A Multicenter Phase Ib/II Clinical Study on the Safety and Efficacy of Selective Internal Radiation Therapy (SIRT) With Yttrium-90 Microspheres in Combination With Nivolumab, Ipilimumab, and Lenvatinib in Patients With Unresectable Hepatocellular Carcinoma
Phase: PHASE1
Conditions: Unresectable Hepatocellular Carcinoma
Sponsor: West China Hospital

Study protocol of a multicenter phase Ib/II clinical study on
the safety and efficacy of selective internal radiation therapy
(SIRT) with Yttrium-90 microspheres in combination with
nivolumab, ipilimumab, and lenvatinib in patients with
unresectable hepatocellular carcinoma
2026-01-20

A multicenter phase Ib/II clinical study on the safety and efficacy of selective internal
radiation therapy (SIRT) with Yttrium-90 microspheres in combination with nivolumab,
ipilimumab, and lenvatinib in patients with unresectable hepatocellular carcinoma
Rui-Hong Dai
1 Fa-Cheng Lu
1 Qing He
1 Wei-Bing Leng
1 Wen-Hao Guo
1 Tao Hai
1 Chang Liu
1★
1: Interventional Diagnosis and Treatment Center, West China Hospital, Sichuan University,
Chengdu 610041, Sichuan, China.
★Corresponding author: Chang Liu, Interventional Diagnosis and Treatment Center, West
China
Hospital,
Sichuan
University,
Chengdu
610041,
Sichuan,
China.
Email:
drliuchang@wchscu.cn; Tel: 18980606382.
Background Despite recent advances in the combination of systemic therapy and local
treatment for patients with advanced unresectable hepatocellular carcinoma, limitations
remain,
including
poor
response
rates
and
the
lack
of
translation
of
short-term
progression-free survival to long-term overall survival. The use of selective internal radiation
therapy (SIRT) with Yttrium-90 microspheres combined with nivolumab, ipilimumab, and
lenvatinib may overcome these shortcomings. This phase 1b/II clinical trial evaluates the
safety and efficacy of this protocol in the treatment of patients with unresectable
hepatocellular carcinoma.
Methods/design This multicenter, single-arm, prospective trial enrolls patients with
unresectable hepatocellular carcinoma. Patients receive Yttrium-90 selective internal
radiation therapy (Y90-SIRT) in combination with nivolumab, ipilimumab, and lenvatinib. The
phase Ib portion of the trial explores the incidence of dose-limiting toxicity (DLT) in the
quadruple therapeutic regimen. Three weeks after receiving Y90-SIRT, the patients are
assigned to one of three dose exploration cohorts: (1) nivolumab 1 mg/kg IV every 3 weeks
(Q3W) + ipilimumab 1 mg/kg IV Q3W for up to 4 cycles; (2) nivolumab 1 mg/kg IV Q3W +
ipilimumab 2 mg/kg IV Q3W for up to 4 cycles; (3) nivolumab 1 mg/kg IV Q3W + ipilimumab
3 mg/kg IV Q3W for up to 4 cycles. After completion of ipilimumab administration,
nivolumab is continued at 480 mg IV every 4 weeks (Q4W) until disease progression,
unacceptable toxicity, withdrawal of informed consent, or a maximum treatment duration of
two years.
Lenvatinib is then administered after discontinuation of ipilimumab,
in
combination with nivolumab, at a dose of 8 mg (body weight <60 kg) or 12 mg (body
weight >60 kg) orally once daily (PO QD), taken at a fixed time each day, with or without
food. The phase II portion represents a single-arm trial using the dose selected in phase Ib.
After completion of all treatments, patients will be followed up for 24 months. The primary
endpoints are the incidence of DLT in phase Ib for the determination of the treatment
Funding: This work was supported by the Chengdu Medical Research Project (Grant No. 2024069) from
the Chengdu Municipal Health Commission.

