet received treatment. Patients were randomly placed into one of three groups: Ziihera plus Tevimbra and chemotherapy (302 patients), Ziihera plus chemotherapy (304 patients), or Herceptin plus chemotherapy (308 patients). Chemotherapy included either capecitabine and oxaliplatin or fluorouracil and cisplatin, given in 21-day treatment cycles.

About 32% of patients had low PD-L1 levels, about 60% had high PD-L1 levels, and about 7% did not have a PD-L1 result available.

Based on these results, Herceptin remains an option for patients who cannot take another HER2-targeting antibody, or when cost, access or personal preference play a role in the decision.

What Side Effects Were Reported in the Trial?

Side effects considered serious enough to interfere with daily life or require additional care, known as grade 3 or 4 side effects, occurred in 73.8% of patients on the three-drug combination, 67.2% of patients on Herceptin plus chemotherapy and 65.6% of patients on Ziihera plus chemotherapy alone.

Side effects that were fatal, known as grade 5 side effects, occurred in 9.5% of patients on the three-drug combination, 7.3% of patients on Herceptin plus chemotherapy and 8.2% of patients on Ziihera plus chemotherapy alone.

Diarrhea was the most common serious side effect, affecting 24.8% of patients on the three-drug combination, 20% of patients on Ziihera plus chemotherapy and 12.9% of patients on Herceptin plus chemotherapy. Serious side effects related to the immune system occurred in 12.2% of patients on the three-drug combination.

References

1. "Immunotherapy and targeted therapy for advanced gastroesophageal cancer: ASCO Living Guideline, version 2026.1.2" by Dr. M.A. Shah, et al., Journal of Clinical Oncology.

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