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Page 8 of 15 Hall et al. Hepatoma Res. 2026;12:20

Table 2. Key clinical studies evaluating Y-90 radioembolization combined with immune checkpoint inhibitors in hepatocellular
carcinoma

Study Primary
Trial ID(Year) Population n Design Intervention Findings
Phase endpoint
PFS6 of 55.6% (95% CI,
Age ≥ 18 years and
NCT03099564(2021) I HCC with CP ≤ B7 27 Prospective Y-90 + PFS6 by 35.3-74.5) and OS of 27.30
and ECOG ≤ 1 Single-arm Pembrolizumab RECIST months (95% CI,
10.15-39.52)
Age ≥ 21 years and Prospective ORR by ORR of 30.6% (95% CI,
NCT03033446(2021) II HCC with CP A and 40 Single-arm Y-90 + Nivolumab RECIST 16.4-48.1)Most common
lesion > 20 mm AE: dermatologic
Combination therapy was
Nivolumab
Age ≥ 18 years and Prospective tolerable with MTD
NCT02837029(2021) I 27 Y-90 + Nivolumab MTD with
HCC with CP ≤ B8 Single-arm established and a CBR of
Y-90
82%
Median TTP 15.2 months
Age ≥ 19 years and Prospective Y-90 + TTP by (95% CI, 6.1-not
NCT04124991 (2022) I/II 24
HCC with CP ≤ B7 Single-arm Durvalumab mRECIST estimated) 2 (8.7%) grade
3 AE, no grade 4
CP: Childs-Pugh score; ECOG: Eastern Cooperative Oncology Group; Y-90: yttrium-90; PFS6: 6-month progression-free survival; RECIST: Response
Evaluation Criteria in Solid Tumors; CI: confidence interval; OS: overall survival; ORR: objective response rate; AE: adverse event; MTD: maximum
tolerated dose; CBR: clinical benefit rate; TTP: time to progression; RECIST: modified Response Evaluation Criteria in Solid Tumors [8,37-39] .
Y-90 plus immune checkpoint inhibitors
Emerging clinical evidence increasingly supports the strategic combination of Y-90 radioembolization with
ICIs to harness the synergistic potential of radiation-induced immunomodulation and immune checkpoint
blockade. This approach leverages the localized cytotoxic effects of Y-90 to promote immunogenic cell death
and neoantigen release, thereby priming the tumor microenvironment to respond more effectively to ICIs.

IMbrave050 exploratory arm
The phase III IMbrave050 trial was designed to evaluate adjuvant atezolizumab plus bevacizumab after
curative resection or ablation [35,36] . An exploratory arm included patients treated with Y-90 before systemic
therapy. Preliminary analyses of the Y-90 subgroup showed improved recurrence-free survival compared
with historical controls, with no unexpected toxicities.

Early-phase trials and case series
Phase I and II studies and retrospective series of Y-90 combined with PD-1/PD-L1 blockade (nivolumab,
pembrolizumab, atezolizumab) have reported ORRs of 30%-50% and mOS approaching 20 months,
exceeding outcomes typically observed with monotherapy. Safety signals were consistent with established ICI
profiles, without evidence of enhanced toxicity. For example, the combination of Y-90 and nivolumab in
NCT02837029 was tolerable and achieved a clinical benefit rate of 82%, including nine out of eleven patients
with stable disease. Key characteristics and outcomes of key clinical trials are summarized in Table 2 [8,37,38,39] .

Ongoing trials
Several prospective studies are in progress. NCT07059494 (phase IV) is evaluating Y-90 with atezolizumab
plus bevacizumab in advanced HCC, with PFS and immune correlates as primary endpoints. Additional
phase II trials (NCT05809869 and NCT06867432) are assessing Y-90-ICI combinations in advanced and
unresectable disease [Table 3] [40-42] .

Toxicity and safety profile
The combination of Y-90 radioembolization with systemic therapies generally demonstrates an acceptable
and manageable safety profile, though careful attention to potential toxicities remains essential.