What is the role of tremilimumab (tremelimumab) and durvalumab in the treatment of a patient with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC), multinodular disease, preserved liver function (Child-Pugh A-B), and good performance status (Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0)?

Tremelimumab and Durvalumab for BCLC Stage B HCC

For your patient with BCLC stage B HCC, multinodular disease, preserved liver function (Child-Pugh A-B), and ECOG PS 0, tremelimumab plus durvalumab is NOT the standard first-line approach—locoregional therapy with TACE remains the primary treatment, but this immunotherapy combination can be considered in highly selected cases when TACE is not feasible or after TACE failure. 1

Primary Treatment Approach for BCLC Stage B

• TACE is the established first-line therapy for BCLC stage B patients with multinodular disease, preserved liver function, and good performance status. 1, 2
• Both conventional TACE (cTACE) and drug-eluting bead TACE (DEB-TACE) are equivalent options, with DEB-TACE particularly beneficial for tumors ≥3 cm. 2
• TACE should be performed through tumor-feeding arteries in a superselective manner to maximize efficacy and minimize complications. 2

When Systemic Therapy Becomes Relevant

Tremelimumab plus durvalumab enters consideration in the following scenarios:

After TACE Failure or Refractoriness

• Patients who fail to respond to more than 3 TACE sessions within 12 months are considered TACE-refractory and become candidates for systemic therapy. 1
• A paradigm shift has occurred where systemic therapy combined with or following TACE can be considered in highly selected BCLC stage B patients with Child-Pugh A and ECOG PS 0-1. 1

When TACE is Contraindicated or Not Amenable

• If locoregional therapy is not feasible due to technical factors or patient-specific contraindications, systemic therapy becomes the primary option. 1

Tremelimumab Plus Durvalumab: Evidence and Efficacy

FDA Approval and Indication

• Durvalumab in combination with tremelimumab is FDA-approved for unresectable hepatocellular carcinoma (uHCC). 3
• This approval is based on the HIMALAYA trial, which demonstrated superiority over sorafenib. 1

HIMALAYA Trial Results

• The combination showed an overall survival hazard ratio of 0.78 (96.02% CI 0.65 to 0.93; p=0.0035) compared to sorafenib. 1
• Median OS was 16.43 months for tremelimumab plus durvalumab versus 13.77 months for sorafenib. 1
• Objective response rate was 20.1% versus 5.1% for sorafenib. 1
• Importantly, the trial excluded patients with main portal vein thrombosis, which is relevant for patient selection. 1

Delayed Treatment Effect

• Kaplan-Meier survival curves showed delayed separation, with hazard ratios before and after 9 months being 0.87 (95% CI 0.68 to 1.11) and 0.70 (95% CI 0.56 to 0.89), respectively. 1
• This delayed effect means patients need adequate liver reserve to survive long enough to benefit from immunotherapy. 1

Safety Profile

• Grade 3-4 adverse events occurred in 50.5% of patients receiving tremelimumab plus durvalumab versus 52.4% with sorafenib. 1
• Immune-related adverse events requiring high-dose glucocorticoid treatment occurred in 20.1% of patients on the combination. 1
• The frequency of hepatic and hemorrhagic adverse events was similar across treatment arms. 1

Guideline Recommendations

First-Line Systemic Therapy Hierarchy

When systemic therapy is indicated, the following hierarchy applies:

1. Atezolizumab plus bevacizumab OR tremelimumab plus durvalumab are recommended as first-line options for Child-Pugh A patients with ECOG PS 0-1. 1

2. Choice between these two combinations depends on:

   • Risk of bleeding and thrombosis (higher with bevacizumab due to VEGF inhibition). 1
   • History of autoimmune disease (consider immune-related adverse event risk with both regimens). 1
   • Presence of varices or bleeding risk (tremelimumab plus durvalumab may be preferred as it avoids bevacizumab). 4

3. If contraindications exist to both combination regimens, sorafenib, lenvatinib, or durvalumab monotherapy may be offered. 1

Quality of Life Considerations

• Median time to deterioration of patient-reported quality of life was 7.5 months for tremelimumab plus durvalumab versus 5.7 months for sorafenib. 1
• This represents a meaningful improvement in maintaining quality of life during treatment. 1

Clinical Decision Algorithm for Your Patient

For BCLC Stage B, Child-Pugh A-B, ECOG PS 0, multinodular HCC:

1. First: Assess TACE eligibility

   • If technically feasible and no contraindications → Proceed with TACE 1, 2
   • If TACE contraindicated or not feasible → Consider systemic therapy

2. If TACE performed but fails (>3 sessions without response in 12 months):

   • Transition to systemic therapy 1

3. When systemic therapy is indicated:

   • Screen for bleeding risk (varices, coagulopathy, recent hemorrhage)
   • If high bleeding risk → Tremelimumab plus durvalumab preferred over atezolizumab plus bevacizumab 1, 4
   • If low bleeding risk → Either combination acceptable; atezolizumab plus bevacizumab has slightly more robust data 4

4. Ensure Child-Pugh A status:

   • Tremelimumab plus durvalumab is only recommended for Child-Pugh A patients 1
   • Child-Pugh B patients have limited evidence and should be approached with caution 1

Important Caveats

• BCLC stage B is heterogeneous: Not all multinodular patients are identical. Those with more extensive disease burden approaching BCLC C characteristics may benefit more from upfront systemic therapy. 1, 5
• Main portal vein invasion is an exclusion: The HIMALAYA trial excluded these patients, so evidence is lacking for this subgroup. 1
• Treatment sequencing matters: There is no robust data on optimal sequencing after progression on tremelimumab plus durvalumab, though TKIs (lenvatinib, sorafenib) are typically used. 1
• Reimbursement considerations: In some regions (e.g., Taiwan), immunotherapy combinations are not reimbursed for first-line use, affecting real-world applicability. 1