regimen, and the objective response rate in the experimental group in the phase II trial.
Discussion This trial aims to establish a safe and effective strategy that combines local
treatment with systemic therapy for patients with unresectable hepatocellular carcinoma,
integrating local Y90-SIRT with systemic immunotherapy and targeted therapy. The results
may provide guidance for future phase III clinical trials.
Trial registration This study has been approved by the Ethics.Committee of West China
Hospital of Sichuan University (IRB No. ).The trial was prospectively registered at ClinicalTrial
Registry () on February 17, 2025.
Keywords: unresectable hepatocellular carcinoma, Yttrium-90 microsphere selective internal
radiation therapy (Y90-SIRT), nivolumab, ipilimumab, lenvatinib, phase Ib/II study
Background
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world.
According to data released by the National Cancer Center of China, there were 367,700 new
diagnoses of primary liver cancer in China in 2022, with the disease currently ranked fourth
among all newly diagnosed cancers (lung, colorectal, thyroid, and liver), and fifth in incidence
rate (lung, female breast, thyroid, colorectal, and liver). In addition, 316,500 deaths due to
primary liver cancer occurred in 2022, with both the number of deaths and the mortality rate
ranking second (lung and liver). Most patients with HCC in China are diagnosed at an
intermediate or advanced stage. Despite recent improvements in diagnostic and therapeutic
techniques, the prognosis for patients with unresectable intermediate or advanced HCC
remains poor, with a 5-year survival rate of only 14.1%. Therefore, the exploration of more
effective
treatment
strategies,
particularly
combination
therapies,
for
unresectable
intermediate or advanced HCC is of great clinical significance.
To date, there has been some progress in the use of systemic therapy combined with
local treatment for patients with unresectable intermediate or advanced HCC. The
EMERALD-1
[1]、LEAP-012
[2] and CARES-005
[3] studies indicate that although the combination
of immunotherapy and targeted therapy with transarterial chemoembolization (TACE) has
achieved a significant improvement in progression-free survival (PFS) compared to TACE
alone, to date, overall survival (OS) has not reached significant thresholds and there is no
evidence as yet of long-term survival benefits. Longer follow-up is needed, and certain
limitations require addressing. Since most patients with liver cancer in China are diagnosed
at an advanced stage, associated with high tumor burden and late staging, the increase in
the 5-year survival has been less than 3% over the past decade, which is still far from the
Healthy China 2030 goal. The efficacy of TACE is limited by incomplete embolization,
increased VEGF levels leading to recurrence and metastasis, impaired liver function caused
by
repeated
treatments,
and
post-embolization
syndrome.
On
the
other
hand,
immune-targeted
combination
regimens
such
as
IMbrave150
(atezolizumab
plus
bevacizumab), CARES310 (camrelizumab plus apatinib), and ORIENT-32 (sintilimab plus
bevacizumab) have all been approved in China as first-line treatments for advanced liver
cancer. However, these regimens still have various issues, such as relatively unsatisfactory

objective response rates (ORRs), no published data on long-term survival (OS), and the
unique adverse event profiles associated with anti-angiogenic therapy. For example, over
30%
of
patients
receiving
immunotherapy
combined
with
bevacizumab
experience
hypertension, while over 40% experience proteinuria, and there is a 15% risk of bleeding.
Therefore, there is an urgent need for an effective and safe systemic therapy combined with
local treatment.
Yttrium-90 microsphere-selective internal radiation therapy (Y90-SIRT) relies on hepatic
arterial catheterization for delivery of microspheres loaded with the radioactive isotope
yttrium-90 (Y90) to the arterial vessels supplying the liver tumor. These microspheres remain
in the terminal vascular network of the tumor, enabling precise coverage of the tumor and
the continuous release of high-energy beta radiation in close proximity to tumor cells. This
leads to irreversible damage to the tumor tissue, leading to necrosis and thereby achieving
effective tumor control
[4]. The beta radiation emitted by Y90 can damage cellular DNA either
directly or indirectly and trigger immune responses in tumor cells, thereby inducing
immunogenic cell death. Y90-SIRT offers several advantages, including marked shrinkage of
the tumor, the promotion of compensatory hyperplasia of the contralateral healthy liver
tissue (thus increasing the future liver remnant volume), regression of portal vein tumor
thrombi, and improvement of the patient’s quality of life.
International studies have confirmed the feasibility of using Y90 in a variety of liver
cancer treatment scenarios, including radical treatment for early-stage disease, downstaging
treatment for intermediate-stage liver cancer, palliative treatment for advanced-stage
disease, and conversion therapy. Compared with TACE treatment, SIRT delivers high-dose
radiation precisely to the capillary bed of the tumor, resulting in a greater degree of necrosis
in specific scenarios
[5]. This treatment has the dual advantages of direct contact with the
tumor and continuous radiotherapy, which not only improve the ORR and disease control
rate, but also significantly reduce the risk of damage to normal liver tissue. A recent
meta-analysis published in 2025 retrieved 1749 potentially relevant papers, ultimately
including 7 retrospective studies and 1 prospective study involving 1026 patients receiving
TACE treatment and 358 patients receiving SIRT treatment. The results showed that
compared with TACE, SIRT resulted in higher ORR (64.4% vs. 55.0%, P = 0.04) and disease
control rate (89.5% vs. 79.3%, P = 0.003), longer survival benefit (1-year OS rate: 56.9% vs.
45.7%, P = 0.02), and lower adverse reactions in patients with HCC. This has led to the use of
SIRT in preference to TACE in European and American countries, where it has become the
preferred local treatment for intermediate and advanced liver cancer
[6].
The
liver
itself
is
a
unique
organ
with
immune
privilege,
and
the
tumor
microenvironment (TME) of HCC exhibits multiple immunosuppressive characteristics. In
addition to the presence of immunosuppressive factors, such as PD-1 and CTLA-4, there is a
significant increase in the number of regulatory T cells. The combination of these factors
leads to immunosuppression and enables the tumor cells to evade immune surveillance. In
this context, treatment with nivolumab combined with ipilimumab promotes the activation
and proliferation of T cells, counteracts T-cell inhibition, and reduces T-cell exhaustion.
These mechanisms work together to facilitate the differentiation of effector T cells into
memory
T
cells,
thereby
enabling
long-term
immune
surveillance.
Thus,
in
the
immunosuppressive HCC TME, these factors combine synergistically, transforming multiple

