What are the indications and dosing regimens for nivolumab (Opdivo) and ipilimumab (Yervoy) in cancer treatment?

Nivolumab and Ipilimumab: Indications and Dosing Regimens in Cancer Treatment

Nivolumab plus ipilimumab combination therapy is FDA-approved for advanced melanoma, renal cell carcinoma, and microsatellite-unstable tumors, with specific dosing regimens tailored to each cancer type to optimize efficacy while managing the significantly higher risk of immune-related adverse events compared to monotherapy.

Approved Indications for Combination Therapy

Advanced Melanoma

• First-line treatment for unresectable or metastatic melanoma 1
• Neoadjuvant therapy for resectable stage III melanoma (clinically positive nodes) 1
• Adjuvant therapy following surgery for high-risk melanoma

Other FDA-Approved Indications

• Renal cell carcinoma (RCC) 1
• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors 1
• Unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) - first-line treatment 2

Dosing Regimens

Melanoma

• Standard FDA-approved regimen: Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity 1, 2
• Alternative "flip-dose" regimen: Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 2-4 doses, followed by nivolumab monotherapy 1
  • Associated with lower toxicity (20% grade 3-4 immune-related adverse events vs. 40% with standard dosing) while maintaining similar efficacy 1

Neoadjuvant Setting for Melanoma

• Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 2 doses before surgery 1
• Pathologic response rates of 77% have been observed with this regimen 1

Other Cancers

• NSCLC: Nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicity, or up to 2 years 2
• Gastric/Esophageal: Nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy 2

Efficacy Outcomes

Melanoma

• CheckMate 067 trial (10-year follow-up): Median overall survival of 71.9 months with nivolumab plus ipilimumab vs. 36.9 months with nivolumab alone and 19.9 months with ipilimumab alone 3
• 5-year survival rate: 52% with combination therapy vs. 44% with nivolumab alone vs. 26% with ipilimumab alone 4
• Pathologic response rates in neoadjuvant setting: 77-80% with combination therapy 1

Special Populations

• Brain metastases: 71% 24-month survival rate with combination therapy 5
• Ocular/uveal melanoma: 36% 24-month survival rate 5
• Mucosal melanoma: 38% 24-month survival rate 5

Safety and Adverse Events

Immune-Related Adverse Events (irAEs)

• Combination therapy has significantly higher rates of grade 3-4 irAEs (55-60%) compared to anti-PD-1 monotherapy (10-20%) 1
• Most common severe irAEs with combination therapy:
  • Colitis (10-13%)
  • Hepatitis (elevated ALT/AST) (10-11%)
  • Endocrinopathies (6-11%)
  • Pneumonitis (1-14%)
  • Myocarditis (rare but potentially fatal) 1

Fatal Adverse Events

• Fatal irAE rate: 1.23% with combination therapy vs. 0.36-0.38% with anti-PD-1 monotherapy 1
• Distribution of fatal irAEs with combination therapy:
  • Colitis (37%)
  • Myocarditis (25%)
  • Hepatitis (22%)
  • Pneumonitis (14%)
  • Myositis (13%) 1

Dosing Considerations and Management

Dose Modifications

• Treatment should be withheld for grade 3 immune-mediated adverse reactions 2
• Permanently discontinue for:
  • Life-threatening (grade 4) immune-mediated adverse reactions
  • Recurrent severe (grade 3) immune-mediated reactions requiring systemic immunosuppression
  • Inability to reduce corticosteroid dose to ≤10 mg prednisone equivalent within 12 weeks 2

Alternative Dosing Strategies

• CheckMate 511 trial: "Flip-dose" regimen (NIVO3/IPI1) showed significantly reduced high-grade TRAEs compared to standard dosing (NIVO1/IPI3) while maintaining efficacy 1
• Fixed-duration therapy: Some trials have explored limiting treatment to 24 months rather than continuing until progression 1

Clinical Decision-Making Algorithm

1. Assess patient eligibility:

   • Confirm cancer type (melanoma, RCC, MSI-H tumors, ESCC)
   • Determine disease stage (unresectable/metastatic)
   • Evaluate BRAF mutation status (for melanoma)
   • Assess performance status and comorbidities

2. Select appropriate regimen based on:

   • Cancer type and stage
   • Patient's performance status and comorbidities
   • Risk tolerance for immune-related adverse events

3. For patients with high risk of toxicity:

   • Consider "flip-dose" regimen (NIVO3/IPI1) for melanoma
   • Consider single-agent nivolumab or pembrolizumab if toxicity concerns are significant

4. Monitor for immune-related adverse events:

   • Baseline and periodic laboratory assessments
   • Regular clinical evaluation for symptoms of colitis, pneumonitis, hepatitis, endocrinopathies
   • Early intervention for grade 2+ toxicities

5. Assess response and duration of therapy:

   • Continue until disease progression or unacceptable toxicity
   • Consider fixed duration therapy (up to 2 years) in select patients with sustained response

Important Caveats and Considerations

• Patient selection is critical: Higher toxicity of combination therapy requires careful assessment of patient fitness and ability to tolerate potential severe adverse events
• Early recognition and management of irAEs is essential to prevent progression to severe or fatal outcomes
• PD-L1 expression testing has not proven sufficiently discriminative for patient selection in melanoma 1
• Treatment discontinuation due to toxicity may not compromise survival benefit if it occurs after at least 3 doses of combination therapy 1