Clinical trialPhase 3Liver cancer

Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study

Lancet · 2025480 patients (237 lenvatinib + pembrolizumab, 243 placebo)

Kudo M, Ren Z, Guo Y, et al. Lancet. 2025. 405:203-215

Study type: Clinical trial
Study name: LEAP-012
Phase: Phase 3
Design: Randomised (1:1), double-blind, placebo-controlled trial, 137 centres in 33 countries or regions; report of the first interim analysis
Sample size: 480 patients (237 lenvatinib + pembrolizumab, 243 placebo)
Source: Lancet · 2025
Trial registration: NCT04246177

In plain words

In this study, patients having chemoembolisation (TACE) for liver cancer confined to the liver were also given lenvatinib tablets and the immunotherapy injection pembrolizumab. This combination extended the time the disease was controlled, on average from 10 months to about 15 months, but at the time of the report its effect on survival was not certain, and severe side effects (especially high blood pressure) were much more common. This combination is not considered an approved or standard treatment for this situation.

Key results

14.6 vs 10.0 months

Median progression-free survival

HR 0.66 (95% CI 0.51–0.84); p=0.0002 (one-sided); final PFS analysis

75% vs 69%

24-month overall survival

HR 0.80 (95% CI 0.57–1.11); p=0.087 (one-sided) — not significant at this interim analysis

71% vs 32%

Treatment-related grade 3 or higher adverse events

169 of 237 vs 76 of 241

Drugs in this study:Lenvatinib (Lenvima)Pembrolizumab (Keytruda)

Dose and schedule cards

TACE + lenvatinib + pembrolizumab (LEAP-012; not approved)

Unresectable, non-metastatic intermediate-stage HCC amenable to TACE; Child-Pugh A, ECOG 0–1Each drug’s schedule in the tableOn the page “Liver cancer” · Intermediate hepatocellular carcinoma: TACE plus systemic therapy (not approved)

Unresectable, non-metastatic intermediate-stage HCC amenable to TACE; Child-Pugh A, ECOG 0–1

Drug	Dose	Route	Schedule
Lenvatinib	Body weight 60 kg or more: 12 mg; less than 60 kg: 8 mg	Oral	Once daily, continuous (21-day cycles)
Pembrolizumab	400 mg	IV	Every 6 weeks, for up to 2 years (about 17 doses)
TACE	Per institutional protocol	Intra-arterial	Together with systemic therapy

Cycle schedule: Lenvatinib daily and continuously (21-day cycles); pembrolizumab every 6 weeks
Duration: Lenvatinib until progression or intolerable toxicity (up to 2 years, about 35 cycles); pembrolizumab up to 2 years

Improved progression-free survival but not overall survival, with far more grade ≥3 treatment-related adverse events; the ESMO guideline regards it only as an option that “may be considered”.

On the page “Liver cancer” · Intermediate hepatocellular carcinoma: TACE plus systemic therapy (not approved)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1TACE + lenvatinib + pembrolizumab

TACE (background procedure with a chemotherapy drug and an embolic agent) plus lenvatinib oral capsule once daily (12 mg for a screening weight of 60 kg or more; 8 mg for weight below 60 kg) in 21-day cycles until disease progression or unacceptable toxicity (maximum 2 years, about 35 cycles, or longer with sponsor approval) + pembrolizumab 400 mg IV infusion every 6 weeks for up to 2 years (about 17 doses).

(TACE chemotherapy drug, number of TACE sessions and timing of TACE relative to the start of the drugs: details in the full text of the paper.)

2TACE + dual placebo (control group)

TACE plus oral placebo matching lenvatinib once daily in 21-day cycles (maximum 2 years, about 35 cycles) and IV placebo matching pembrolizumab every 6 weeks (maximum 2 years, about 17 doses).

Source of the regimen details: Abstract of the paper (Lancet 2025); ClinicalTrials.gov NCT04246177 (arm descriptions: weight-based lenvatinib dose, 21-day cycle, pembrolizumab 400 mg every 6 weeks, maximum 2 years). Details of TACE delivery in the full text of the paper.

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults aged 18 years or older with unresectable, non-metastatic HCC not amenable to curative treatment but suitable for TACE, with ECOG performance status 0 or 1 and Child-Pugh A. According to ClinicalTrials.gov: controlled blood pressure (with or without medication) and adequate organ function were required; liver transplant candidates and patients with gastric bleeding in the previous 6 months, ascites not controlled with medication, significant cardiovascular disease in the previous 12 months or prior local therapy to existing liver lesions were excluded. Median age 66 years; 72% Asian.

Endpoints

Primary endpoints: progression-free survival per RECIST 1.1 (modified for this study) by blinded independent central review, and overall survival, in the intention-to-treat population.

Safety and side effects

Treatment-related grade 3 or higher adverse events occurred in 169 (71%) of 237 patients in the lenvatinib + pembrolizumab group and 76 (32%) of 241 patients in the placebo group; the most common were hypertension (24% vs 7%) and thrombocytopenia (11% vs 6%). Deaths from treatment-related adverse events: 4 (2%) in the intervention group (liver failure, gastrointestinal bleeding, myositis and immune-mediated hepatitis) and one (less than 1%) in the placebo group (brainstem haemorrhage).

Clinical significance and place in guidelines

LEAP-012 showed improved progression-free survival, but in this analysis overall survival did not differ significantly and toxicity was considerably higher. As far as we have checked, this combination is not FDA-approved for use with TACE, and the AASLD 2023 guidance does not recommend combining systemic therapy with arterial therapies in stage B outside a clinical trial. Final overall survival results are essential to define the place of this approach.

Limitations

Report based on the first interim analysis; overall survival was not yet significant; RECIST criteria were modified for this study; grade 3 or higher adverse events were much more frequent in the intervention group; most patients were Asian.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.