layers of suppression into potent activation and overcoming the efficacy bottleneck of
previous immunotherapy regimens. In the phase II CheckMate 040 study, the optimal dosing
regimen was found to be nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3
weeks (Q3W) for up to four cycles, followed by nivolumab 480 mg every 4 weeks (Q4W) until
disease progression, the development of unacceptable toxicity, or a maximum treatment
duration of two years. The CheckMate-9DW study
[7] is a global, randomized, open-label
phase III clinical study that investigated the efficacy and safety of nivolumab combined with
ipilimumab versus sorafenib/lenvatinib as first-line treatment for advanced HCC. Analysis of
the primary endpoint showed that nivolumab plus ipilimumab significantly improved OS
compared to sorafenib/lenvatinib in first-line HCC patients, with a median OS of 23.7
months, notably higher than that of 20.6 months observed in the control group (HR=0.79,
p=0.018). Importantly, 38% of patients treated with nivolumab plus ipilimumab survived for
longer than 3 years (3-year OS rate: 38% vs 24%), highlighting the long-term survival
advantage of dual immunotherapy. The secondary endpoint, the ORR, reached 36%, higher
than that found in all previous similar phase III studies (20.1‒27.3%), indicating that over
one-third of patients achieved significant tumor shrinkage. Notably, 7% of patients in the
combination group achieved complete response (CR), and, among patients with evaluable
target lesions, 37% showed over 50% shrinkage of target lesions, while nearly 20% of patients
experienced shrinkage of over 75%, indicating that nivolumab plus ipilimumab induces deep
responses and significantly reduces the tumor burden. In terms of safety, the incidence of
treatment-related grade 3/4 adverse events was 41% versus 43% in the control group, with
the most common adverse events being hepatitis, colitis, rash, and thyroid dysfunction, and
no new safety signals were observed. Currently, the dual immunotherapy regimen has been
approved both in China and by the US FDA for first-line treatment of adult patients with
unresectable or advanced HCC. Compared to the combination of targeted therapy and
immunotherapy, dual immunotherapy offers advantages in terms of higher ORR (36%),
significant long-term survival benefit (3-year OS rate: 38%), and a manageable safety profile.
The combination of lenvatinib with dual immunotherapy aims to address the early crossing
of survival curves seen with dual immunotherapy alone, with the goal of achieving
short-term benefits in both progression-free survival (PFS) and ORR, as well as long-term
OS benefits.
Iparomlimab and Tuvonralimab (QL1706) is a dual combination antibody that targets
PD-1/CTLA-4. The phase II portion of the DUBHE-H-308 study presented at the 2025 ESMO
conference evaluated the efficacy and safety of three regimens, namely QL1706 plus
Bevacizumab Biosimilar plus XELOX, QL1706 plus Bevacizumab Biosimilar, and QL1706 plus
XELOX, in comparison with Sintilimab plus Bevacizumab Biosimilar as the first-line treatment
for advanced HCC. After a median follow-up of 15.2 months, the ORR reached 40% in both
the QL1706 plus Bevacizumab Biosimilar plus XELOX group and the QL1706 plus
Bevacizumab Biosimilar group, which was double that of the 20.7% ORR found in the control
group. This indicates that dual-immunotherapy combinations can induce tumor shrinkage in
a higher proportion of patients. Comparison of the QL1706 plus Bevacizumab Biosimilar
group and the control group showed PFS values of 8.1 months vs. 5.9 months, respectively,
while the 12-month OS rates were 65.5% and 62.1%, respectively, with both showing an
increase. In terms of safety, the incidence of adverse events (AEs) of grade 3 or above was

