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.
While immunotherapy is largely ineffective in metastatic microsatellite stable (MSS) colorectal cancer, emerging data suggests it may have surprising efficacy in the early-stage (neoadjuvant) setting. This differential response is likely due to a more favorable tumor microenvironment in earlier disease, suggesting a new therapeutic window.
The STELLAR-303 trial is the first Phase III study to show a significant overall survival benefit for an immunotherapy-based combination (zanzalintinib + atezolizumab) in refractory microsatellite stable (MSS) metastatic colorectal cancer. This validates the IO+TKI approach in a notoriously "cold" tumor type where prior IO trials failed.
For fit patients with metastatic MSI-high colorectal cancer, the combination of ipilimumab and nivolumab is the preferred frontline treatment over pembrolizumab monotherapy. This is based on Phase III data showing the dual IO approach is superior. Single-agent PD-1 inhibitors are reserved for frail patients or those with autoimmune comorbidities.
A study found that structured exercise after adjuvant chemotherapy for high-risk Stage II/III colon cancer significantly improved disease-free and overall survival. The impact, with a hazard ratio of 0.6 for OS, is comparable to some approved drugs, making it a practice-changing and cost-effective intervention.
The ALASCA trial showed that daily low-dose aspirin reduces cancer recurrence by nearly 50% in colorectal cancer patients with specific PI3K pathway mutations. This finding suggests a need for routine molecular sequencing of early-stage tumors to identify patients for this simple, practice-changing intervention.
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.
Many deaths from colon cancer occur in patients with Stage II disease not offered adjuvant therapy due to a lack of traditional risk factors. Post-surgical ctDNA testing can identify a ~10% subset with minimal residual disease who are at high risk of recurrence and would benefit from chemotherapy.