In a recent “Ask the Author” session, Professor Kudo discussed the LEAP-012 trial and its implications for treating hepatocellular carcinoma (HCC) with Professor Dufour. The study, titled “TACE combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic HCC LEAP-012,” investigates a novel approach to treating this condition.
Watch the Full Interview here
Background
For years, there has been an interest in combining local therapies with systemic treatments for hepatocellular carcinoma. Prior studies combining TACE with TKIs like Sorafenib have been unsuccessful. The EMERALD trial showed positive results for a combination of TACE with a systemic treatment, and now the LEAP-012 trial also demonstrates positive outcomes.
Trial Design of LEAP-012
LEAP-012 is a phase 3, multicenter, randomized, double-blind study. The trial design involved comparing lenvatinib plus pembrolizumab plus TACE versus dual placebo plus TACE in patients with intermediate-stage hepatocellular carcinoma without vascular invasion or extrahepatic disease . Patients were randomized 1:1 to either the treatment or the placebo group .
- Endpoints: The primary endpoints were progression-free survival (PFS) and overall survival (OS) . The trial would be considered positive if either endpoint was met .
- Stratification Factors: The trial included stratification factors such as AFP value (greater or less than 400 nanograms per mL), tumor burden score (up to 6, 6-12, or over 12), and ALBI grade .
- Treatment Timing: Uniquely, lenvatinib plus pembrolizumab was introduced two to four weeks before the first TACE session and continued after TACE until disease progression . This differs from other trials .
Key Findings
The primary results of the LEAP-012 trial were positive .
- PFS: Progression-free survival met its primary endpoint, with a hazard ratio of 0.66 . The median progression-free survival was 14.6 months in the lenvatinib plus pembrolizumab group and 10.0 months in the placebo group.
- OS: Overall survival events were immature, but an optimistic trend was observed, with a hazard ratio of 0.80 . The 24-month overall survival rate was 75% in the lenvatinib plus pembrolizumab group and 69% in the placebo group.
- Adverse Events: Grade 3 or worse treatment-related adverse events occurred more frequently in the lenvatinib plus pembrolizumab group (71%) compared to the placebo group (32%), with hypertension and decreased platelet count being the most common.
Rationale for the Treatment Approach
The rationale behind introducing lenvatinib before TACE is based on the following :
- Anti-VEGF Activity: Lenvatinib contains anti-VEGF activity, which can improve TACE efficacy by normalizing abnormal vessel cells and improving drug delivery .
- TACE-Induced Hypoxia: TACE induces hypoxia, which increases vascular endothelial growth factor (VEGF) and can increase anti-immune cells. Lenvatinib helps to counter this effect .
Implications for Standard of Care
Professor Kudo believes that, for non-metastatic HCC, TACE combined with IO plus anti-VEGF should be the standard of care . The LEAP-012 trial, along with other positive phase three trials, is changing the field, offering a safe and tolerable combination that benefits patients . The study abstract concludes that TACE plus lenvatinib plus pembrolizumab showed a significant and clinically meaningful improvement in progression-free survival compared to TACE plus placebo in patients with unresectable, non-metastatic hepatocellular carcinoma.
Join the Conversation
We invite oncologists, hepatologists, and all specialists in liver cancer management to watch this insightful interview and share your perspectives.