What is the role of durvalumab (durvalumab) in the treatment of hepatocellular carcinoma (HCC)?

Durvalumab for Hepatocellular Carcinoma

Durvalumab in combination with tremelimumab is a fully FDA-approved first-line treatment option for unresectable hepatocellular carcinoma (HCC), demonstrating superior overall survival compared to sorafenib. 1

First-Line Treatment Options

Recommended Regimens

For first-line treatment of patients with advanced Child-Pugh A HCC, either atezolizumab plus bevacizumab OR tremelimumab plus durvalumab are recommended, unless any medications are contraindicated. 1

The durvalumab-based regimen uses the STRIDE protocol (Single Tremelimumab Regular Interval Durvalumab): 1

• Tremelimumab 300 mg as a single priming dose on day 1
• Durvalumab 1,500 mg every 4 weeks starting on day 1 and continuing thereafter

Efficacy Data from HIMALAYA Trial

The phase III HIMALAYA trial (n=1,171 patients with unresectable HCC, no prior systemic therapy) demonstrated: 1, 2

• Median overall survival: 16.43 months with durvalumab/tremelimumab vs. 13.77 months with sorafenib
• Overall survival hazard ratio: 0.78 (96.02% CI 0.65-0.93; p=0.0035), demonstrating statistical superiority 1
• 36-month overall survival: 30.7% with durvalumab/tremelimumab vs. 20.2% with sorafenib 2
• Objective response rate: 20.1% vs. 5.1% with sorafenib 1

The survival benefit showed delayed separation of Kaplan-Meier curves, with hazard ratios of 0.87 before 9 months and 0.70 after 9 months, indicating increasing benefit over time. 1

Durvalumab Monotherapy Alternative

Where contraindications exist to combination immunotherapy (atezolizumab/bevacizumab or durvalumab/tremelimumab), durvalumab monotherapy, sorafenib, or lenvatinib may be offered as first-line treatment. 1

Durvalumab monotherapy (1,500 mg every 4 weeks) was noninferior to sorafenib for overall survival: 1

• Hazard ratio: 0.86 (95.67% CI 0.73-1.03; noninferiority margin 1.08)
• Median overall survival: 16.56 months vs. 13.77 months with sorafenib
• Significantly lower grade 3-4 adverse events compared to sorafenib (RR 0.71,95% CI 0.60-0.83) 1

Patient Selection Criteria

Appropriate candidates for durvalumab-based therapy include: 1, 3

• Unresectable HCC confirmed histologically
• Child-Pugh class A liver function (well-compensated liver disease)
• ECOG performance status 0-1 1
• No prior systemic therapy for first-line indication
• No main portal vein invasion (per HIMALAYA trial criteria) 1

Safety Profile and Management

Adverse Events

Grade 3-4 treatment-emergent adverse events occurred in 50.5% of patients receiving durvalumab/tremelimumab, comparable to 52.4% with sorafenib. 1, 2

Key safety considerations: 1

• Immune-related adverse events requiring high-dose corticosteroids: 20.1% with durvalumab/tremelimumab vs. 1.9% with sorafenib
• Most common severe imAEs: enterocolitis/diarrhea, liver injury, interstitial lung disease, rashes 4
• Hepatic/hemorrhage adverse events: similar frequency across all treatment arms 1

Critical Management Point

Severe immune-related adverse events requiring high-dose corticosteroid treatment do not appear to negatively impact antitumor efficacy, with some patients achieving objective responses despite requiring immunosuppression. 4 Among patients with objective responses, progression-free survival at 10 months remained excellent (100% with high-dose corticosteroids vs. 70.3% without). 4

Steroid-refractory enterocolitis may require infliximab administration. 4

Quality of Life Outcomes

Durvalumab/tremelimumab treatment was associated with delayed worsening of disease-related symptoms, physical functioning, and global quality of life compared to sorafenib. 1

Specific QOL data: 1

• Median time to deterioration: 7.5 months with durvalumab/tremelimumab vs. 5.7 months with sorafenib
• Median time to deterioration with durvalumab monotherapy: 7.4 months

Contraindications and Alternative Approaches

When immune checkpoint inhibitor combinations are contraindicated, lenvatinib or sorafenib should be considered as standard first-line therapy. 1

The ASCO guideline specifically states that where contraindications exist to atezolizumab/bevacizumab or durvalumab/tremelimumab, these tyrosine kinase inhibitors remain appropriate alternatives. 1

Progression-Free Survival Caveat

Progression-free survival was NOT significantly different between durvalumab/tremelimumab and sorafenib (HR 0.90,95% CI 0.77-1.05), despite the overall survival benefit. 1 This delayed separation pattern is characteristic of immunotherapy responses and should not deter treatment selection based on the robust overall survival advantage.