Background
Phase III double-blind RCT, N=616 (randomized 1:1:1), patients ≥18 years with unresectable HCC amenable to TACE, ECOG PS 0–1, ≥1 measurable intrahepatic lesion. Enrolled at 157 sites in 18 countries Nov 2018–Jul 2021. Stratified by TACE method, region, and portal vein invasion. Primary comparison: Arm A vs Arm C for PFS.
Interventions and follow up
Arm A: TACE + durvalumab 1500mg IV q4wk, then 1120mg IV q3wk + bevacizumab 15mg/kg IV q3wk (n=204)
Arm B: TACE + durvalumab + placebo (same schedule, no bevacizumab) (n=207)
Arm C: TACE + dual placebo (control arm) (n=205)
Primary endpoint: PFS by BICR per RECIST 1.1 (Arm A vs Arm C)
Median follow up: 27.9mo
Arm B: TACE + durvalumab + placebo (same schedule, no bevacizumab) (n=207)
Arm C: TACE + dual placebo (control arm) (n=205)
Primary endpoint: PFS by BICR per RECIST 1.1 (Arm A vs Arm C)
Median follow up: 27.9mo
Results
PFS (Arm A vs C): 15.0 vs 8.2mo, HR 0.77 (95% CI 0.61–0.98), P=.032
PFS (Arm B vs C): 10.0 vs 8.2mo, HR 0.94 (0.75–1.19), P=.64 — not significant
OS: Not mature at this analysis; 2-yr OS rate ~86% in Arm A (further data pending)
PFS (Arm B vs C): 10.0 vs 8.2mo, HR 0.94 (0.75–1.19), P=.64 — not significant
OS: Not mature at this analysis; 2-yr OS rate ~86% in Arm A (further data pending)
Adverse events
Most common grade 3–4 (by arm): hypertension 6% (Arm A); anaemia 4% (Arm B); post-embolisation syndrome 4% (Arm C).
Fatal: Treatment-related deaths 0 (Arm A), 3 (1%; Arm B), 3 (2%; Arm C); no new safety signals beyond known profiles of each agent.
Fatal: Treatment-related deaths 0 (Arm A), 3 (1%; Arm B), 3 (2%; Arm C); no new safety signals beyond known profiles of each agent.
Conclusions
TACE plus durvalumab and bevacizumab significantly improved PFS versus TACE alone in embolization-eligible unresectable HCC, the first ICI-based regimen in a global phase 3 trial to show a statistically significant and clinically meaningful PFS improvement over TACE. Durvalumab alone (Arm B) did not significantly improve PFS versus TACE.
Key Limitations
PFS is not a validated surrogate for OS in TACE trials; OS data are not yet mature and the PFS benefit may not translate to survival. The active control (TACE alone) is procedurally heterogeneous — variation in TACE technique across 157 sites in 18 countries may affect comparability. The benefit was restricted to the triplet (TACE + durva + bev); the durvalumab-alone arm did not benefit, suggesting bevacizumab is the critical immunostimulatory partner. Safety analysis sample sizes differ from the ITT.
Clinical Context
EMERALD-1 and LEAP-012 both demonstrated PFS benefit when adding systemic immunotherapy to TACE; neither has yet demonstrated OS benefit. Both were published the same day (January 2025, Lancet). FDA approval of the EMERALD-1 triplet (TACE+durvalumab+bevacizumab) is under review. The durvalumab+bev combination parallels IMbrave150's backbone (atezo+bev), suggesting VEGF inhibition enhances ICI benefit in HCC across settings. BCLC-B (intermediate-stage) HCC management is rapidly evolving with these locoregional-systemic combination strategies.
References