What are the current guidelines and clinical trials for the use of Tyrosine Kinase Inhibitors (TKIs) and Immune Checkpoint Inhibitors (ICIs) in the management of advanced Hepatocellular Carcinoma (HCC)?

Management of Advanced HCC with TKIs and ICIs

For patients with advanced hepatocellular carcinoma (BCLC C) and preserved liver function (Child-Pugh A), combination immunotherapy regimens containing PD-1/PD-L1 inhibitors should be offered as first-line therapy, specifically atezolizumab plus bevacizumab or the STRIDE regimen (tremelimumab plus durvalumab), as these have demonstrated superior overall survival compared to sorafenib. 1

First-Line Systemic Therapy

Preferred Regimens

Combination immunotherapy regimens are now the standard of care for first-line treatment:

• Atezolizumab plus bevacizumab achieved an objective response rate of 27.3% and demonstrated superior survival outcomes across all etiologies including non-viral liver disease 1, 2

• STRIDE regimen (single dose tremelimumab plus durvalumab) showed superior OS versus sorafenib (median OS 16.43 vs. 13.77 months; HR 0.78,95% CI 0.65-0.93; p = 0.0035) with a 20.1% response rate 1

• Nivolumab plus ipilimumab demonstrated superior OS versus lenvatinib/sorafenib (median OS 23.7 vs. 20.6 months; HR 0.79; 95% CI 0.65–0.96; p = 0.0180) with a 36% response rate 1

Alternative First-Line Options

TKI monotherapy remains appropriate when ICI combinations are contraindicated or unavailable:

• Sorafenib (FDA-approved) or lenvatinib (non-inferior to sorafenib) are first-line alternatives for patients with well-preserved liver function 1, 3

• These TKIs provide median OS of approximately 10-13 months 1

Critical Pre-Treatment Requirements

For bevacizumab-containing regimens:

• All patients with liver cirrhosis must undergo esophagogastroduodenoscopy to screen for varices before initiating therapy 1

• Patients with grade 2 or higher varices must be treated (band ligation or nonselective beta blockers) before starting bevacizumab due to bleeding risk 1

• STRIDE regimen has lower hemorrhage risk and does not require mandatory endoscopy 1

Patient Selection Criteria

Eligible patients must have:

• Child-Pugh A liver function 1
• ECOG performance status 0-1 1
• No contraindications to immunotherapy 1

Etiology does not influence treatment selection - similar efficacy has been demonstrated across HBV, HCV, and non-viral etiologies including MASLD 1

Second-Line Systemic Therapy

After First-Line ICI Combination Therapy

Following progression on atezolizumab plus bevacizumab, TKI therapy should be offered:

• Sorafenib or lenvatinib are preferred options 1
• Cabozantinib or regorafenib are also reasonable alternatives 1
• Approximately 36% of patients in IMbrave 150 received subsequent TKI therapy 1

After First-Line TKI Therapy

Multiple options exist with varying levels of evidence:

• Cabozantinib or regorafenib (TKI options with proven efficacy) 1
• Ramucirumab for patients with AFP ≥400 ng/mL (29% reduction in death risk) 1
• Atezolizumab plus bevacizumab may be considered if not used first-line 1
• Pembrolizumab or nivolumab are reasonable options, especially for patients with contraindications to TKIs 1

Note: Nivolumab monotherapy failed to meet its primary endpoint in CheckMate-459 and FDA approval was withdrawn, though it remains an option in certain contexts 1

ICI Monotherapy Performance

Single-agent ICIs show modest activity:

• Pembrolizumab achieved 18% response rate but no OS benefit versus placebo in second-line setting 1
• Nivolumab demonstrated 14.3% ORR in single-arm studies 1
• Combination regimens consistently outperform monotherapy 1

Failed Combination Trials

Recent negative trials that should not guide current practice:

• COSMIC-312 (cabozantinib plus atezolizumab vs. sorafenib) failed to demonstrate survival benefit 1
• LEAP-002 (lenvatinib plus pembrolizumab vs. lenvatinib alone) failed to show OS advantage 1

Third-Line Therapy

No formal recommendations exist for third-line therapy 1

• May be considered in Child-Pugh A patients with good performance status using shared decision-making 1
• Options include TKIs not previously used or clinical trial enrollment 1

Safety Considerations

ICI-Related Toxicity

Life-threatening immune-related adverse events can occur with ICIs 1

• Meta-analyses show serious adverse events are lower with ICIs than TKIs 1
• Liver toxic effects are similar between ICIs and TKIs 1
• Most immune-related adverse events are manageable but require vigilant monitoring 1

TKI-Related Toxicity

Common grade 3 adverse events with sorafenib:

• Diarrhea (8-9%) and hand-foot skin reaction (8-16%) 1
• Discontinuation due to adverse events occurs in approximately 15% 1

Practical Implementation

Multidisciplinary Approach

All cases should be discussed in multidisciplinary team meetings 1

• Early oncologic referral while hepatic function is preserved is imperative 1
• Coordination between hepatology, oncology, interventional radiology, and surgery optimizes outcomes 1

Biomarker Status

Currently, biomarkers do not guide treatment selection:

• PD-L1 status does not appear crucial in HCC 1
• AFP ≥400 ng/mL identifies patients who may benefit from ramucirumab 1
• Limited genetic or IHC biomarkers exist for TKI or ICI selection 1

Regional Considerations

Cost remains a limiting factor in many regions:

• In MENA region, TKIs are covered by most governments while ICIs are not, influencing treatment choices 1
• This economic reality may necessitate TKI monotherapy despite inferior efficacy compared to ICI combinations 1