What is the first line of therapy for Microsatellite Instability-High (MSI-H)/Deficient Mismatch Repair (dMMR) Colorectal Cancer (CRC) stage 1?

First-Line Therapy for MSI-H/dMMR Colorectal Cancer Stage I

Immunotherapy is strongly recommended as the first-line therapy for MSI-H/dMMR colorectal cancer, including stage I disease. 1

Rationale for Immunotherapy in MSI-H/dMMR CRC

• Immunotherapy has demonstrated superior outcomes in MSI-H/dMMR colorectal cancer patients compared to conventional chemotherapy, with significant improvements in progression-free survival and overall survival 1
• The 2024 ASCO guidelines provide a strong recommendation for immunotherapy in MSI-H/dMMR rectal cancers (evidence quality: low; strength of recommendation: strong) 1
• MSI-H/dMMR tumors respond exceptionally well to immune checkpoint inhibitors due to their high mutation burden, which creates numerous neoantigens that can be recognized by the immune system 2

Specific Treatment Recommendations

• PD-1 inhibitors (pembrolizumab, nivolumab) are the preferred first-line agents for MSI-H/dMMR CRC stage I 1
• For patients who cannot receive immunotherapy due to contraindications, the following alternatives should be considered:
  • Surgical resection alone may be sufficient for stage I disease 1
  • Fluoropyrimidine-based chemotherapy can be considered, though historically less effective in dMMR tumors 1

Clinical Evidence Supporting Immunotherapy

• Multiple studies have demonstrated high response rates to PD-1 inhibitors in MSI-H/dMMR colorectal cancer 1
• In locally advanced rectal cancer with dMMR/MSI-H, neoadjuvant immunotherapy has shown complete response rates of up to 90% 3
• Clinical complete response has been observed in as little as 3.8 months (range 0.7-6.5) after initiating anti-PD-1 therapy 4
• Two-year disease-free survival and overall survival rates of 100% have been reported in patients with dMMR/MSI-H rectal cancer treated with immunotherapy 4

Important Considerations

• MMR/MSI testing should be performed on all colorectal cancer specimens to identify patients eligible for immunotherapy 1
• Patients with stage I MSI-H/dMMR CRC have excellent prognosis compared to more advanced stages, but immunotherapy is still preferred due to its superior efficacy and favorable safety profile 1
• Monitoring for immune-related adverse events is essential when administering immunotherapy 3
• For patients with contraindications to immunotherapy, surgical resection remains the cornerstone of treatment for stage I disease 1

Treatment Algorithm

1. Confirm MSI-H/dMMR status through immunohistochemistry or PCR testing 2
2. If confirmed MSI-H/dMMR:
   • First choice: PD-1 inhibitor immunotherapy (pembrolizumab or nivolumab) 1
   • If contraindicated: Proceed with surgical resection alone 1
3. Monitor response with appropriate imaging and endoscopy, recognizing that discrepancies between imaging and endoscopic findings are common 5
4. Continue immunotherapy for recommended duration per specific agent guidelines 1

Caveats and Pitfalls

• Imaging and endoscopy may show discrepancies in up to 54% of cases when evaluating response to immunotherapy, requiring careful interpretation 5
• Not all patients respond to immunotherapy; approximately 10% of dMMR/MSI-H patients may not achieve complete response 3
• Immune-related adverse events must be monitored and managed appropriately 3
• Patients with contraindications to immunotherapy should be identified early to initiate alternative treatment approaches 1