What are the first and second line treatment options for hepatocellular carcinoma (HCC) in a medical oncology setting?

First-Line and Second-Line Treatment Options for Hepatocellular Carcinoma

For patients with advanced hepatocellular carcinoma (HCC), atezolizumab plus bevacizumab is the preferred first-line systemic therapy, followed by durvalumab plus tremelimumab, with second-line options including tyrosine kinase inhibitors (TKIs) such as cabozantinib, regorafenib, or ramucirumab depending on specific patient factors. 1

First-Line Systemic Therapy Options

Preferred First-Line Options:

1. Atezolizumab plus Bevacizumab

   • Gold standard first-line therapy for most patients with:
     • Child-Pugh class A liver function
     • ECOG performance status 0-1
     • Properly managed esophageal varices 1
   • Demonstrated superior overall survival compared to sorafenib (HR = 0.58) 1
   • Important safety consideration: Requires screening and management of esophageal varices prior to initiation due to bleeding risk 1

2. Durvalumab plus Tremelimumab

   • Strong alternative first-line option
   • Demonstrated survival benefit over sorafenib (HR = 0.78) 1
   • May be particularly beneficial in:
     • Patients with non-viral HCC
     • Patients with AFP ≥400 μg/L 2

Alternative First-Line Options (when immunotherapy combinations are contraindicated):

1. Sorafenib

   • For patients with contraindications to immunotherapy combinations
   • 400 mg twice daily 1
   • Consider in patients with autoimmune disorders or high bleeding risk

2. Lenvatinib

   • For patients with contraindications to immunotherapy combinations
   • Dosing based on weight: 12 mg daily (≥60 kg) or 8 mg daily (<60 kg) 3
   • May have higher response rates than sorafenib 4

3. Durvalumab monotherapy

   • Alternative when immunotherapy combinations are contraindicated 1

Second-Line Systemic Therapy Options

After Atezolizumab plus Bevacizumab:

1. Tyrosine Kinase Inhibitors (TKIs):

   • Cabozantinib: Preferred option 1
   • Sorafenib: If not used in first-line
   • Lenvatinib: If not used in first-line
   • Regorafenib: Particularly for patients who previously tolerated sorafenib 1

2. Ramucirumab:

   • For patients with AFP ≥400 ng/mL 1

3. Nivolumab plus Ipilimumab:

   • May be considered, though evidence is limited to case series 1

After Durvalumab plus Tremelimumab:

1. TKIs are recommended:
   • Cabozantinib, sorafenib, or lenvatinib 1

After Sorafenib or Lenvatinib:

1. Preferred options:

   • Cabozantinib
   • Regorafenib (for patients who previously tolerated sorafenib)
   • Ramucirumab (for AFP ≥400 ng/mL)
   • Nivolumab plus ipilimumab
   • Durvalumab 1

2. Alternative options:

   • Atezolizumab plus bevacizumab (if not accessible in first-line)
   • Pembrolizumab or nivolumab monotherapy 1

Third-Line Therapy Considerations

• Consider agents with non-identical mechanisms of action to previously received therapies
• Limited to Child-Pugh class A patients with good performance status 1

Special Considerations

Child-Pugh B Patients:

• Use caution with systemic therapy
• Reduced dosing and close monitoring required 1

Bleeding Risk Assessment:

• Screen for and manage esophageal varices before starting atezolizumab plus bevacizumab
• Consider risk of bleeding and thrombosis with VEGF inhibitors 1

Autoimmune Disease:

• Consider risk of immune-related adverse effects with immunotherapy
• May need to select TKIs instead of immunotherapy 1

Treatment Selection Algorithm

1. Assess liver function: Child-Pugh class and ECOG performance status
2. Screen for contraindications:
   • Bleeding risk/varices (for bevacizumab-containing regimens)
   • Autoimmune disease (for immunotherapy)
   • Cardiovascular disease (for TKIs)
3. Select first-line therapy:
   • If Child-Pugh A, ECOG 0-1, no contraindications → Atezolizumab plus bevacizumab
   • If contraindicated → Durvalumab plus tremelimumab, sorafenib, or lenvatinib
4. Monitor response using standard imaging criteria
5. Upon progression, select second-line therapy based on:
   • Prior therapy received
   • AFP level (for ramucirumab consideration)
   • Tolerability of prior therapy
   • Comorbidities

The treatment landscape for HCC continues to evolve rapidly, with combination immunotherapy approaches demonstrating significant improvements in overall survival compared to traditional TKIs 5.