What is the recommended management for a patient with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma, good performance status (Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1), and Child-Pugh A liver function?

Management of BCLC Stage C Hepatocellular Carcinoma

For patients with BCLC stage C hepatocellular carcinoma, Child-Pugh A liver function, and ECOG performance status 0-1, atezolizumab plus bevacizumab should be offered as first-line systemic therapy, provided there are no contraindications. 1

First-Line Systemic Therapy Options

Preferred Regimen: Atezolizumab Plus Bevacizumab

• Atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg IV every 3 weeks is the preferred first-line treatment for most patients with advanced HCC, Child-Pugh A liver function, and ECOG PS 0-1. 1

• This combination demonstrated superior overall survival compared to sorafenib (median OS 19.2 months vs 13.4 months; HR 0.58,95% CI 0.42-0.79; p <0.001) in the IMbrave150 trial. 1, 2

• Progression-free survival was also significantly improved (HR 0.59,95% CI 0.47-0.76; p <0.001), with an objective response rate of 27.3% versus 11.9% for sorafenib. 1

Critical Pre-Treatment Requirements for Atezolizumab Plus Bevacizumab

• All patients must undergo endoscopic screening for esophageal varices prior to initiating therapy. 1

• Patients with untreated or incompletely treated varices with bleeding or high risk for bleeding must have varices managed according to institutional guidelines before starting treatment. 1

• Exclude patients with variceal bleeding within 6 months prior to treatment. 2

Alternative First-Line Regimen: Durvalumab Plus Tremelimumab (STRIDE)

• Durvalumab plus a single priming dose of tremelimumab (STRIDE regimen) is an alternative first-line option for patients with Child-Pugh A and ECOG PS 0-1. 1

• The HIMALAYA trial demonstrated superior OS versus sorafenib (median OS 16.43 vs 13.77 months; HR 0.78,95% CI 0.65-0.93; p = 0.0035). 1

• This regimen is particularly valuable for patients with contraindications to bevacizumab (bleeding risk, thrombosis risk) or atezolizumab (active autoimmune disease). 1

• Patients with main portal vein thrombosis were excluded from the HIMALAYA trial, which should be considered when selecting this regimen. 1

• Real-world data shows no significant difference in overall survival between atezolizumab plus bevacizumab and STRIDE (median OS 15.4 vs 15.5 months; HR 0.94,95% CI 0.73-1.22). 3

Tyrosine Kinase Inhibitors as First-Line Alternatives

When combination immunotherapy regimens cannot be used (contraindications to both atezolizumab/bevacizumab and durvalumab/tremelimumab), the following options are available:

• Sorafenib 400 mg orally twice daily is an established first-line option for Child-Pugh A, ECOG PS 0-1 patients. 1

• Lenvatinib (12 mg for body weight ≥60 kg or 8 mg for body weight <60 kg) orally once daily demonstrated non-inferiority to sorafenib in the REFLECT trial. 1, 4

• Lenvatinib showed median OS of 13.6 months versus 12.3 months for sorafenib (HR 0.92,95% CI 0.79,1.06) with superior progression-free survival (7.3 vs 3.6 months; HR 0.64,95% CI 0.55,0.75). 4

• Durvalumab monotherapy may be considered as it demonstrated non-inferiority to sorafenib for OS (HR 0.86,95% CI 0.73-1.03). 1

Contraindications to Consider

For Atezolizumab Plus Bevacizumab:

• Active or history of autoimmune disease (consider immune-related adverse effects with atezolizumab). 1
• Untreated or high-risk esophageal varices (bleeding risk with bevacizumab). 1
• History of significant bleeding or thrombotic events (VEGF inhibitor bevacizumab increases these risks). 1
• Allogeneic stem cell or solid organ transplantation. 1
• Idiopathic pulmonary fibrosis or pneumonitis. 1

For Durvalumab Plus Tremelimumab:

• Main portal vein invasion (excluded from HIMALAYA trial). 1
• Active autoimmune disease (immune-related adverse effects). 1

Treatment Selection Algorithm

Step 1: Confirm Child-Pugh A liver function and ECOG PS 0-1. 1

Step 2: Perform endoscopic evaluation for esophageal varices. 1

Step 3: Assess for contraindications to immunotherapy combinations:

• If no contraindications and varices managed → Atezolizumab plus bevacizumab 1
• If bleeding/thrombosis risk or main portal vein invasion → Durvalumab plus tremelimumab (STRIDE) 1
• If contraindications to both immunotherapy combinations → Lenvatinib or sorafenib 1

Step 4: Consider patient-specific factors:

• Medical history and comorbidities 1
• Treatment-related toxicity profiles 1
• Cost and access to medications 1
• Patient preference after shared decision-making 1

Common Pitfalls to Avoid

• Do not initiate atezolizumab plus bevacizumab without variceal screening and management - this is a critical safety requirement that prevents life-threatening bleeding complications. 1

• Do not use these regimens in Child-Pugh B or C patients - all major trials excluded patients with decompensated cirrhosis, and these patients should receive only symptomatic treatment. 1, 5

• Do not use immunotherapy combinations in patients with ECOG PS ≥2 - these patients were excluded from pivotal trials and have poor prognosis regardless of treatment. 1

• Do not overlook autoimmune disease history - patients with active or documented autoimmune disease face increased risk of severe immune-related adverse events with checkpoint inhibitors. 1