What is the role of immunotherapy in treating stage four rectal cancer?

Immunotherapy for Stage IV Rectal Cancer

For stage IV rectal cancer, immunotherapy is the preferred first-line treatment ONLY if the tumor is dMMR/MSI-H, with PD-1 inhibitors (pembrolizumab, dostarlimab, or nivolumab) demonstrating superior outcomes compared to chemotherapy; however, for pMMR/MSS tumors (which represent 94-97% of metastatic rectal cancers), immunotherapy has no role and standard chemotherapy remains the treatment of choice. 1, 2

Critical First Step: MMR/MSI Testing

• All stage IV rectal cancers must be tested for MMR/MSI status using immunohistochemistry (IHC) for MMR proteins or PCR-based microsatellite instability testing 1, 2
• This single biomarker determines whether immunotherapy has any role whatsoever in treatment 1
• Only 3.5-6.5% of stage IV colorectal cancers are MSI-H/dMMR 3

For dMMR/MSI-H Stage IV Rectal Cancer (The Minority)

First-Line Treatment Options

The NCCN and ASCO guidelines recommend PD-1 inhibitors as first-line therapy for metastatic dMMR/MSI-H colorectal cancer, with the following interchangeable options 1, 2:

• Dostarlimab (objective response rate 43.5%; median PFS 8.4 months in previously treated patients) 2
• Pembrolizumab (immune-related objective response rate 40% in dMMR CRC; 20-week PFS rate 78%) 3
• Nivolumab alone or with ipilimumab 1, 2

Why Immunotherapy Works in dMMR/MSI-H

• dMMR tumors contain thousands of mutations that encode mutant proteins recognizable by the immune system 3
• These tumors upregulate PD-L1, allowing immune evasion that PD-1 inhibitors can reverse 3
• Historically, fluoropyrimidine-based chemotherapy has been less effective in dMMR tumors, making immunotherapy the superior choice 3, 1

Treatment Duration and Monitoring

• Continue immunotherapy per FDA-approved duration for the specific agent 1
• Grade ≥3 treatment-related adverse events occur in approximately 16% of patients 2
• Monitor for response using standard imaging (CT/MRI) and tumor markers 2

For pMMR/MSS Stage IV Rectal Cancer (The Majority)

Immunotherapy Has NO Role

Immunotherapy as a single agent or in combination with other immune checkpoint inhibitors, targeted therapy, chemotherapy, or radiotherapy has proven inefficient in pMMR/MSS colorectal cancer 4

• The immune-related objective response rate for pembrolizumab in MMR-proficient CRC was 0% (95% CI, 0%-20%) 3
• The 20-week PFS rate was only 11% compared to 78% in dMMR tumors 3
• Standard chemotherapy-based regimens remain the treatment of choice 4

Rare Exceptions (Extremely Limited)

• A small subset with POLE/POLD1 mutations may respond to immunotherapy 4
• Patients without liver metastasis appear to have marginally better response rates 4
• However, concrete biomarkers of response are lacking, making routine use unjustified 4

Common Pitfalls to Avoid

1. Never assume immunotherapy works for all rectal cancers - it is biomarker-dependent 1, 4
2. Do not delay MMR/MSI testing - this should be performed at diagnosis to guide first-line therapy 1, 2
3. For dMMR/MSI-H tumors, do not default to chemotherapy first - immunotherapy is superior and should be first-line 1, 2
4. For pMMR/MSS tumors, do not waste time with immunotherapy trials - proceed directly to standard chemotherapy 4

Treatment Algorithm for Stage IV Rectal Cancer

1. Obtain MMR/MSI status immediately (IHC or PCR) 1, 2
2. If dMMR/MSI-H (3-6% of cases):
   • First-line: Dostarlimab, pembrolizumab, or nivolumab ± ipilimumab 1, 2
   • Expected response rate: 40-44% 3, 2
   • Continue per FDA-approved duration 1
3. If pMMR/MSS (94-97% of cases):
   • Immunotherapy has no role 4
   • Proceed with standard chemotherapy-based regimens 4
   • Consider clinical trials for novel approaches 4