Trials like the dostarlimab study in rectal cancer and NICHE in colon cancer show neoadjuvant immunotherapy can induce profound responses in MSI-high tumors. This is creating a new paradigm where major surgery might be avoided entirely for some patients, marking a significant shift in treatment strategy.

An MSK trial of neoadjuvant dostarlumab for MSI-high locally advanced rectal cancer showed a 100% complete clinical response rate. This groundbreaking result allows for non-operative management, sparing patients from chemotherapy, radiation, and life-altering surgery, potentially representing a cure with immunotherapy alone.

The success of neoadjuvant immunotherapy trials like Niagara and those with EV-Pembro means most patients will receive immune therapy before surgery. This fundamentally shifts the clinical landscape, making the question of starting adjuvant immunotherapy less relevant as perioperative treatment becomes the standard.

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.

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 neoadjuvant-only immunotherapy has a strong rationale, a patient-level cross-trial comparison of CheckMate 816 (neoadjuvant) and 770T (perioperative) suggests the addition of adjuvant therapy improves event-free survival, favoring a full perioperative approach.

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.

Historically, resectability was a static, pre-treatment judgment. With neoadjuvant immunotherapy causing significant tumor and nodal downstaging, surgeons must now dynamically re-evaluate resectability after systemic therapy, expanding surgical options for patients previously deemed inoperable.