What is the recommended first-line treatment for a patient with advanced hepatocellular carcinoma (HCC), atezolizumab + bevacizumab or the STRIDE protocol?

First-Line Treatment for Advanced Hepatocellular Carcinoma: Atezolizumab + Bevacizumab vs STRIDE Protocol

Atezolizumab plus bevacizumab is the preferred first-line treatment for advanced HCC with Child-Pugh A liver function and ECOG PS 0-1, demonstrating superior overall survival (HR 0.58) compared to sorafenib, while the STRIDE protocol (durvalumab plus tremelimumab) serves as an effective alternative when bevacizumab or atezolizumab are contraindicated. 1, 2

Primary Recommendation: Atezolizumab + Bevacizumab

The combination of atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg IV every 3 weeks is the established standard of care for first-line treatment of unresectable or metastatic HCC. 1, 3

Efficacy Data Supporting Atezolizumab + Bevacizumab

• Median overall survival 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) after 15.6 months follow-up 4
• Median progression-free survival of 6.9 months versus 4.3 months with sorafenib (HR 0.65; 95% CI 0.53-0.81) 4
• Objective response rate of 29.8% compared to 11.4% with sorafenib 5, 4
• Disease control rate of 68% in real-world studies 6

Mandatory Pre-Treatment Requirements for Atezolizumab + Bevacizumab

All patients must undergo esophagogastroduodenoscopy within 6 months prior to treatment initiation to assess and manage esophageal varices due to bleeding risk with bevacizumab. 1, 2

• Patients with untreated or high-risk esophageal varices must have varices adequately treated according to institutional guidelines before starting therapy 1, 2
• Patients on adequately dosed nonselective β-blockers who are deemed low risk by hepatology specialists may be considered without repeat EGD if evaluated outside the 6-month window 1

Absolute Contraindications to Atezolizumab + Bevacizumab

• Active or history of autoimmune disease (risk of immune-related adverse effects) 2
• Myocardial infarction or stroke within the previous 3 months 1
• Therapeutic anticoagulation 1
• Untreated esophageal varices with high bleeding risk 1, 2
• Child-Pugh B or C liver function 1
• ECOG performance status ≥2 1, 2

Alternative Recommendation: STRIDE Protocol (Durvalumab + Tremelimumab)

The STRIDE protocol—durvalumab plus a single priming dose of tremelimumab—is recommended as first-line therapy when contraindications to atezolizumab or bevacizumab exist, particularly for patients with untreated varices or high bleeding risk. 1, 2, 5

Efficacy Data Supporting STRIDE Protocol

• Median overall survival of 16.4 months versus 13.8 months with sorafenib (HR 0.78; 96.02% CI 0.65-0.93; p=0.0035) 1, 2
• Objective response rate of 20.1% versus 5.1% with sorafenib 1
• Critically, the risk of variceal bleeding is reduced compared to atezolizumab-bevacizumab due to absence of anti-VEGF agent 1, 5

Key Advantages of STRIDE Over Atezolizumab + Bevacizumab

• Lower hepatic/hemorrhage adverse event rates compared to bevacizumab-containing regimens 1
• Does not require mandatory endoscopic screening for varices prior to initiation 1, 5
• Suitable for patients with portal hypertension who cannot undergo variceal management 1, 5

Important Limitation of STRIDE Protocol

Patients with main portal vein thrombosis were excluded from the HIMALAYA trial, making this a relative contraindication to the STRIDE protocol. 2

Safety Profile of STRIDE Protocol

• Immune-related adverse events requiring high-dose glucocorticoids occurred in 20.1% of patients 1, 5
• Grade 3-4 adverse events occurred in 50.5% versus 52.4% with sorafenib 1
• Anti-durvalumab antibodies detected in 3.1% and anti-tremelimumab antibodies in 11% of patients 1

Treatment Selection Algorithm

Step 1: Confirm Eligibility Criteria

• Child-Pugh A liver function (mandatory for both regimens) 1, 2
• ECOG performance status 0-1 (mandatory for both regimens) 1, 2
• No active autoimmune disease 1, 2

Step 2: Assess for Bevacizumab-Specific Contraindications

• If no contraindications to bevacizumab AND varices are managed: Choose atezolizumab + bevacizumab 1, 2
• If untreated varices, high bleeding risk, or contraindications to bevacizumab: Choose STRIDE protocol 1, 2, 5
• If main portal vein thrombosis present: Choose atezolizumab + bevacizumab (STRIDE excluded patients with this condition) 2

Step 3: If Both Immunotherapy Combinations Contraindicated

• Lenvatinib 12 mg daily (≥60 kg) or 8 mg daily (<60 kg) as alternative first-line option 1, 2
• Sorafenib 400 mg orally twice daily as alternative first-line option 1, 2

Common Pitfalls and How to Avoid Them

Pitfall 1: Initiating Atezolizumab + Bevacizumab Without Variceal Assessment

Always perform EGD within 6 months before starting atezolizumab-bevacizumab, as bleeding complications with bevacizumab can be fatal. 1, 2 The one exception is patients already on adequately dosed nonselective β-blockers deemed low risk by hepatology 1.

Pitfall 2: Using STRIDE in Patients With Main Portal Vein Invasion

The HIMALAYA trial excluded patients with main portal vein invasion, making efficacy data unavailable for this population 2. In these patients, atezolizumab-bevacizumab remains the preferred option if varices are managed 2.

Pitfall 3: Overlooking Child-Pugh Status

Both regimens require Child-Pugh A liver function 1, 2. Patients with Child-Pugh B or C should not receive either combination and require alternative approaches 1, 7.

Second-Line Treatment After Progression

After Atezolizumab + Bevacizumab Progression

No prospective randomized data exist for second-line treatment after atezolizumab-bevacizumab, but tyrosine kinase inhibitors (sorafenib, lenvatinib, cabozantinib, or regorafenib) are reasonable based on mechanism of action. 1, 5

• Real-world data show median PFS of 3.4 months and median OS of 14.7 months with second-line multikinase inhibitors 8
• Lenvatinib demonstrated significantly longer median PFS than sorafenib (6.1 vs 2.5 months; p=0.004) in the second-line setting 8
• Treatment-related adverse events occurred in 85.7% of patients, with grade 3 events in 16.3% 8

After STRIDE Protocol Progression

Similar to atezolizumab-bevacizumab, tyrosine kinase inhibitors represent reasonable second-line options, though specific data are limited 1.

Safety Considerations

Atezolizumab + Bevacizumab Safety Profile

• Treatment-related grade 3/4 adverse events in 43% of patients 4
• Treatment-related grade 5 (fatal) events in 2% of patients 4
• Bleeding events grade ≥3 occurred in 10% of patients in real-world studies, with 2% fatal outcomes 9

STRIDE Protocol Safety Profile

• Grade 3-4 adverse events in 50.5% versus 37.1% with durvalumab monotherapy 1
• Hepatic/hemorrhage adverse events similar across all treatment arms in HIMALAYA trial 1
• Lower bleeding risk compared to bevacizumab-containing regimens 1, 5