LEAP-012
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
Phase 3N = 480NCT04246177
- Population
- Adults with unresectable, non-metastatic HCC not amenable to curative treatment but amenable to TACE, ECOG performance status 0 or 1, Child-Pugh class A
- Design
- Multicentre, randomised (1:1), double-blind phase 3 study at 137 sites in 33 countries or regions: TACE plus lenvatinib (12 mg if body weight 60 kg or more, 8 mg if less; once daily) plus pembrolizumab 400 mg every 6 weeks for up to 2 years, versus TACE plus matched dual placebo. Primary end points were progression-free survival (BICR, modified RECIST 1.1) and overall survival in the ITT population. Results are from the first interim analysis (the final analysis for progression-free survival).
- Primary endpoint
- PFS, OS
- Arms
- TACE plus lenvatinib plus pembrolizumab (experimental, n = 237): TACE plus oral lenvatinib once daily plus pembrolizumab 400 mg every 6 weeks for up to 2 years
- TACE plus dual placebo (control, n = 243): TACE plus matched oral and intravenous placebo
- People
- Kudo M
PFSHR 0.66 (95% CI 0.51–0.84)Δ median PFS+4.6 monthsOSHR 0.80 (95% CI 0.57–1.11)Δ 24-month OS+6 points
Show the numbers
| Endpoint | Analysis | TACE plus lenvatinib plus pembrolizumab | TACE plus dual placebo | Effect |
|---|---|---|---|---|
| PFSProgression-free survival by BICR per RECIST 1.1 modified for the study (up to five hepatic target tumours; new intrahepatic tumours had to meet LI-RADS 5 criteria to count as progression) | finalmedian follow-up 25.6 monthsKudo 2025 | median 14.6 months (12.6–16.7) | median 10 months (8.1–12.2) | HR 0.66 (95% CI 0.51–0.84)P=0.0002One-sided p; the threshold for progression-free survival was one-sided p = 0.025. The abstract describes this first interim analysis as the final analysis for progression-free survival. Median follow-up 25.6 months (IQR 19.5-32.4). |
| OSOverall survival (primary end point) at the first interim analysis; 24-month overall survival rate | interimmedian follow-up 25.6 monthsKudo 2025 | 75% at 2 y (68–80%) | 69% at 2 y (62–74%) | HR 0.80 (95% CI 0.57–1.11)P=0.087One-sided p; the prespecified threshold for overall survival was one-sided p = 0.0012, so the difference was not statistically significant at this analysis. 69 of 237 patients in the lenvatinib plus pembrolizumab group and 82 of 243 in the placebo group had died. |
| Endpoint | Analysis | TACE plus lenvatinib plus pembrolizumab | TACE plus dual placebo | Effect |
|---|---|---|---|---|
| PFSProgression-free survival by BICR per RECIST 1.1 modified for the study (up to five hepatic target tumours; new intrahepatic tumours had to meet LI-RADS 5 criteria to count as progression) | finalmedian follow-up 25.6 monthsKudo 2025 | median 14.6 months (12.6–16.7) | median 10 months (8.1–12.2) | HR 0.66 (95% CI 0.51–0.84)P=0.0002One-sided p; the threshold for progression-free survival was one-sided p = 0.025. The abstract describes this first interim analysis as the final analysis for progression-free survival. Median follow-up 25.6 months (IQR 19.5-32.4). |
| OSOverall survival (primary end point) at the first interim analysis; 24-month overall survival rate | interimmedian follow-up 25.6 monthsKudo 2025 | 75% at 2 y (68–80%) | 69% at 2 y (62–74%) | HR 0.80 (95% CI 0.57–1.11)P=0.087One-sided p; the prespecified threshold for overall survival was one-sided p = 0.0012, so the difference was not statistically significant at this analysis. 69 of 237 patients in the lenvatinib plus pembrolizumab group and 82 of 243 in the placebo group had died. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.66 | 0.51–0.84 |
| OS | 0.8 | 0.57–1.11 |
- TACE plus lenvatinib plus pembrolizumab (experimental)
- TACE plus dual placebo (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | TACE plus lenvatinib plus pembrolizumab | TACE plus dual placebo |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 9 | 65.2% | 53.6% |
| 18 | 42.5% | 28.7% |
| 27 | 27.8% | 15.4% |
| 37 | 17.3% | 7.7% |
Appears in
Sources
Kudo M, Ren Z, Guo Y, Han G, Lin H, Zheng J, et al. 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. 2025;405(10474):203-215.