What is the recommended treatment for patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors?

Treatment of dMMR/MSI-H Tumors

Immunotherapy is the recommended initial treatment for patients with dMMR/MSI-H tumors across multiple cancer types, with PD-1 inhibitors (pembrolizumab, nivolumab, dostarlimab) demonstrating superior outcomes compared to conventional chemotherapy. 1

Locally Advanced Rectal Cancer (dMMR/MSI-H)

Primary Treatment Approach

• Immunotherapy is strongly recommended as the initial approach for MSI-H or dMMR rectal cancers (evidence quality: low; strength of recommendation: strong). 1

• Dostarlimab achieved 100% clinical complete response (cCR) rates in locally advanced rectal cancer, with all 42 patients who completed treatment maintaining cCR with zero progression or recurrence at 2024 ASCO data analysis. 2

• No grade 3 or higher adverse events were reported with dostarlimab monotherapy in this population. 2

• Alternative PD-1 inhibitors include pembrolizumab and nivolumab, which are also guideline-recommended options. 2, 3

For Patients with Contraindications to Immunotherapy

• The treatment options outlined for proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumors are recommended, including total neoadjuvant therapy (TNT) or chemoradiation. 1

• Important caveat: dMMR tumors have been shown to be sensitive to chemoradiation therapy (CRT), but historically fluorouracil-based chemotherapy has been less effective in patients with dMMR. 1

Nonoperative Management After Complete Response

• For patients achieving cCR with immunotherapy, nonoperative management (NOM) may be discussed as an alternative to total mesorectal excision. 1

• A preference for NOM may be greater among patients who require abdominoperineal resection (APR) or coloanal anastomosis. 1

• Rigorous surveillance is mandatory: Digital rectal examination (DRE) and flexible sigmoidoscopy every 4 months for the first 2 years, then every 6 months for 3 additional years. 1, 2

• Rectal MRI should be performed every 6 months for the first 2 years and yearly for the following 3 years. 1

• Critical timing: 94-99% of tumor regrowth occurs within the first 2-3 years, making this surveillance window essential. 2

• Definition of cCR for NOM eligibility: DRE and rectoscopy showing no palpable tumor material, no residual tumor material, and no erythematous ulcer or scar; MRI showing substantial downsizing with no observable residual tumor material or residual fibrosis only. 1

• Endoscopic biopsy is not mandatory or required to define cCR and should not be performed, especially if DRE, rectoscopy, and MRI criteria for cCR are all fulfilled. 1

Metastatic/Advanced Colorectal Cancer (dMMR/MSI-H)

First-Line Treatment

• Pembrolizumab is FDA-approved and guideline-recommended as first-line therapy for metastatic dMMR/MSI-H colorectal cancer, with an objective response rate of 43.5% (95% CI, 34.3-53.0%). 2, 4

• NCCN recommends dostarlimab, pembrolizumab, or nivolumab (alone or with ipilimumab) as interchangeable first-line options for dMMR/MSI-H metastatic disease. 2

• In the phase I GARNET study of 115 colorectal cancer patients with dMMR who had received prior systemic therapy, median progression-free survival was 8.4 months, and median duration of response and overall survival were not yet reached. 2

• Grade ≥3 treatment-related adverse events occurred in 16.3% of the GARNET safety population. 2

Chemotherapy Considerations

• Fluoropyrimidine-only adjuvant chemotherapy is not routinely recommended for patients with dMMR or MSI tumors (harms outweigh benefits; evidence quality: moderate; strength of recommendation: strong). 1

• Fluorouracil-based chemotherapy has been historically less effective in patients with dMMR, with some evidence suggesting it may even be detrimental in stage II disease. 1, 5

• In one pooled analysis, patients with stage II disease and dMMR tumors receiving fluorouracil-based treatment had reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04). 5

Gastric Cancer (dMMR/MSI-H)

First-Line Treatment Options

• Nivolumab plus fluoropyrimidine and oxaliplatin-based chemotherapy is recommended as first-line treatment for MSI-H gastric cancer, independent of PD-L1 status (Category 2A preferred option). 1, 6

