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Wu et al. Hepatoma Res 2023;9:6 https://dx.doi.org/10.20517/2394-5079.2022.37 Page 9 of 15

was a statistically significant improvement in progression-free survival at 16 weeks [0.19 in TACE group vs.
0.79 in the combination group (P = < 0.05)]. Overall, bevacizumab was well tolerated, without significant
bleeding risk. The Authors concluded that the addition of bevacizumab to TACE was a feasible and safe
[63]
option in selected HCC patients .

Unfortunately, the AVATACE-1 trial (ClinicalTrials.gov Identifier: NCT00280007), which compared TACE
with Bevacizumab vs. TACE alone, was terminated early due to safety concerns in the treatment arm, but
the sample size was only 32 participants. However, a large clinical trial combining Bevacizumab with
Atezolizumab was compared to sorafenib and showed improved overall survival at 12 months 67.2%
(95%CI: 61.3-73.1) with atezolizumab-bevacizumab vs. 54.6% (95%CI: 45.2-64.0) with sorafenib .
[11]
Currently, Bevacizumab is being studied in combination with Atezolizumab following TACE
(ClinicalTrials.gov: NCT04224636)

TACE with lenvatinib
In a retrospective study involving 120 patients, the overall survival rates were significantly higher in the
[64]
TACE + lenvatinib arm (88.4% and 79.8%) than in the TACE arm alone (79.2% and 49.2%, P = 0.047) .

An Open-label, Single-arm, Phase 2 Trial (Thalen) will analyze the safety and efficacy of TACE plus
Lenvatinib for patients with unresectable HCC; the study is currently recruiting new subjects.
(ClinicalTrials.gov Identifier NCT04531228). Data from the Phase Ib study of lenvatinib + Pembrolizumab
showed promising results with a median Progression-free survival of 9.3 months, and median Overall
[65]
survival of 22.0 months .
TACE with axitinib
Axitinib is an oral multi-targeted receptor TKI, binding vascular endothelial growth factor receptor
(VEGF), PDGFR, and c-KITR. Axitinib is FDA-approved for use as a second-line age for advanced renal
cell carcinoma . A phase II trial examined the efficacy of the TACE plus axitinib combination in the
[66]
treatment of unresectable HCC. The 2-year overall survival rate was 43.7%, and the median OS was 18.8
[67]
months which is better than the average overall survival in the TACE monotherapy (31%) . Although the
overall survival was not different from the placebo, Axitinib showed improvement in progression-free
survival and time to tumor progression .
[68]
TACE with other molecular agents
Multiple trials that combined TACE with other agents have been done. There are several that did not show
survival benefits, including TACE, BRISK-TA, SPACE, ORIENTAL, and TACE-2. The BRISK-TA
compared TACE with placebo vs. TACE with Brivanib - a fibroblast growth factor receptor and VEGF
receptor inhibitor- the endpoint was overall survival which was not different among the two arms .
[69]
The ORIENTAL trial examined orantinib- a VEGF and PDGF inhibitor- compared to a placebo. The
overall survival was not significantly different among both groups. OS was 31.1 and 32.3 months in the
orantinib and placebo groups, respectively (HR: 1.090; 95%CI: 0.878-1.352; P = 0.435) .
[70]

TACE with immunotherapy
In recent years, the combination of TACE and immunotherapy has emerged as a promising therapy as it has
demonstrated a favorable antitumor immune response. A study looked at the efficacy and safety of
tremelimumab (anti-CTLA4) combined with TACE in BCLC stage B patients with HCC. Median TTP was
7.4 months median OS was 12.3 months during a follow-up of 18.8 months (this included an additional
BCLC stage C group treated with thermal ablation instead of TACE) . A more recent study by Ji et al.
[71]