What is the recommended treatment approach for a patient with stage IV rectal adenocarcinoma and microsatellite instability-high (MSI-H) or mismatch repair deficiency (MMR)?

Treatment Approach for Stage IV MSI-H/dMMR Rectal Adenocarcinoma

Immunotherapy with PD-1 inhibitors (pembrolizumab, nivolumab, or dostarlimab) is the recommended first-line treatment for stage IV rectal adenocarcinoma with MSI-H or dMMR status, achieving superior outcomes compared to conventional chemotherapy. 1, 2, 3

Initial Biomarker Testing

• All patients with stage IV rectal cancer must undergo MMR/MSI testing using immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6, PMS2) or PCR-based microsatellite analysis before initiating systemic therapy 1, 2
• Testing should be performed at diagnosis to avoid unnecessary exposure to ineffective fluoropyrimidine-based chemotherapy, which has historically shown lower response rates in dMMR tumors (5% versus 44% in pMMR) 4

First-Line Treatment Options

The NCCN and FDA recommend the following PD-1 inhibitors as interchangeable first-line options for metastatic MSI-H/dMMR colorectal cancer: 1, 2, 3

• Pembrolizumab - FDA-approved with objective response rate of 43.5% 1
• Dostarlimab - FDA-approved and guideline-recommended with objective response rate of 43.5% (95% CI, 34.3-53.0%) 1
• Nivolumab monotherapy - FDA-approved for MSI-H/dMMR metastatic CRC 3
• Nivolumab plus ipilimumab - FDA-approved combination option for MSI-H/dMMR metastatic CRC 3

Dosing Regimens

For adult patients with stage IV MSI-H/dMMR rectal cancer: 3

• Nivolumab monotherapy: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks until disease progression or unacceptable toxicity
• Continue treatment until disease progression or unacceptable toxicity occurs

Rationale for Immunotherapy Over Chemotherapy

Immunotherapy is strongly preferred over chemotherapy in this population based on multiple factors: 4, 1, 5

• dMMR/MSI-H tumors have high tumor mutational burden and generate mutation-associated neoantigens that create ideal conditions for T-cell priming and antitumor immunity 5, 6
• Response rates to first-line fluoropyrimidine-based chemotherapy are significantly lower in dMMR mCRC patients (5%) compared to pMMR patients (44%) 4
• In the KEYNOTE-177 control arm, dMMR mCRC patients receiving chemotherapy with/without targeted treatment showed lower-than-expected response rates of 33.1% and PFS of only 8.2 months 4
• Population-based studies show worse median overall survival in dMMR mCRC patients receiving chemotherapy (16.0 months) compared to pMMR patients (23.6 months) 4

Clinical Outcomes with Immunotherapy

Immunotherapy demonstrates superior efficacy in MSI-H/dMMR metastatic colorectal cancer: 1, 5, 7

• Objective response rates of 40-45.8% with PD-1 inhibitors 1, 2
• Durable responses with dramatic long-term benefit compared to chemotherapy 7
• In the GARNET study of 115 dMMR colorectal cancer patients who had received prior systemic therapy, median PFS was 8.4 months, and median duration of response and overall survival were not yet reached 1
• Grade ≥3 treatment-related adverse events occurred in only 16.3% of patients 1

Treatment Algorithm

Step 1: Confirm MSI-H/dMMR status via IHC or PCR testing 1, 2

Step 2: Initiate first-line PD-1 inhibitor immunotherapy with one of the following options: 1, 2, 3

• Pembrolizumab
• Dostarlimab
• Nivolumab (alone or with ipilimumab)

Step 3: Continue immunotherapy until disease progression or unacceptable toxicity 3

Step 4: Monitor for response using standard imaging and tumor markers 1

Critical Pitfalls to Avoid

Do not initiate fluoropyrimidine-based chemotherapy as first-line treatment in confirmed MSI-H/dMMR stage IV rectal cancer, as this represents suboptimal therapy with inferior outcomes compared to immunotherapy 4, 1, 2

Do not delay MMR/MSI testing - this must be performed at diagnosis to guide appropriate first-line therapy selection 1, 2

Avoid using anti-EGFR therapy without KRAS/NRAS testing, though this is less relevant in MSI-H/dMMR disease where immunotherapy is preferred 1

Special Considerations

• Approximately 20-30% of dMMR mCRC patients do not respond to immunotherapy 4
• For the minority of patients who progress on or are ineligible for immunotherapy, chemotherapy options include FOLFOX, FOLFIRI, or CAPOX with or without bevacizumab, though response rates are historically lower 4
• Combination approaches with immunotherapy plus chemotherapy are being investigated but are not currently standard first-line therapy 8