Page 64 - Read Online

Page 10 of 15 Li et al. Hepatoma Res. 2026;12:36

intrahepatic changes. OS remained immature at the published interim analysis, with 24-month survival rates
of 75% vs. 69% (HR = 0.80). Grade 3 or worse treatment-related adverse events were frequent, occurring in
71% vs. 32%, indicating that systemic-first triple therapy requires careful toxicity management.

More importantly, LEAP-012 provides useful clues for future population refinement. Subgroup results
suggested stronger PFS benefit in patients with BCLC stage B disease, ECOG PS 0, ALBI grade 1, Child-Pugh
score 5, alpha-fetoprotein > 400 ng/mL, and medium-to-high tumor burden. However, OS data remain
immature, and these subgroup findings should be interpreted as exploratory. Thus, the major lesson of
LEAP-012 is not simply that systemic-first triple therapy improves early disease control, but that future trials
should prospectively enrich for patients with sufficient risk of TACE failure to justify systemic
intensification, while still preserving enough liver function and performance status to tolerate sustained
combination therapy.

THE TALENTACE TRIAL
TALENTACE was a phase III, open-label, randomized trial comparing on-demand TACE plus atezolizumab
and bevacizumab with on-demand TACE alone in systemically untreated, unresectable HCC. Its key design
feature was population enrichment. Eligible patients had intermediate-to-high tumor burden, defined as
maximum tumor diameter plus tumor number ≥ 6; most had BCLC stage B disease, while selected BCLC
stage C patients with limited portal vein invasion, mainly Vp1-2, or ECOG PS 1 were also allowed. Thus,
TALENTACE focused on a clinically important boundary population: patients who are still technically
suitable for TACE, but at sufficient risk of TACE failure to justify systemic intensification.

In the experimental arm, atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks was initiated at
least 14 days and within 8 weeks after the first TACE. This TACE-first strategy differs from the systemic-first
design of LEAP-012 and preserves real-world retreatment flexibility by avoiding a fixed per-tumor TACE
cap. The co-primary endpoints were TACE-PFS and OS. TACE-PFS was defined as time to untreatable
progression, TACE failure/refractoriness, or death, making it closer to a treatment-strategy failure endpoint
than conventional RECIST progression alone.

At the first interim analysis, TALENTACE met its TACE-PFS endpoint, with a median of 11.30 months vs.
7.03 months (HR = 0.71). RECIST 1.1 PFS also favored the combination arm, 10.32 months vs. 6.37 months
(HR = 0.64). However, OS remained immature, with only 38.6% of events reported; median OS was 34.53
months vs. 35.38 months (HR = 0.96). The apparently neutral early survival result may reflect several factors:
immature follow-up, unexpectedly long survival in the control arm, subsequent treatment after progression,
and the possibility that improved TACE-PFS mainly delays treatment-strategy failure rather than
immediately translating into death reduction.

The current subgroup data should be interpreted cautiously. Publicly available reports suggest generally
consistent TACE-PFS benefit across predefined subgroups, but detailed subgroup hazard ratios have not yet
been fully published. Therefore, TALENTACE should not yet be used to define a definitive biomarker-like
beneficiary subgroup. Its deeper implication is conceptual: future trials may need to enrich for patients with
both high risk of inadequate TACE control and sufficient liver and performance reserve to tolerate sustained
systemic therapy. Toxicity remains a key constraint, as grade 3-4 treatment-related adverse events occurred
in 60.8% vs. 40.5%, and treatment withdrawal due to adverse events occurred in 21.1% vs. 2.3%. Thus,
TALENTACE represents a shift from asking whether triple therapy works in all embolization-eligible
patients to asking whether it works in a risk-enriched population using an endpoint that captures TACE-
strategy failure rather than radiographic progression alone.