Page 59 - Read Online

Li et al. Hepatoma Res. 2026;12:36 Page 5 of 15

outperformed sorafenib in OS (16.4 months vs. 13.8 months; HR = 0.76) . The recently reported CheckMate
[43]
9DW trial demonstrated a significant OS improvement for the combination of nivolumab and ipilimumab
[44]
vs. lenvatinib/sorafenib (23.7 months vs. 20.6 months; HR = 0.79). Together with the results of the
HIMALAYA trial, these findings confirm the efficacy of the combination protocol of CTLA-4 inhibitor plus
PD-(L)1 inhibitor.

Notably, China-developed combination regimens have also demonstrated equally remarkable efficacy. In the
ORIENT-32 trial, sintilimab plus a bevacizumab biosimilar significantly improved OS and PFS compared
with sorafenib . Subsequently, the RATIONALE-301 trial , which compared PD-(L)1 inhibitor
[46]
[45]
tislelizumab with sorafenib, reported a non-inferior OS outcome (15.9 months vs. 14.1 months; HR = 0.85),
providing crucial evidence for global research on single-agent immunotherapy. Furthermore, in the
CARES-310 trial, camrelizumab plus apatinib achieved a median OS of 23.8 months (vs. 15.2 months for
sorafenib, HR = 0.64) . Recently, the SCT-I10A-C301 trial showed that finotonlimab plus a bevacizumab
[47]
biosimilar significantly prolonged OS compared with sorafenib (22.1 months vs. 14.2 months; HR = 0.60) .
[48]
The HEPATORCH trial demonstrated that toripalimab plus bevacizumab improved OS compared with
sorafenib (20.0 months vs. 14.5 months; HR = 0.76) . Together, these studies have expanded the range of
[49]
first-line systemic treatment options for HCC, particularly in China, and underscore the growing
contribution of regionally developed regimens to the global evidence base.

EXPLORATION OF TACE COMBINED WITH SYSTEMIC THERAPY
Since the introduction of sorafenib into clinical practice, continuous efforts have been made to enhance the
efficacy of TACE by combining with systemic therapy. The three combination strategies-sequential,
interrupted, and continuous- were systematically proposed by Strebel in 2008 , established a crucial
[50]
theoretical framework for subsequent clinical trial designs, as shown in Figure 1. Early randomized trials
combining TACE with TKIs or antiangiogenic agents in intermediate-to-advanced HCC yielded largely
negative results, whereas later studies demonstrated that trial success is highly sensitive to (i) the timing of
systemic exposure around TACE; (ii) progression/response assessment criteria that govern TACE
continuation; and (iii) whether TACE is delivered in a protocol-mandated “scheduled” manner or as
response-guided “on-demand” treatment.

DUAL THERAPY: TACE PLUS TARGETED OR ANTIANGIOGENIC THERAPY
Evolution and heterogeneity of TACE-TKI timing strategies
Early TACE-TKI studies showed substantial heterogeneity in systemic-treatment timing and TACE
scheduling. The Post-TACE trial adopted a delayed sequential strategy, initiating sorafenib only after
[51]
planned TACE had been completed and objective response achieved; more than half of patients started
sorafenib beyond 9 weeks after TACE, and time to progression (TTP) was not significantly improved (5.4
months vs. 3.7 months; HR = 0.87). Subsequent trials moved systemic therapy closer to TACE but used
different models. SPACE started sorafenib 3-7 days before scheduled DEB-TACE, yet TTP remained
[52]
statistically negative (169 days vs. 166 days; HR = 0.80). TACE-2 initiated sorafenib/placebo and followed
[53]
by DEB-TACE 2-5 weeks later and response-guided retreatment, but failed to improve PFS (7.8 months vs.
7.5 months; HR = 0.99) or OS (19.5 months vs. 18.4 months; HR = 0.91). In contrast, TACTICS moved
[54]
toward a systemic-first and on-demand strategy, administering sorafenib 2-3 weeks before cTACE and
continuing treatment until unTACEable progression, improving TACE-specific PFS (22.8 months vs. 13.5
months; HR = 0.66) but not OS (36.2 months vs. 30.8 months; HR = 0.86). The DEB-TACE-apatinib trial [55]
adopted a TACE-first strategy, with apatinib started 3-5 days after DEB-TACE and held before subsequent
sessions, improving PFS (7.1 months vs. 5.2 months) and OS (23.3 months vs. 18.9 months). LAUNCH [56]
represented a different paradigm in advanced HCC, where lenvatinib served as the systemic backbone, and
TACE was added for intrahepatic control, improving PFS (10.6 months vs. 6.4 months; HR = 0.43) and OS