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Hall et al. Hepatoma Res. 2026;12:20 Page 7 of 15

An important consideration is that this landmark trial compared combination therapy with targeted
monotherapy, rather than addressing this review’s focus on how combination therapy may be superior to
SIRT monotherapy. Moreover, a post-hoc analysis of the SORAMIC trial assessed the follow-up images of
177 patients by mRECIST (modified Response Evaluation Criteria in Solid Tumors) and demonstrated a
significantly increased objective response rate (ORR), complete response rate, and disease control rate
among patients treated with combination therapy .
[32]
The SARAH (Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres
compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma) trial, a pivotal phase
III randomized controlled study, compared Y-90 radioembolization with oral multi-kinase inhibitor
sorafenib monotherapy in patients with advanced HCC . Although the trial did not demonstrate a
[7]
statistically significant superiority of Y-90 over sorafenib for overall survival (OS), subgroup analyses
suggested potential benefits in select patient populations - particularly those with preserved liver function
and limited tumor burden. This trial highlighted the importance of careful patient stratification when
considering combination therapies.

The Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients with HCC (SIRveNIB)
trial, a phase III randomized trial, also compared OS between patients with advanced HCC managed with
Y-90 versus sorafenib . Again, no significant difference in OS was found, but Y-90 radioembolization
[33]
demonstrated a superior toxicity profile to sorafenib. These trials underscore the need for additional studies
to identify cohorts most likely to benefit from Y-90-based combination strategies.

Retrospective and prospective clinical studies
Several retrospective studies have provided encouraging evidence supporting the additive effects of
combining Y-90 with ICIs. Notably, Lee et al. reported results from a 2023 phase I/II trial investigating the
efficacy and safety of Y-90 radioembolization combined with durvalumab in patients with unresectable
HCC . This study demonstrated a median progression-free survival (PFS) of 6.9 months and an ORR of
[8]
83.3%, outcomes that compare favorably to Y-90 monotherapy (PFS, 3 months; ORR, 42-57%). Importantly,
the combination exhibited a tolerable safety profile, with common adverse events including fatigue,
hypertension, and transient liver enzyme elevations, all manageable with dose modifications and supportive
care .
[27]

Another study evaluating the combination of Y-90 with targeted agents demonstrated comparable survival
outcomes between groups and confirmed an acceptable safety profile. Facciorusso et al. conducted a
retrospective propensity score-matched study of 135 patients with intermediate-to-advanced HCC.
Outcomes between Y-90 plus sorafenib and Y-90 alone were compared . The combination group showed
[34]
no significant difference in median overall survival (mOS) (10 vs. 10 months; P = 0.711) or PFS (6 vs. 7
months; P = 0.992). Importantly, adverse events were manageable, and no unexpected toxicities were
identified .
[34]
Mechanistic and clinical implications
The rationale for combining Y-90 with targeted therapies centers on disrupting tumor vasculature and
cellular proliferation through complementary mechanisms. While Y-90 induces localized radiation damage
and vascular disruption, targeted agents inhibit signaling pathways such as VEGFR and PDGFR, mitigating
angiogenic rebound and systemic tumor growth. Clinical data to date support the hypothesis that this dual
approach may lead to improved local control, delayed disease progression, and potentially enhanced overall
survival in carefully selected patients [7,9,11] .