What is the role of Yervoy (ipilimumab) in treating Microsatellite Instability-high (MSI-high) colon cancer?

Role of Ipilimumab (Yervoy) in MSI-High Colon Cancer

Ipilimumab in combination with nivolumab is indicated for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. 1

Efficacy and Approval Status

• Ipilimumab (Yervoy) received FDA approval for use in combination with nivolumab for MSI-H/dMMR metastatic colorectal cancer that has progressed following standard chemotherapy, based on the CheckMate-142 clinical study 1
• The combination of nivolumab plus ipilimumab demonstrated high response rates (55%), encouraging progression-free survival and overall survival at 12 months (71% and 85%, respectively) in previously treated MSI-H/dMMR colorectal cancer 2
• The 2024 Chinese Society of Clinical Oncology (CSCO) Guidelines recommend nivolumab combined with ipilimumab for the treatment of MSI-H/dMMR advanced colorectal cancer in the first-, second-, and third-line settings (Grade 3 recommendation) 3

First-Line Treatment Options for MSI-H/dMMR Colorectal Cancer

• PD-1/PD-L1 inhibitors are strongly recommended for patients with MSI-H/dMMR tumors (Level of Evidence: III, Grade of Recommendation: A) 3

• First-line treatment options for MSI-H/dMMR metastatic colorectal cancer include:

  • Pembrolizumab monotherapy 3
  • Nivolumab monotherapy 3
  • Nivolumab plus ipilimumab combination 3
  • Dostarlimab-gxly 3

• The phase III KEYNOTE-177 study demonstrated that pembrolizumab significantly improved progression-free survival compared to chemotherapy (16.5 vs 8.2 months; HR, 0.60) in first-line treatment of MSI-H/dMMR metastatic colorectal cancer 3

• The CheckMate 8HW phase III study showed that nivolumab plus ipilimumab significantly improved progression-free survival compared to chemotherapy in the first-line setting, with a 79% reduction in the risk of disease progression or death (HR, 0.21) 3

Second-Line and Later Treatment

• For patients who have progressed on prior PD-1 inhibitor therapy, the combination of nivolumab plus ipilimumab may provide clinical benefit 4
• The CheckMate-142 study showed that nivolumab plus ipilimumab demonstrated robust clinical benefit in previously treated MSI-H/dMMR colorectal cancer, with an objective response rate of 55% and disease control rate of 80% 2
• The combination therapy has shown durable responses, with 94% of responses ongoing at data cutoff in the CheckMate-142 study 2

Safety Considerations

• Grade 3-4 treatment-related adverse events occurred in 22-32% of patients receiving nivolumab plus ipilimumab 2, 5
• Common immune-mediated side effects affect the skin, liver, kidneys, gastrointestinal tract, lungs, and endocrine systems 3
• Pneumonitis is one of the most serious side effects, occurring in approximately 3-7% of patients on checkpoint inhibitor therapy 3
• Despite potential toxicity concerns, the combination has demonstrated a manageable safety profile, with most adverse events being manageable 2

Emerging Applications

• Neoadjuvant use of nivolumab and ipilimumab for MSI-H/dMMR colon cancer has shown promising results in the NICHE trial 6
• Ongoing research is exploring the role of ipilimumab in combination with nivolumab as adjuvant therapy for early-stage MSI-H/dMMR colorectal cancer 7

Clinical Pearls and Caveats

• Testing for MSI/MMR status should be performed before or during standard treatment of advanced solid tumors to determine eligibility for immunotherapy 3
• The combination of nivolumab plus ipilimumab may be particularly beneficial for patients who have progressed on single-agent PD-1 inhibitors 4
• When considering ipilimumab plus nivolumab for patients not appropriate for intensive therapy, be aware that this is a category 2B recommendation due to potential toxicity concerns 3
• Patient-reported outcomes have shown stable or improved quality of life metrics during treatment with nivolumab plus ipilimumab 2, 5

In summary, ipilimumab in combination with nivolumab represents an important treatment option for MSI-H/dMMR colorectal cancer, with demonstrated efficacy in both previously treated and first-line settings. The combination offers robust response rates and durable clinical benefit, though careful monitoring for immune-related adverse events is necessary.