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.

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.

The STELLAR-303 trial is the first to show an immunotherapy-based regimen provides an overall survival benefit in microsatellite-stable CRC. Crucially, this benefit extends to patients with liver metastases, a subgroup that has historically shown profound resistance to immunotherapy, highlighting the drug's novel mechanism.

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.

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.

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.

A meta-analysis of over 3,000 patients shows that neoadjuvant chemotherapy for MSS colon cancer provides a 5% improvement in survival. This benefit is clinically meaningful and equivalent in magnitude to the landmark addition of oxaliplatin to 5-FU in the original MOSAIC trial.

Clinical trial data suggests immunotherapy's timing is crucial in early-stage TNBC. Given with chemotherapy before surgery (neoadjuvant), it improves outcomes. However, when given alone after surgery (adjuvant), the IMPASSION 030 trial showed no benefit and was halted for futility, indicating pre-surgical tumor priming is essential.

Dr. Radvanyi advocates for a paradigm shift: treating almost all cancers with neoadjuvant immunotherapy immediately after diagnosis. This "kickstarts" an immune response before standard treatments like surgery and chemotherapy, which are known to be immunosuppressive, can weaken the patient's natural defenses against the tumor.