What is the treatment approach for an adult patient with hepatocellular carcinoma (HCC) and underlying liver disease using Lenvatinib (lenvatinib) plus Transarterial Chemoembolization (TACE)?

Lenvatinib Plus TACE for Hepatocellular Carcinoma

Primary Recommendation

The combination of lenvatinib plus TACE should NOT be routinely used for HCC, as current British Society of Gastroenterology guidelines explicitly state there is insufficient evidence to recommend combining TACE with immune checkpoint inhibitors or multikinase inhibitors, despite promising early signals. 1

However, emerging high-quality evidence from the phase III LAUNCH trial demonstrates significant survival benefits, suggesting this combination may become standard practice pending regulatory approval and guideline updates.

Current Guideline Position

TACE should not be combined with multikinase inhibitors according to 2024 BSG guidelines, which represent the most authoritative current guidance for UK practice. 1

Standard Treatment Pathways

For intermediate-stage HCC (BCLC-B):

• TACE alone remains standard of care for patients with limited tumor burden (solitary nodule <7 cm or fewer than four tumors), Child-Pugh A or B7 without ascites, and ECOG performance status <2 1, 2
• Best candidates have preserved liver function and no macroscopic vascular invasion or extrahepatic spread 1

For advanced-stage HCC:

• Lenvatinib is an alternative first-line systemic therapy (not combined with TACE) for patients who decline or have contraindications to atezolizumab plus bevacizumab 1
• Lenvatinib can be used as second-line therapy after progression on atezolizumab plus bevacizumab in Child-Pugh A patients with PS 0-1 1

Emerging Evidence for Combination Therapy

Phase III LAUNCH Trial Results (2023)

The LAUNCH trial demonstrated superior outcomes for lenvatinib plus TACE versus lenvatinib monotherapy in advanced HCC:

• Median OS: 17.8 months versus 11.5 months (HR 0.45, p<0.001) 3
• Median PFS: 10.6 months versus 6.4 months (HR 0.43, p<0.001) 3
• Objective response rate: 54.1% versus 25.0% (p<0.001) 3
• Portal vein tumor thrombus and treatment allocation were independent risk factors for OS 3

Real-World Evidence

A multicenter retrospective study (n=211) showed:

• Median OS: 15.9 months for combination versus 8.6 months for lenvatinib alone (p=0.0022) 4
• Median PFS: 8.6 months versus 4.4 months (p<0.001) 4
• ORR: 46.48% versus 13.05% (p<0.001) 4
• Treatment option was an independent prognostic factor (adjusted HR 0.53 for OS, 0.42 for PFS) 4

Network Meta-Analysis Findings

A 2024 systematic review comparing multiple treatment modalities found:

• Triple therapy (TACE + lenvatinib + PD-1/L1 inhibitors) showed optimal outcomes across all metrics 5
• TLP had highest probability for best ORR (75.5%), DCR (76.1%), OS (86.0%), and PFS (97.0%) 5
• Lenvatinib plus TACE was superior to either monotherapy 5

Clinical Scenarios Where Combination May Be Considered

Advanced HCC with Portal Vein Tumor Thrombus

• Lenvatinib plus TACE showed superiority over sorafenib plus TACE in patients with PVTT 6
• ORRs of 53.1%-75%, median PFS of 6.15-11.6 months, median OS of 14.5-18.97 months reported 6

Intermediate-Stage HCC Beyond Up-to-Seven Criteria

• Combination therapy may be preferable when tumor burden exceeds traditional TACE criteria 6
• Large-volume intrahepatic disease may benefit more from systemic therapy or combination approaches 1

Safety Profile

Most adverse events are manageable:

• Most common AEs: elevated AST (54.9% in combination group) and fatigue (46.4%) 4
• Majority of AEs were mild-to-moderate 4
• No significant increase in severe toxicity compared to monotherapy 3, 4

Critical Contraindications to TACE Component

Absolute contraindications that preclude combination therapy:

• Decompensated cirrhosis (Child-Pugh C or decompensated B) 1, 2
• Complete main portal vein occlusion 1, 2
• ECOG performance status ≥2 1, 2
• Advanced kidney dysfunction 1
• Obstructive jaundice 2

Practical Implementation Considerations

If Pursuing Combination Therapy Off-Guideline

Patient selection criteria:

• Child-Pugh A liver function mandatory 3, 4
• ECOG performance status 0-1 3
• No contraindications to either TACE or lenvatinib 3
• Treatment-naive or initial recurrent advanced HCC 3

Dosing and timing:

• Lenvatinib: 12 mg once daily for patients ≥60 kg; 8 mg once daily for patients <60 kg 3
• Initiate lenvatinib within 3 days of treatment decision 3
• TACE initiated one day after lenvatinib initiation 3
• On-demand TACE approach with 1-2 month intervals between sessions 2, 3

Monitoring:

• Assess response at 4-6 weeks post-procedure using CT or MRI with mRECIST criteria 2
• Cease TACE if no radiological response after 2-3 sessions or if liver function deteriorates 2

Common Pitfalls to Avoid

Do not perform extensive TACE with massive chemo-embolic materials for more than half of the liver, as this significantly increases risk of post-procedural liver failure 2

Ensure superselective catheterization when treating patients with compromised liver function and small tumors 2

Do not use combination therapy in patients with decompensated cirrhosis, even if tumor characteristics appear favorable 1, 2

Ongoing Clinical Trials

The LEAP-012 trial (NCT04246177) is evaluating lenvatinib plus pembrolizumab plus TACE versus placebo plus TACE in intermediate-stage HCC, with dual primary endpoints of OS and PFS. 7 Results from this 950-patient phase III study will provide definitive evidence for triple therapy combinations.