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.

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.

Following positive Phase III data for adjuvant atezolizumab plus chemotherapy in Stage III MSI-high colon cancer, clinicians are extrapolating this approach to high-risk Stage II patients. For some, they favor using immunotherapy alone, omitting chemotherapy due to its perceived limited additional benefit in the Stage II setting.

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.

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.

Retrospective data suggests patients with MSI-high rectal cancer might not just respond poorly to standard neoadjuvant chemoradiation (TNT), but their disease could actually progress. This makes immunotherapy a potentially safer and more effective first-line neoadjuvant choice, not just an alternative.

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.

The COMET study found combining chemotherapy with atezolizumab did not improve overall survival versus atezolizumab alone. However, it nearly eliminated early progressive disease (2.8% vs. 32.4%), suggesting a critical role for patients with high tumor burden who cannot risk initial progression on monotherapy.