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.

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.

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.

The traditional CRC treatment path (chemo-surgery-chemo) is being upended. New data shows giving immunotherapy before surgery can be so effective that the surgery itself becomes the "adjuvant" or follow-up treatment, representing a major paradigm shift.

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.

Data from trials like CheckMate 816 shows that achieving a Pathologic Complete Response (PCR) after neoadjuvant chemo-immunotherapy is a powerful early surrogate endpoint. Patients with PCR demonstrate markedly improved overall and event-free survival.