What is the treatment for liver toxicity associated with Ipilimumab (Yervoy) and Nivolumab (Opdivo) therapy?

Treatment of Liver Toxicity from Ipilimumab plus Nivolumab

For immune-mediated hepatitis from ipilimumab plus nivolumab combination therapy, immediately withhold both agents and initiate high-dose systemic corticosteroids (equivalent to 1-2 mg/kg/day prednisone) for Grade 2 or higher liver enzyme elevations, with 100% of patients requiring corticosteroid therapy according to FDA labeling and ESMO guidelines. 1, 2

Grading and Initial Management

Grade 1 (AST/ALT <3x ULN):

• Continue immunotherapy with close monitoring of liver enzymes every 1-2 weeks 2
• No corticosteroids required at this stage 2

Grade 2 (AST/ALT 3-5x ULN or Total Bilirubin 1.5-3x ULN):

• Withhold both ipilimumab and nivolumab immediately 1
• Initiate prednisone 0.5-1 mg/kg/day (or methylprednisolone equivalent) 2
• Monitor liver function tests every 3-5 days 2
• Resume immunotherapy only after liver enzymes return to Grade 1 or baseline 1

Grade 3-4 (AST/ALT >5x ULN or Total Bilirubin >3x ULN):

• Permanently discontinue both agents 1
• Initiate high-dose corticosteroids: methylprednisolone 1-2 mg/kg/day IV or prednisone 1-2 mg/kg/day orally 2, 1
• 100% of patients with immune-mediated hepatitis require systemic corticosteroids 1

Specific Considerations for Combination Therapy

The combination of ipilimumab 3 mg/kg with nivolumab 1 mg/kg carries particularly high hepatotoxicity risk:

• Immune-mediated hepatitis occurs in 15% of patients receiving this regimen 1
• Grade 3-4 hepatitis occurs in 11-13% of patients 1
• Hepatitis leads to permanent discontinuation in 8% of patients 1

For the alternative dosing of nivolumab 3 mg/kg with ipilimumab 1 mg/kg:

• Immune-mediated hepatitis occurs in 7% of patients 1
• Grade 3-4 hepatitis occurs in approximately 6% 1

Corticosteroid Management Algorithm

Initial Treatment:

• Start methylprednisolone 1-2 mg/kg/day IV or prednisone equivalent orally 2, 1
• Continue high-dose corticosteroids until liver enzymes improve to Grade 1 or baseline 2
• This typically requires 3-5 days to see initial response 2

Corticosteroid Taper:

• Once liver enzymes improve to Grade 1, taper corticosteroids over 4-6 weeks minimum 2
• Monitor liver function tests weekly during taper 2
• Rapid taper increases risk of hepatitis flare 3

Steroid-Refractory Hepatitis

If no improvement after 3-5 days of high-dose corticosteroids or worsening despite treatment:

• Add mycophenolate mofetil (MMF) 1 gram twice daily (2 g/day total) 3
• Approximately 9-19% of patients with immune-mediated hepatitis require addition of mycophenolic acid to high-dose corticosteroids 1
• MMF has demonstrated efficacy in steroid-refractory cases, allowing successful corticosteroid taper 3
• Alternative agents include infliximab, though this carries its own hepatotoxicity risk and should be used with extreme caution 4

Monitoring Requirements

During Active Hepatitis:

• Check AST, ALT, total bilirubin, and alkaline phosphatase every 3-5 days initially 2
• Once improving, transition to weekly monitoring 2

During Corticosteroid Taper:

• Monitor liver function tests weekly 2
• Watch for hepatitis recurrence, which occurs in 57-71% of patients who restart therapy after Grade 3-4 hepatitis 1

Critical Diagnostic Considerations

Rule out alternative causes before attributing to immunotherapy:

• Viral hepatitis (hepatitis A, B, C, E) 2
• Drug-induced liver injury from other medications 4
• Metastatic disease progression 2
• Consider liver biopsy for Grade 3-4 toxicity when diagnosis is uncertain and would alter management 2

Rechallenge Considerations

For patients who had hepatitis withheld (not permanently discontinued):

• Of patients restarting after Grade 2 hepatitis improvement, 82% experience recurrence 1
• For combination therapy, recurrence rates are 57-71% depending on dosing regimen 1
• Do not rechallenge patients who had Grade 3-4 hepatitis 1
• If rechallenge is attempted for Grade 2, use single-agent nivolumab only, not combination therapy 1

Resolution Rates

• Hepatitis resolves in 88-91% of patients with appropriate corticosteroid management 1
• Resolution typically occurs over 4-8 weeks with proper treatment 2
• Approximately 35% of patients with adrenal insufficiency from corticosteroid therapy may require ongoing hormone replacement 1

Special Monitoring with Cabozantinib Combination

When nivolumab is combined with cabozantinib (not ipilimumab), additional hepatotoxicity occurs:

• Grade 3-4 ALT/AST elevations occur in 11% of patients 1
• Requires more frequent liver enzyme monitoring than single-agent therapy 1
• 28% of patients with Grade ≥2 elevations require systemic corticosteroids 1