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Li et al. Hepatoma Res. 2026;12:36 Page 11 of 15

THE CAP-ACE TRIAL
The CAP-ACE, also reported as CARES-005, was a multicenter, open-label, randomized phase II trial
conducted in China that compared TACE plus camrelizumab and rivoceranib/apatinib with TACE alone in
patients with unresectable HCC eligible for embolization. Eligible patients had no extrahepatic metastasis,
Child-Pugh class A liver function, and ECOG PS 0-1. Most patients had BCLC stage B or C disease.

A key feature of CAP-ACE was its crossover design. Patients initially assigned to TACE alone were allowed
to cross over to receive camrelizumab plus rivoceranib/apatinib after progression. This design was clinically
and ethically reasonable and also resembles real-world practice, in which patients are often switched to
combined systemic therapy after TACE failure. However, this inevitably reduced the ability of the trial to
detect an OS difference because the control group could later receive the active systemic regimen. The
primary endpoint was RECICL-assessed PFS, which is particularly relevant in TACE-based trials because it
better captures viable tumor response after embolization than size-based criteria alone. CAP-ACE showed a
strong PFS advantage: median PFS was 10.8 months vs. 3.2 months (HR = 0.34), and time to unTACEable
progression was also prolonged, 13.7 months vs. 3.9 months, suggesting that early systemic intensification
can delay the point at which a TACE-based strategy becomes ineffective. Subgroup analyses showed
RECICL-PFS benefit in both BCLC A/B and BCLC C disease, with hazard ratios of 0.34 and 0.39,
respectively; however, OS benefit was not confirmed. Safety is another important limitation. Grade 3 or
higher treatment-related adverse events were more frequent with the combination, including aspartate
aminotransferase elevation, alanine aminotransferase elevation, hypertension, and platelet count decrease.
These toxicities were described as manageable, but they highlight the recurring challenge in TACE-based
triple therapy: stronger early disease control may come at the cost of greater hepatic and systemic toxicity.

Overall, CAP-ACE reinforces two important concepts. First, RECICL-based PFS and time to unTACEable
progression may better capture the benefit of delaying TACE-strategy failure than conventional radiographic
endpoints alone. Second, when crossover is allowed, OS becomes strongly influenced by post-progression
treatment pathways and may underestimate the value of early combination therapy. Thus, CAP-ACE
provides strong randomized evidence that early TACE plus camrelizumab and rivoceranib/apatinib
improves disease control and delays unTACEable progression, but it should not be overinterpreted as
definitive proof of OS benefit.

FUTURE CONSIDERATIONS
The central challenge for future TACE-based combination trials is no longer whether systemic therapy can
enhance early tumor control, but how to design treatment strategies that preserve enough effective TACE
and systemic exposure to convert early disease control into durable survival benefit. Biologically, this PFS-OS
dissociation may reflect the fact that triple therapy primarily enhances early intrahepatic tumor control
rather than fully modifying the later determinants of survival in HCC. TACE can reduce viable tumor
burden and promote antigen release, while anti-VEGF/TKI therapy may suppress post-embolization
angiogenic rebound and render the tumor microenvironment more permissive to ICI activity [8-10] . These
mechanisms are well suited to improve radiographic response and delay progression. However, OS is
additionally influenced by hepatic functional reserve, cirrhosis-related competing mortality, cumulative liver
injury after repeated TACE, treatment-related toxicities and interruptions, and effective post-progression
therapies or crossover in control arms. Therefore, PFS may serve as a more sensitive signal of biological
synergy, whereas OS requires sustained tumor control together with preservation of liver function. This
discrepancy underscores several critical areas that require attention in future research.

First, the optimal timing and sequencing of TACE combined with systemic therapies must be directly
compared. Current studies utilize heterogeneous strategies, including systemic-first and TACE-first, without