What are the treatment options for advanced hepatocellular carcinoma (HCC) using immunotherapy, such as nivolumab (nivolumab) or pembrolizumab (pembrolizumab)?

Immunotherapy Options for Advanced Hepatocellular Carcinoma

For patients with advanced hepatocellular carcinoma (HCC), the combination of atezolizumab plus bevacizumab or tremelimumab plus durvalumab are the recommended first-line immunotherapy options, with both regimens demonstrating superior survival outcomes compared to sorafenib. 1

First-Line Immunotherapy Options

Preferred Regimens

1. Atezolizumab plus bevacizumab

   • Demonstrated superior overall survival compared to sorafenib 1
   • Important considerations:
     • Requires endoscopic screening for esophageal varices prior to treatment
     • Contraindicated in patients with grade 2 or higher varices due to bleeding risk
     • Patients should have well-preserved liver function (Child-Pugh A)

2. Tremelimumab plus durvalumab (STRIDE regimen)

   • Single dose of tremelimumab with regular interval durvalumab
   • Demonstrated superiority over sorafenib with OS HR of 0.78 1
   • Advantages:
     • Lower risk of hemorrhage compared to bevacizumab-containing regimens
     • Endoscopy not a prerequisite
     • Option for patients with contraindications to bevacizumab

Second-Line Immunotherapy Options

For patients who progress on or are intolerant to first-line therapy:

1. Pembrolizumab monotherapy

   • Has accelerated FDA approval as second-line option 1
   • Objective response rate of 17% in patients who progressed on sorafenib 1

2. Nivolumab plus ipilimumab

   • Has accelerated FDA approval as second-line option 1
   • Objective response rate of 33% in patients previously treated with sorafenib 1
   • Higher response rates compared to single-agent immunotherapy

3. Nivolumab monotherapy

   • Note: FDA approval was withdrawn based on negative results from the phase III CheckMate-459 trial 1
   • May still be considered in select patients who are intolerant to other options

Patient Selection and Monitoring

Key Eligibility Criteria

• Well-preserved liver function (Child-Pugh A) 1
• ECOG Performance Status 0-1 1
• For bevacizumab-containing regimens:
  • Absence of high-grade esophageal varices
  • No main portal vein invasion or clear bile duct invasion

Monitoring During Treatment

• Assess tumor response using dynamic CT or MRI studies every 3 months 1
• Use modified RECIST (mRECIST) criteria to evaluate response to therapy 1
• Monitor for immune-related adverse events, which are generally manageable but can occasionally be life-threatening 1

Treatment Algorithm

1. First-line therapy for advanced HCC (Child-Pugh A):

   • Preferred: Atezolizumab plus bevacizumab or tremelimumab plus durvalumab
   • If immunotherapy contraindicated: Sorafenib or lenvatinib

2. Second-line therapy (after progression on first-line):

   • If progression on atezolizumab plus bevacizumab or tremelimumab plus durvalumab:
     • Pembrolizumab monotherapy or nivolumab plus ipilimumab
   • If progression on TKIs (sorafenib/lenvatinib):
     • Pembrolizumab monotherapy or nivolumab plus ipilimumab

3. Third-line therapy:

   • Consider ipilimumab plus nivolumab for patients who progressed on prior ICI-based combinations
   • Small studies show objective response rates of 16-30% in this setting 2, 3

Special Considerations

• Immune-related adverse events: Checkpoint inhibitor therapy can cause a wide range of immune-related adverse events that require prompt recognition and management 1
• Liver dysfunction: Most clinical trials enrolled patients with well-preserved liver function (Child-Pugh A); limited data exists for patients with more advanced liver dysfunction
• Biomarkers: Currently, there are no validated biomarkers to predict response to immunotherapy in HCC 1
• Cost considerations: The high cost of immunotherapy may be a limiting factor in some regions 1

Emerging Approaches

• Combination strategies with local therapies (TACE, radiation) are under investigation
• Novel immunotherapy combinations are being explored to overcome resistance mechanisms
• Conversion therapy (using systemic therapy to downstage initially unresectable disease) is an emerging concept 1

Immunotherapy has transformed the treatment landscape for advanced HCC, offering improved survival outcomes compared to traditional therapies. The choice between atezolizumab plus bevacizumab and tremelimumab plus durvalumab should be based on patient-specific factors, particularly the risk of bleeding and presence of esophageal varices.