The HORIZON-GEA1 trial demonstrated that zanidatumab, a bispecific antibody, provides a significant survival benefit in HER2-positive gastroesophageal cancers, even in patients with PD-L1 negative tumors. This finding challenges the conventional wisdom that checkpoint inhibitors are the primary driver of benefit in combination therapies.
Diarrhea from the HER2-directed antibody zanidatumab is a common side effect, but it's most frequent and manageable in the first two cycles. Clinicians should proactively prescribe loperamide and educate patients, as the issue often resolves and rarely leads to treatment discontinuation.
Experts recommend using the most effective first-line therapy, like zanidatumab combinations, for HER2-positive gastric cancer, despite the risk of the tumor losing HER2 expression upon progression. The substantial upfront survival benefit outweighs the concern of losing a second-line target like T-DXd.
Before starting a second-line HER2-targeted therapy like trastuzumab deruxtecan, it is critical to re-biopsy the tumor if feasible. HER2 status can change after first-line treatment, and confirming persistent HER2 positivity is essential to ensure the subsequent therapy will be effective.
In the community setting, the choice between zolbetuximab (anti-claudin) and immunotherapy for dually positive gastric cancer is often driven by practicality. Zolbetuximab's challenging side effects (nausea) and long infusion times make immunotherapy the preferred, less resource-intensive option for many centers.
When choosing between therapies for dually positive (Claudin+/PD-L1+) gastric cancer, the existence of robust five-year survival data for immunotherapy regimens provides a compelling reason to prioritize it over newer agents like zolbetuximab, which lack such long-term follow-up.
For MSI-high gastric cancer, a sophisticated first-line approach is to start with combination chemo-immunotherapy (e.g., FOLFOX + nivolumab) but with a pre-planned, low threshold to discontinue chemotherapy after a few cycles. This strategy aims to achieve a rapid response while minimizing chemotherapy toxicity.
Some experts advocate for using immunotherapy in PD-L1 negative (CPS 0) gastric adenocarcinoma, arguing the biomarker test itself is unreliable. Factors like stromal sampling variability mean a "zero" score might not be truly negative, justifying treatment in a patient who would otherwise be excluded.
With the rise of targeted therapies, about 25% of gastric cancers are now considered "triple negative": Claudin-negative, HER2-negative, and PD-L1 negative. This newly defined subgroup represents a significant unmet need and highlights the necessity for novel treatment strategies beyond current biomarkers.
The long-term separation of survival curves for zolbetuximab, a Claudin 18.2 antibody, suggests it does more than just target a protein. The "tail on the curve" effect is similar to that seen with immunotherapies, indicating that zolbetuximab may be activating a durable, sustained anti-tumor immune response.
Clinicians should not rely on endoscopic biopsies to determine if a primary gastric tumor is responding to therapy. Symptoms like dysphagia can persist even during a positive response, making this method unreliable. Endoscopy is better suited for re-evaluating biomarkers or assessing toxicity.