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Li et al. Hepatoma Res. 2026;12:36 Page 9 of 15

The primary endpoint was PFS assessed according to RECIST 1.1. TACE was performed according to local
practice, with one to four procedures permitted and all planned sessions required to be completed within 16
weeks after the first procedure. Durvalumab was initiated at least 7 days after the first TACE session, whereas
bevacizumab was delayed until at least 14 days after the final session. This design clearly prioritized peri-
procedural safety, particularly by avoiding concurrent exposure to bevacizumab during embolization.
Mechanistically, however, the potentially long interval between the first embolization and bevacizumab
initiation may have reduced coverage of the early post-embolization window characterized by hypoxia and
VEGF upregulation [60,61] .

The trial showed that triple therapy significantly prolonged PFS compared with TACE plus placebo (15.0
months vs. 8.2 months, HR = 0.77). In contrast, the TACE plus durvalumab group did not show PFS benefit
(10.0 months vs. 8.2 months, HR = 0.94). The finding suggests that bevacizumab is not merely an additional
component, but may be essential for effective synergy. Notably, curve separation appeared closer to the
period after bevacizumab introduction rather than immediately after embolization, further supporting the
contribution of anti-angiogenic therapy. Nevertheless, OS remains immature. Given its exploratory role in
triple therapy development, the broad eligibility criteria of EMERALD-1 are understandable and provide
useful subgroup signals for future trial design. Current PFS-based subgroup analyses suggest potentially
greater benefit in patients with no vascular invasion, multifocal intrahepatic disease, and ECOG PS 0,
however, these findings remain hypothesis-generating and require further validation. In addition, RECIST
1.1 may trigger early reassessment when new intrahepatic lesions appear, and treatment discontinuation due
to adverse events occurred in approximately 28% of patients in the triple therapy group. Therefore,
EMERALD-1 provides proof of concept that adding both durvalumab and bevacizumab can improve early
disease control, but future trials must better optimize anti-angiogenic timing, response criteria, toxicity
management, and post-progression treatment pathways.

THE LEAP-012 TRIAL
LEAP-012 was a global, randomized, double-blind phase III trial evaluating TACE plus lenvatinib and
[13]
pembrolizumab vs. TACE plus dual placebo in unresectable, non-metastatic HCC. Unlike EMERALD-1,
which enrolled a broader embolization-eligible population, LEAP-012 used stricter selection criteria: patients
had Child-Pugh class A liver function, Eastern Cooperative Oncology Group performance status 0-1, liver-
confined disease, and tumors technically suitable for embolization. Extreme tumor burden was excluded,
including tumors ≥ 10 cm, more than 10 tumors, or tumor occupation of ≥ 50% of the liver. Therefore,
LEAP-012 tested triple therapy in a more standardized, TACE-suitable population rather than in all
embolization-eligible patients.

The design was also more synchronized with the biological window of TACE. Lenvatinib and
pembrolizumab were started before embolization, with the first TACE performed 2-4 weeks after
randomization. Lenvatinib was administered at 8 or 12 mg once daily according to body weight, and
pembrolizumab was administered at 400 mg every 6 weeks. To improve safety, lenvatinib was interrupted
around the time of TACE, and each tumor could receive no more than 2 TACE sessions. This approach
reduced procedural heterogeneity and the risk of excessive embolization; however, the fixed per-tumor
TACE cap may also have limited effective locoregional exposure in selected patients who could still have
benefited from additional selective embolization.

LEAP-012 met its PFS endpoint, with a median of 14.6 months vs. 10.0 months and a hazard ratio of 0.66.
The primary endpoint was RECIST 1.1 by blinded central review, modified to allow up to five intrahepatic
target lesions and to require new intrahepatic tumors to meet LI-RADS 5 criteria before being considered
progression. This design attempted to balance regulatory rigor with the clinical complexity of post-TACE