HER2-Targeted Regimens Transform Frontline Management of Upper GI Cancers
Key Points
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Data from HERIZON-GEA-01 suggest zanidatamab combined with chemotherapy with or without immunotherapy may be practice-changing in the treatment of HER2–positive gastroesophageal cancer, with median overall survival (OS) exceeding 26 months.
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As agents like zanidatamab and trastuzumab deruxtecan (T-DXd) move into earlier lines of therapy, differences in efficacy, durability of response, and management of distinct toxicity profiles will guide clinical decision-making.
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Re-biopsy at progression to reassess HER2 status is increasingly important to guide therapy selection.
The treatment landscape in upper gastrointestinal cancers is rapidly evolving, driving changes in clinical practice for both academic and community oncologists. At the 2026 ASCO Gastrointestinal Cancers Symposium, Meghana Singh, MD, of West Virginia University, and Richard Dunne, MD, MS, of University of Rochester, discussed how clinicians should prioritize new and emerging data.
The most significant update was from the HERIZON-GEA-01 trial, according to Dr. Dunne. He highlighted survival outcomes seen with zanidatamab-based regimens. Median OS exceeded 26 months with zanidatamab, chemotherapy, and immunotherapy. In the zanidatamab plus chemotherapy alone arm, median OS was over 24 months. Although there are toxicity concerns, such as diarrhea and infusion-related reactions, Dr. Dunne explained that these appear manageable.
Upon review of the DESTINY-Gastric05 study, Dr. Dunne and Dr. Singh shared how upcoming frontline data with T-DXd may influence treatment decisions. While there are considerations regarding toxicity with zanidatamab and T-DXd, Dr. Dunne said treatment selection will depend on relative efficacy, depth and durability of response, and tolerability.
The discussion then addressed the importance of reassessing HER2 status at progression, especially considering data showing diminished T-DXd efficacy in HER2–negative disease. Routine tissue biopsy at progression has been successfully integrated into practice, with patients typically receptive when the rationale is clearly explained, Dr. Dunne said. In cases where tissue biopsy can’t be performed, he said liquid biopsy remains an option.