Ep. 2: Managing Efficacy and Toxicity With Zanidatamab in HER2-Positive Disease
Key Points
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Zanidatamab demonstrated superior activity compared with trastuzumab in HER2-positive metastatic gastric and gastroesophageal junction (GEJ) cancer, supporting a shift in frontline standard of care.
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The addition of tislelizumab further improved outcomes, with ongoing questions regarding patient selection by PD-L1 status.
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Diarrhea remains the most clinically relevant toxicity, but proactive prophylaxis and monitoring significantly reduce severity.
Zanidatamab Efficacy and Clinical Implications
At an event coinciding with the 2026 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with Geoffrey Ku, MD, of Memorial Sloan Kettering Cancer Center; Rutika Mehta, MD, MB, MPH, of Weill Cornell Medicine; Manish Shah, MD, of Weill Cornell Medicine; and Nataliya Uboha, MD, PhD, of the University of Wisconsin School of Medicine and Public Health, to review emerging frontline strategies for HER2-positive metastatic gastric and GEJ adenocarcinoma.
Dr. Uboha continued the discussion by highlighting the HERIZON-GEA-01 data. “Zanidatamab is way more active than trastuzumab. There is no question it should replace trastuzumab in standard practice,” she said. Although therapy often includes chemotherapy plus trastuzumab and pembrolizumab for PD-L1–positive tumors, zanidatamab-based regimens demonstrated superior progression-free survival (PFS) and promising overall survival (OS), challenging the current standard.
The trial evaluated 3 arms: trastuzumab plus chemotherapy (control), zanidatamab plus chemotherapy, and zanidatamab plus chemotherapy with tislelizumab. Early analyses showed that adding tislelizumab improved both PFS and OS, regardless of PD-L1 status. “Until that data comes out, I think every patient should get the experimental regimen once it’s approved,” Dr. Uboha said.
Toxicity Management and Practical Considerations
Diarrhea was the most commonly observed adverse event in the study, exacerbated by the capecitabin and oxaliplatin chemotherapy backbone. Dr. Mehta noted that prophylactic loperamide reduced severe diarrhea, and careful monitoring during the first cycle allows clinicians to adjust prophylaxis as needed. Phase 1 data showed grade 3 diarrhea in over 50% of patients, which dropped to 20% to 25% once prophylaxis was implemented.
The study also permitted discontinuation of chemotherapy after 6 cycles, supporting potential long-term maintenance with zanidatamab alone or with tislelizumab. Dr. Shah emphasized that zanidatamab monotherapy has a favorable safety profile in biliary tract cancer, suggesting this approach may be feasible for select patients. For individuals who are frail or have persistent diarrhea, reducing chemotherapy doses while continuing targeted therapy may optimize tolerability without compromising efficacy.