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While immunotherapy is approved for gastroesophageal cancer with a PD-L1 CPS score of 1 or higher, clinical data reveals the most significant and durable survival benefit is largely confined to patients with high expression (CPS ≥10) or MSI-high status. The benefit for patients with CPS scores from 1 to 9 is considered borderline.
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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.
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.
Retrospective data suggests that chemotherapy for localized MSI-high gastroesophageal cancer may be neutral or even deleterious. The concern is that it could blunt the patient's immune response, hindering the profound efficacy of checkpoint inhibitors in this specific subgroup. Experts are increasingly avoiding chemotherapy here.
Two phase 2 trials (NEONAPIGA, INFINITY) show that preoperative combination immunotherapy achieves pathologic complete response rates of nearly 60% in MSI-high gastric cancers. This success establishes a new paradigm, potentially allowing non-operative management and avoidance of surgery for patients who respond well.
Given that PD-L1 scores for gastroesophageal cancers can be exceptionally variable between labs, some clinicians prefer a simple CPS cutoff of 1. This 'some expression versus no expression' approach is considered more reproducible and practical for decision-making than relying on specific higher scores that may not be consistent across different testing sites.
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.
In small Phase 2 trials, combining anti-PD-1 and anti-CTLA-4 therapies for 2-3 months yielded pathologic complete response rates of 60% in localized MSI-high gastroesophageal cancer. This stunning result, with high long-term survival, opens the possibility of non-operative management for these patients.
Experts favor a Nivolumab plus Ipilimumab (NIVO+EP) combination for newly diagnosed, MSI-high, stage IV gastroesophageal cancer patients who can tolerate it. This approach avoids chemotherapy and yields high, sustained response rates, including potential for complete pathologic responses in metastatic settings.
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.
In the increasingly common scenario of a patient with multiple positive biomarkers, a clear hierarchy exists for treatment decisions. Based on the robustness and maturity of clinical trial data, HER2-directed therapy is the top priority, followed by PD-L1 immunotherapy, with Claudin-18.2 targeting considered third.
