Dr Shah on the Potential Role for Zanidatamab-Based Regimens in HER2+ GEA

"It's very possible that with zanidatamab, a drug that is a better activator of the immune system, PD-L1 [status may not] matter that much, and adding [tislelizumab] may be effective either way."

Manish A. Shah, MD, director of the Gastrointestinal Oncology Program at Weill Cornell Medicine, as well as chief of the Solid Tumor Service and co-director of the Center for Advanced Digestive Disease at NewYork-Presbyterian, discussed whether results from the phase 3 HERIZON-GEA-01 trial (NCT05152147) support expanded access to zanidatamab-hrii (Ziihera) in combination with chemotherapy with or without tislelizumab-jsgr (Tevimbra) for patients with PD-L1–negative gastroesophageal adenocarcinoma (GEA).

HERIZON-GEA-01 compared the efficacy of this combination with that of standard-of-care (SOC) trastuzumab (Herceptin) plus chemotherapy for patients with unresectable, locally advanced, recurrent, or metastatic HER2-positive GEA. Of note, pembrolizumab (Keytruda) was FDA approved in combination with this SOC in 2025, but the triplet is restricted to patients whose tumors express PD-L1 with a combined positive score (CPS) of 1 or greater. However, HERIZON-GEA-01 enrolled an all-comer population to receive this triplet regimen.

Primary findings from the trial presented at the 2026 Gastrointestinal Cancers Symposium showed significant overall survival and progression-free survival advantages with the zanidatamab-containing combinations over trastuzumab and chemotherapy. These survival benefits were found to be consistent across key prespecified subgroups, including PD-L1 tumor area positivity score and geographic region.

Shah noted that the efficacy of zanidatamab in PD-L1–low populations is noteworthy. He suggested that because zanidatamab is a more potent activator of the immune system, PD-L1 status may not be as critical for benefit as it is with other checkpoint inhibitor regimens. Although previous data showed that adding pembrolizumab to trastuzumab and chemotherapy could potentially result in worse survival outcomes for PD-L1–negative patients, HERIZON-GEA-01 data suggest that tislelizumab may be effective regardless of the score when paired with zanidatamab. Shah concluded that although more data are needed to definitively isolate the benefit of tislelizumab in high vs low PD-L1 groups, these results support the potential for zanidatamab to become a new SOC for a broader range of patients.