• The survival benefit is dramatic: median OS of 38.7 months versus 12.3 months with chemotherapy alone (HR 0.34) in the CheckMate-649 trial subset analysis. 1, 6

• For MSI-H patients with PD-L1 CPS ≥5, the benefit was even more pronounced: 44.8 months versus 8.8 months (HR, 0.29). 1, 6

Alternative Options

• Pembrolizumab monotherapy is a Category 2A preferred option for MSI-H tumors, with an ORR of 45.8% and median PFS of 11 months in previously treated MSI-H gastric cancer. 6

• Nivolumab plus ipilimumab is a Category 2A preferred option for first-line MSI-H disease, with median OS not reached versus 10 months with chemotherapy (HR 0.28). 1, 6

Safety Profile

• Grade 3-4 treatment-related adverse events occurred in 59% with nivolumab plus chemotherapy versus 44% with chemotherapy alone in CheckMate-649. 1, 6

• Sixteen treatment-related deaths occurred in the nivolumab plus chemotherapy group versus 4 in chemotherapy alone. 1, 6

• Monitor closely for immune-related adverse events including colitis, hepatitis, pneumonitis, and endocrinopathies. 6

Stage II Colon Cancer (dMMR/MSI-H)

Adjuvant Treatment Recommendations

• Adjuvant fluoropyrimidine-only chemotherapy is not routinely recommended for patients with dMMR or MSI tumors (harms outweigh benefits; evidence quality: moderate; strength of recommendation: strong). 1

• For patients with dMMR or MSI who have T4 tumors and/or other high-risk features (with the exception of poor differentiation), oxaliplatin-containing chemotherapy may be considered. 1

• Important distinction: Poor differentiation is not considered a high-risk prognostic factor in patients with dMMR or MSI tumors. 1

Clinical Decision Algorithm

Step 1: Universal Testing

• Test all colorectal cancers for MMR/MSI status using immunohistochemistry (IHC) for MMR proteins or PCR for MSI. 2, 3

Step 2: Treatment Selection Based on Stage and Tumor Type

For Locally Advanced Rectal Cancer (Stage II/III):

• Offer dostarlimab, pembrolizumab, or nivolumab as initial therapy. 2, 3
• Assess for cCR at 6 months using MRI, PET/CT, endoscopy, DRE, and biopsy. 2
• If cCR achieved, discuss nonoperative management with intensive surveillance protocol. 1, 2
• If contraindications to immunotherapy exist, proceed with TNT or chemoradiation (noting dMMR tumors are sensitive to CRT). 1

For Metastatic Colorectal Cancer:

• First-line options: dostarlimab, pembrolizumab, or nivolumab ± ipilimumab. 2, 4
• Continue immunotherapy per FDA-approved duration (typically up to 24 months or until progression). 6

For Gastric Cancer:

• Preferred: nivolumab plus fluoropyrimidine and oxaliplatin (independent of PD-L1 status). 1, 6
• Alternative: pembrolizumab monotherapy or nivolumab plus ipilimumab. 6

For Stage II Colon Cancer:

• Avoid fluoropyrimidine-only adjuvant chemotherapy. 1
• Consider oxaliplatin-containing regimens only for T4 tumors or other high-risk features (excluding poor differentiation). 1

Step 3: Monitoring and Reassessment

• For patients on immunotherapy achieving cCR and pursuing NOM: implement intensive surveillance with DRE and sigmoidoscopy every 4 months for 2 years, then every 6 months for 3 years. 1, 2
• For metastatic disease: restage after 2-3 cycles with CT imaging to assess response. 6
• Monitor for immune-related adverse events throughout treatment. 6

Common Pitfalls to Avoid

• Do not use fluoropyrimidine-based chemotherapy alone in dMMR/MSI-H stage II colon cancer, as it provides no benefit and may cause harm. 1, 5
• Do not perform endoscopic biopsy to confirm cCR if DRE, rectoscopy, and MRI criteria are all fulfilled, as this is not recommended. 1
• Do not consider poor differentiation as a high-risk feature in dMMR/MSI-H tumors when making treatment decisions. 1
• Do not delay immunotherapy in favor of chemotherapy for dMMR/MSI-H tumors, as immunotherapy demonstrates superior outcomes. 1, 2