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Page 4 of 15 Li et al. Hepatoma Res. 2026;12:36

Table 1. Efficacy summary of phase III first-line systemic therapy trials in advanced HCC
Trial name Year Regimen Primary endpoint Key efficacy results (months)
*
OS: 10.7 vs. 7.9 (HR = 0.69)
SHARP [37] 2008 Sorafenib vs. placebo OS & TTP
TTP: 5.5 vs. 2.8 (HR = 0.58)
OS OS: 13.6 vs. 12.3 (HR = 0.92)
REFLECT [38] 2018 Lenvatinib vs. sorafenib
non-inferiority PFS: 7.4 vs. 3.7 (HR = 0.66)
OS: 12.1 vs. 10.3 (HR = 0.83)
ZGDH3 [40]# 2021 Donafenib vs. sorafenib OS
PFS: 3.7 vs. 3.6 (HR = 0.91)
OS: NE vs. 10.4 (HR = 0.57)
ORIENT-32 [45]# 2021 Sintilimab plus bevacizumab biosimilar vs. sorafenib OS & PFS
PFS: 4.6 vs. 2.8 (HR = 0.56)
OS: 19.2 vs. 13.4 (HR = 0.66)
IMbrave150 [42] 2022 Atezolizumab plus bevacizumab vs. sorafenib OS & PFS
PFS: 6.9 vs. 4.3 (HR = 0.65)
OS: 15.9 vs. 14.1 (HR = 0.85)
RATIONALE-301 [46]# 2023 Tislelizumab vs. sorafenib OS non-inferiority
PFS: 2.1 vs. 3.4 (HR = 1.11)
OS: 23.8 vs. 15.2 (HR = 0.64)
CARES-310 [47]# 2025 Camrelizumab plus apatinib vs. sorafenib OS & PFS
PFS: 5.6 vs. 3.7 (HR = 0.54)
OS: 16.4 vs. 13.8 (HR = 0.76)
HIMALAYA [43] 2025 Tremelimumab plus durvalumab vs. sorafenib OS
PFS: 3.8 vs. 4.1 (HR = 0.90)
OS: 23.7 vs. 20.6 (HR = 0.79)
CheckMate 9DW [44] 2025 Nivolumab plus ipilimumab vs. lenvatinib/sorafenib OS
PFS: 9.1 vs. 9.2 (HR = 0.87)
Finotonlimab plus bevacizumab biosimilar vs. OS: 22.0 vs. 14.5 (HR = 0.76)
SCT-I10A-C301 [48]# 2025 OS & PFS
sorafenib PFS: 7.1 vs. 2.9 (HR = 0.50)
OS: 20.0 vs. 14.5 (HR = 0.76)
HEPATORCH [49]# 2025 Toripalimab plus bevacizumab vs. sorafenib OS & PFS
PFS: 5.8 vs. 4.0 (HR = 0.69)
* Year refers to the publication year of the data source used in this table; Denotes trials investigating China-developed drug regimens. For trials with
#
subsequently published mature or final analyses, the most mature peer-reviewed data were preferentially reported. OS: Overall survival; PFS:
progression-free survival; TTP: time to progression; HR: hazard ratio; NE: not estimable.

2008 demonstrated that the multi-target TKI sorafenib significantly improved OS (10.7 months vs. 7.9
months; HR = 0.69) compared to placebo, establishing sorafenib as the sole first-line standard for years .
[37]
Lenvatinib subsequently demonstrated non-inferiority in OS while improving progression-related endpoints
and response rates, expanding first-line options . The Chinese-developed TKI donafenib also showed
[38]
superior OS to sorafenib in the ZGDH3 trial (12.1 months vs. 10.3 months; HR = 0.83), with lower drug-
related grade ≥ 3 adverse events (AEs). Sorafenib, lenvatinib, and donafenib are all oral multi-target TKIs, yet
their mechanisms and clinical profiles differ. Sorafenib primarily inhibits VEGFR-2/3, platelet-derived
growth factor receptor (PDGFR)-β, and (rapidly accelerated fibrosarcoma) RAF kinases, establishing its
historical standard role by blocking angiogenesis and tumor proliferation. Lenvatinib demonstrates broader
and more potent inhibition of the VEGFR family (1-3) and, most distinctively, strongly targets fibroblast
growth factor receptors (FGFR) 1-4 . This concurrent blockade of the FGFR pathway is the key mechanism
[39]
behind its significantly higher ORR observed in the REFLECT trial. Donafenib is a deuterated derivative of
sorafenib , sharing a similar core target profile but with optimized pharmacokinetics, which explains the
[40]
better balance between efficacy and safety.

The advance of ICIs, mainly including programmed cell death-(ligand) protein 1 [PD-(L)1] inhibitors and
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have fundamentally reshaped the treatment
paradigm. Although initial attempts with PD-(L)1 inhibitors in the first-line setting (e.g., nivolumab in
CheckMate 459 ) failed to meet their primary survival endpoints, combination strategies proved
[41]
revolutionary. The updated landmark IMbrave150 trial established the combination of the PD-(L)1 inhibitor
atezolizumab and the VEGF inhibitor bevacizumab as a new global standard, demonstrating significantly
superior OS compared to sorafenib (19.2 months vs. 13.4 months; HR = 0.66) . The STRIDE regimen
[42]
[CTLA-4 inhibitor tremelimumab plus PD-(L)1 inhibitor durvalumab] in the HIMALAYA trial also