The Matterhorn clinical trial has simplified the treatment approach for operable gastroesophageal cancer. It established FLOT chemotherapy combined with the checkpoint inhibitor durvalumab as the preferred perioperative regimen, resolving previous debates about the optimal strategy.
A modern strategy for localized MSI-high gastroesophageal cancer is to begin with dual immune checkpoint blockade. Clinicians can then perform an early response assessment and pivot to chemoimmunotherapy if the initial response is suboptimal, allowing for a flexible, response-adapted approach.
Unlike colorectal cancer, where MSI is often clonal, MSI in gastric cancer is typically sporadic. This can lead to regional heterogeneity within a single tumor, with some parts being MSI-high and others MSS (microsatellite stable), which has significant implications for immunotherapy efficacy.
Severe nausea from the Claudin-18.2 antibody zolbetuximab dropped from ~20% in early trials to zero in a recent study. This was achieved not by changing the drug, but by clinicians learning and applying more effective proactive antiemetic strategies, demonstrating the power of evolving supportive care.
When communicating with anxious, newly diagnosed patients, oncologists can point to the long-term survival 'tail' on modern immunotherapy trial curves. Simply stating, 'there is a chance that you will be alive and well,' provides crucial hope, reduces anxiety, and helps patients better engage with their treatment plan.
For HER2-positive gastric cancer, treatment choice depends on patient fitness. For young, fit patients, the more potent but toxic HORIZON-GA regimen (zanidatamab-based) is preferred. For elderly or less fit patients, the better-tolerated KEYNOTE-811 regimen (pembrolizumab/trastuzumab) remains the standard of care.
In metastatic gastroesophageal cancer, physicians should use their most effective therapies first. With data showing 40-50% of patients in trials never receive second-line treatment due to disease progression, holding potent agents in reserve means a large portion of patients will never benefit from them.
The antibody-drug conjugate TDxD is a promising first-line therapy for HER2+ gastric cancer because of its bystander effect. The chemotherapy payload can kill adjacent HER2-low or negative cells, directly addressing the tumor heterogeneity that limits the efficacy of traditional HER2-targeted agents in this disease.