Is Yervoy (ipilimumab) + Opdivo (nivolumab) considered a first-line treatment?

Yervoy (ipilimumab) + Opdivo (nivolumab) as First-Line Treatment

Yes, Yervoy (ipilimumab) + Opdivo (nivolumab) is considered a first-line treatment option for patients with MSI-H/dMMR metastatic colorectal cancer (mCRC), based on the most recent NCCN guidelines and clinical trial data. 1

Evidence Supporting First-Line Use

• The 2024 NCCN Clinical Practice Guidelines explicitly recommend nivolumab, alone or in combination with ipilimumab, as a first-line treatment option for patients with MSI-H/dMMR mCRC, regardless of whether intensive therapy is recommended 1
• The FDA has approved Yervoy (ipilimumab) in combination with nivolumab for the treatment of MSI-H/dMMR mCRC, although the initial approval was for patients who had progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan 2
• The phase II CheckMate-142 trial demonstrated robust efficacy of nivolumab plus ipilimumab as first-line treatment for MSI-H/dMMR mCRC with:
  • Objective response rate (ORR) of 69% (95% CI, 53%–82%) 1
  • Disease control rate of 84% (95% CI, 70.5%–93.5%) 1
  • Complete response rate of 13% 1, 3
  • Median duration of response not reached at 29 months follow-up 1

Recent Evidence Strengthening First-Line Recommendation

• The phase III CheckMate 8HW study compared nivolumab plus ipilimumab to chemotherapy in the first-line setting for MSI-H/dMMR mCRC 1, 4
• With a median follow-up of 24.3 months, the combination showed:
  • 79% reduction in the risk of disease progression or death compared to chemotherapy (HR, 0.21; 95% CI, 0.14–0.32; P <.0001) 1
  • Lower percentage of grade ≥3 treatment-related adverse events compared with chemotherapy (23% vs 48%) 1
• The most recent data from CheckMate 8HW (2025) demonstrated superior progression-free survival with nivolumab plus ipilimumab versus nivolumab alone across all treatment lines (HR 0.62,95% CI 0.48-0.81; p=0.0003) 4

Safety Considerations

• While generally well-tolerated, serious immune-mediated adverse reactions occur in 21-41% of patients on checkpoint inhibitor therapy 1
• Common immune-mediated side effects affect:
  • Skin, liver, kidneys, gastrointestinal tract, lungs, and endocrine systems 1, 5
  • Pneumonitis is one of the most serious side effects, occurring in 3-7% of patients 1
• In the CheckMate-142 trial, 20% of patients experienced grade 3 or 4 treatment-related adverse events, and 13% discontinued treatment due to adverse events 1, 3

Important Caveats and Considerations

• The NCCN panel notes that the recommendation for nivolumab plus ipilimumab is category 2B when intensive therapy is not recommended due to concerns about potential toxicity 1
• Two treatment-related deaths were reported in the immunotherapy combination arm of CheckMate 8HW, compared to none with chemotherapy 1
• Patient selection is critical - testing for MSI/MMR status should be performed before treatment to determine eligibility for immunotherapy 5
• The combination may also be beneficial for other MSI-H/dMMR gastrointestinal cancers, with studies ongoing in gastric and esophagogastric junction cancers 6

Treatment Algorithm

1. First step: Test for MSI-H/dMMR status in all patients with metastatic colorectal cancer
2. If MSI-H/dMMR positive:
   • For patients eligible for intensive therapy: Nivolumab plus ipilimumab is a category 1 recommended first-line option
   • For patients not eligible for intensive therapy: Nivolumab plus ipilimumab is a category 2B option (consider single-agent nivolumab or pembrolizumab instead)
3. Dosing regimen: Nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks 3
4. Duration: Continue until disease progression or unacceptable toxicity

In conclusion, based on the most recent and highest quality evidence from the 2024 NCCN guidelines and the CheckMate 8HW trial, nivolumab plus ipilimumab is an effective first-line treatment option for MSI-H/dMMR mCRC with significant improvements in progression-free survival compared to chemotherapy.