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.

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.

Long-term follow-up from multiple major trials (Checkmate 649, Keynote 590) consistently demonstrates that adding a checkpoint inhibitor to first-line chemotherapy produces durable benefits. This combination more than doubles or triples the 5-year overall survival rate from ~3-5% with chemotherapy alone to over 11-13% with immunotherapy.

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.

Analysis across multiple studies suggests that longer treatment durations with neoadjuvant immunotherapy, up to six months, are associated with higher rates of complete pathologic response in localized MSI-high colorectal cancer. This indicates that treatment duration is a critical variable for optimizing patient outcomes and designing future trials.