What is the comparison of atezolizumab (Atezolizumab) vs durvalumab (Durvalumab) vs toripalimab (Toripalimab) in the treatment of hepatocellular carcinoma (HCC)?

Comparison of Atezolizumab vs Durvalumab vs Toripalimab in Hepatocellular Carcinoma

Atezolizumab plus bevacizumab is the first-choice standard of care for first-line treatment of unresectable HCC, with superior overall survival compared to sorafenib (HR 0.58, median OS 19.2 months), while durvalumab plus tremelimumab represents an effective alternative with reduced variceal bleeding risk (HR 0.78 vs sorafenib, median OS 16.4 months); toripalimab is not mentioned in current Western guidelines and lacks comparative data against these regimens. 1

First-Line Treatment Hierarchy

Atezolizumab Plus Bevacizumab (Preferred Standard)

• Demonstrates superior efficacy with median OS of 19.2 months (95% CI 17.0-23.7) versus 13.4 months with sorafenib (HR 0.66; 95% CI 0.52-0.85) 2
• Objective response rate of 29.8% compared to 11.4% with sorafenib 1
• Real-world evidence confirms trial efficacy with 65% OS at 12 months and 39% at 24 months in Child-Pugh A patients 3
• Requires careful pre-treatment assessment for contraindications to either agent, particularly variceal bleeding risk 1
• Patients with portal hypertension must have upper GI endoscopy within 6 months with adequately treated varices before initiation 1, 4

Durvalumab Plus Tremelimumab (Alternative First-Line)

• Effective alternative when atezolizumab-bevacizumab is contraindicated, particularly for bleeding concerns 1
• HIMALAYA trial demonstrated OS HR 0.78 (96.02% CI 0.65-0.93; p=0.0035) versus sorafenib with median OS 16.4 months 1
• ORR of 20.1% versus 5.1% with sorafenib 1
• Lower variceal bleeding risk compared to atezolizumab-bevacizumab due to absence of anti-VEGF agent 1
• Uses STRIDE regimen: single dose tremelimumab 300mg plus durvalumab every 4 weeks 1
• Grade 3-4 adverse events in 50.5% versus 52.4% with sorafenib 1
• Delayed separation of survival curves with HR 0.70 (95% CI 0.56-0.89) after 9 months 1

Toripalimab Status

• Not mentioned in current British Society of Gastroenterology, EASL, or SITC guidelines for HCC treatment 1
• No comparative efficacy data available against atezolizumab-bevacizumab or durvalumab-tremelimumab in Western literature
• Not approved by NICE or FDA for HCC indication based on available evidence 1

Treatment Selection Algorithm

When to Choose Atezolizumab-Bevacizumab

• First-line choice for all eligible patients with Child-Pugh A, PS 0-1, and no contraindications 1
• Patients without portal hypertension or with adequately treated varices 1, 4
• No history of significant bleeding events or high bleeding risk 4
• Acceptable for patients who can tolerate intravenous therapy every 3 weeks 1

When to Choose Durvalumab-Tremelimumab

• Patients with contraindications to bevacizumab, particularly untreated varices or high bleeding risk 1
• Patients with portal hypertension who cannot undergo or have failed variceal treatment 1
• When reduced hemorrhagic risk is priority over slightly higher response rates 1
• Patients declining or unable to access atezolizumab-bevacizumab 1

When Single-Agent Durvalumab May Be Considered

• Non-inferior to sorafenib (HR 0.86,95.67% CI 0.73-1.03) when combination therapy contraindicated 1
• Patients at high risk for complications with dual-ICI therapy 1
• Alternative when both bevacizumab and tremelimumab are contraindicated 1

Critical Safety Considerations

Atezolizumab-Bevacizumab Specific Risks

• Variceal bleeding risk requires mandatory endoscopic screening within 6 months before treatment 1, 4
• Grade 3-4 treatment-related adverse events in 43% of patients 2
• Contraindicated in patients with prior solid organ transplantation 4
• Requires hepatitis B/C screening with appropriate antiviral therapy before initiation 4

Durvalumab-Tremelimumab Specific Risks

• Immune-related adverse events requiring high-dose glucocorticoids in 20.1% versus 1.9% with sorafenib 1
• Anti-tremelimumab antibodies detected in 11% of patients 1
• Hepatic/hemorrhage adverse events similar across all treatment arms 1

Second-Line Treatment After Progression

After Atezolizumab-Bevacizumab Failure

• No prospective randomized data exist, but multikinase inhibitors are reasonable based on mechanism of action 1
• Lenvatinib shows superior PFS (6.1 vs 2.5 months, p=0.004) compared to sorafenib as second-line therapy 5
• Both sorafenib and lenvatinib approved for Child-Pugh A, PS 0-1 patients after progression 1
• Objective response rate 6.1% and disease control rate 63.3% with second-line MKIs 5

Common Pitfalls to Avoid

• Do not initiate atezolizumab-bevacizumab without recent endoscopy in patients with cirrhosis or portal hypertension 1, 4
• Do not use in patients with untreated hepatitis B without prophylactic antiviral therapy 4
• Do not assume durvalumab-tremelimumab is inferior to atezolizumab-bevacizumab; it represents a valid alternative with different risk profile 1
• Do not consider toripalimab as equivalent option without guideline support or comparative efficacy data in non-Asian populations 1