What are the treatment options for a patient with Hepatocellular Carcinoma (HCC) at the Barcelona Clinic Liver Cancer (BCLC) stage C, considering immunotherapy with checkpoint inhibitors such as Ipilimumab (Ipilimumab) and Nivolumab (Nivolumab) or Durvalumab (Durvalumab) and Tremelimumab (Tremelimumab)?

Treatment Options for HCC BCLC Stage C: Durvalumab/Tremelimumab vs Ipilimumab/Nivolumab

For patients with unresectable hepatocellular carcinoma BCLC Stage C, durvalumab plus tremelimumab (STRIDE regimen) is FDA-approved and guideline-recommended as first-line therapy, offering superior survival (median OS 16.43 months) with the critical advantage of not requiring pre-treatment endoscopy, unlike atezolizumab/bevacizumab. 1, 2 Ipilimumab plus nivolumab is also FDA-approved for HCC but is primarily positioned as a second-line option after failure of other immune checkpoint inhibitor combinations. 3, 4

First-Line Therapy: STRIDE Regimen (Durvalumab + Tremelimumab)

FDA Approval and Guideline Support

• Durvalumab plus tremelimumab is FDA-approved specifically for unresectable HCC and represents a guideline-endorsed first-line option for BCLC Stage C disease. 2
• The STRIDE regimen demonstrates a 22% reduction in death risk compared to sorafenib (median OS 16.43 vs 13.77 months) with an objective response rate of 20.1% versus only 5.1% with sorafenib. 1

Critical Patient Selection Criteria

• Child-Pugh A liver function is mandatory—no data exists for Child-Pugh B or C patients with this regimen. 1
• ECOG performance status 0-1 is required for treatment eligibility. 1
• Contraindicated in solid organ transplant recipients due to rejection risk. 1

Major Clinical Advantage: No Endoscopy Requirement

• Unlike atezolizumab/bevacizumab, the STRIDE regimen does not require mandatory upper endoscopy within 6 months prior to treatment, eliminating a major barrier for patients with esophageal varices or bleeding risk. 1
• This makes STRIDE particularly valuable for patients who cannot undergo endoscopic evaluation or have documented varices that would preclude bevacizumab use. 1

Dosing Regimen

• Durvalumab 1,500 mg IV every 4 weeks (for patients ≥30 kg body weight). 2
• Tremelimumab administered prior to durvalumab on the same day for the initial dosing cycles. 2

Second-Line Therapy: Ipilimumab + Nivolumab

Current Positioning in Treatment Algorithm

• Ipilimumab plus nivolumab is FDA-approved for hepatocellular carcinoma but Asian and European guidelines position it primarily after failure of first-line immune checkpoint inhibitor-based therapies. 5, 3
• The Pan-Asian ESMO guidelines state that "immunotherapy with nivolumab can be considered in patients who are intolerant to, or have progressed under approved tyrosine kinase inhibitors." 5

Evidence for Sequential Use After ICI Failure

• A multicenter retrospective study demonstrated that ipilimumab/nivolumab after prior ICI-based combination therapy failure achieved an ORR of 30% and DCR of 40%, with median PFS of 2.9 months and median OS of 7.4 months. 4
• This provides proof-of-concept that dual checkpoint blockade can be effective even after prior ICI exposure, though survival outcomes are modest. 4

Dosing for HCC

• Ipilimumab 3 mg/kg every 3 weeks with nivolumab 1 mg/kg every 3 weeks for a maximum of 4 doses in combination. 3
• After completing 4 combination doses, continue nivolumab as single agent until disease progression or unacceptable toxicity. 3

Patient Selection Requirements

• Child-Pugh A liver function with reasonable hepatic reserve. 5
• ECOG performance status 0-1 for optimal tolerability. 5
• Not recommended as first-line therapy given superior alternatives now available. 5

Comparative Considerations

Why STRIDE Over Ipilimumab/Nivolumab First-Line

• Superior survival data: The STRIDE regimen has demonstrated better OS outcomes in the first-line setting compared to historical controls. 1
• No endoscopy barrier: Critical for rapid treatment initiation in patients with varices or bleeding risk. 1
• FDA label specifically for first-line unresectable HCC, whereas ipilimumab/nivolumab lacks this specific first-line indication for HCC. 2, 3

When to Consider Ipilimumab/Nivolumab

• After progression on atezolizumab/bevacizumab or STRIDE regimen, as retrospective data supports activity in this setting. 4
• Patients intolerant to prior ICI-based combinations who maintain adequate liver function. 5
• Clinical trial settings where dual checkpoint blockade is being prospectively evaluated. 6

Safety Profile Differences

STRIDE Regimen Toxicity

• Serious adverse events are lower with immune checkpoint inhibitors compared to tyrosine kinase inhibitors, though liver toxic effects remain similar. 1
• No bevacizumab-related bleeding risk, which is the major safety advantage over atezolizumab/bevacizumab. 1

Ipilimumab/Nivolumab Toxicity

• Higher rates of immune-related adverse events with dual checkpoint blockade compared to single-agent ICI therapy. 3, 6
• Requires careful monitoring for hepatotoxicity—particularly relevant in HCC patients with underlying liver disease. 3
• Dose modifications required for Grade 3-4 immune-mediated adverse reactions, with permanent discontinuation for life-threatening events. 3

Critical Implementation Requirements

Multidisciplinary Team Discussion Mandatory

• All advanced HCC cases must be discussed in multidisciplinary team including hepatology, medical oncology, interventional radiology, and surgery before initiating systemic therapy. 5, 1

Monitoring During Treatment

• Liver function tests every 2 weeks for first 2 months, then monthly to detect hepatotoxicity early. 7
• Imaging every 6-8 weeks to assess response per RECIST v1.1 or mRECIST criteria. 4
• Vigilance for immune-related adverse events affecting any organ system, with prompt corticosteroid intervention when indicated. 3

Contraindications to Avoid

• Never use either regimen in Child-Pugh B or C patients outside clinical trials—no safety or efficacy data exists. 1
• Never delay antiviral therapy in HBV-positive patients—start entecavir or tenofovir immediately to prevent reactivation during immunotherapy. 7
• Never use in solid organ transplant recipients due to unacceptable rejection risk. 1

Alternative Considerations for BCLC C

If Immunotherapy Contraindicated

• Lenvatinib or sorafenib remain options for patients with contraindications to immunotherapy, though inferior to combination ICI regimens. 5
• Locoregional therapies (TACE, HAIC) may be considered for selected BCLC C patients with macrovascular invasion but no extrahepatic spread. 5

Regional Practice Variations

• In China, sintilimab, toripalimab, and camrelizumab are available as alternative PD-1 inhibitors, though data supporting their use in combination regimens for HCC is limited. 5