53.3% in the QL1706 plus Bevacizumab Biosimilar group vs. 44.8% in the control group. The
proportion of treatment discontinuations resulting from treatment-related adverse events
(TRAE) was 23.3% vs. 10.3%. Tolerable toxicity was observed in the QL1706 combination
group, and the primary AE of grade 3 or above was hypertension
[8].
Studies have shown that radiotherapy (RT), including Y90-SIRT, acts synergistically with
immunotherapy. Firstly, RT can promote the release of tumor antigens and increase the
number and enhance the maturation of antigen-presenting dendritic cells, and the resulting
increases in antigen presentation help stimulate T-cell activation and strengthen the
anti-tumor immune response [9]. Secondly, immune-mediated mechanisms can occasionally
induce tumor responses at sites distant from the irradiated area, a phenomenon termed the
“abscopal effect” [10]. Thirdly, RT can activate the downstream activation of stimulator of
interferon genes (STING), resulting in increased production of type I interferons (IFN-I),
which is crucial for immune cell recruitment, particularly of dendritic cells or CD8+ T cells,
thereby inducing antigen presentation and promoting the transformation of the TME from
“cold ”
to “ hot ”
[11]. Compared to patients who received either TACE or no preoperative
treatment,
those
treated
with
Y90-SIRT
showed
significantly
increased
levels
of
tumor-infiltrating lymphocytes, CD4+ and CD8+ T cells, as well as increased expression of
granzyme B in tumor tissues
[12].
The hypoxic microenvironment caused by abnormalities in the tumor vasculature is an
important factor contributing to radioresistance. Inhibition of vascular endothelial growth
factor (VEGF) inhibitors can normalize tumor blood vessels and alleviate hypoxia, thereby
increasing tumor radiosensitivity. Clinical studies have also confirmed that RT combined with
anti-VEGF agents can enhance the anti-tumor response. Although VEGF inhibitors may
prevent further tumor angiogenesis, which could potentially favor radioresistance, many
clinical studies have shown that the combination of RT and anti-VEGF agents can enhance
the anti-tumor response
[13]. Blockade of VEGF has been found in both preclinical models and
clinical trials to synergize with RT and immunotherapy in various ways. In summary, SIRT in
combination with molecular-targeted therapy and the application of immune checkpoint
inhibitors has a synergistic effect; the anti-angiogenic agents can normalize the tumor
vasculature, thereby not only increasing radiosensitivity but also improving the TME and
enhancing the efficacy of immunotherapy.
In a comparative study of Y90-SIRT combined with targeted immunotherapy, Amel et al.
conducted a retrospective analysis of 35 patients, of whom 27 had received Y90-SIRT alone,
and 8 had undergone Y90-SIRT combined with atezolizumab plus bevacizumab. At the time
of publication, the median OS had not yet been reached in the group receiving Y90-SIRT
combined with atezolizumab plus bevacizumab, while the median OS for patients treated
with Y90-SIRT alone was 14 months. The median PFS was higher in the group receiving
Y90-SIRT combined with atezolizumab plus bevacizumab compared to treatment with
Y90-SIRT alone (87% vs 60%). Eight patients achieved tumor downstaging (23%), while four
underwent surgical resection (one in the Y90-SIRT combined with atezolizumab plus
bevacizumab group), and four were treated with liver transplantation (one in the Y90-SIRT
combined with atezolizumab plus bevacizumab group). No grade 3 or above AEs occurred
after treatment. These findings suggest that, for unresectable HCC, administration of
atezolizumab plus bevacizumab before and after SIRT may help improve OS and PFS

compared to SIRT alone
[14][15]. However, the design of this study was retrospective, with
potential intergroup imbalances and a small sample size, which may have led to
confounding bias.
The combination of Y90-SIRT and dual immunotherapy is a major focus of ongoing
investigation. However, there are no reports on the use of the more complex triple therapy,
involving Y90-SIRT, dual immunotherapy, and targeted agents. Therefore, exploring the
feasibility, safety, and synergistic mechanisms of triple therapy will be an important direction
for future research.
In terms of dose exploration, previous phase I/II studies on dose exploration have
shown that the safety profile of nivolumab is similar for different tumor types and dose levels
(0.1 –10 mg/kg)
[16]. The incidence of AEs with ipilimumab is clearly dose-dependent. The
CA184-022 study evaluated the anti-tumor activity, OS, and safety of ipilimumab at doses of
0.3, 3, and 10 mg/kg. The results showed that ipilimumab efficacy was positively correlated
with dose, and the incidence of immune-related adverse events (irAEs) increased with higher
doses. Most AEs were grade 1–2, and mainly affected the skin and gastrointestinal tract
[17].
Study 117 investigated dose-limiting toxicity and identified the dose combination of
nivolumab 240 mg Q2W with lenvatinib 8 mg or 12 mg/day
[18]. Therefore, in the phase Ib
part of the present study, we incorporated a dose escalation for ipilimumab to identify the
optimal dose combination.
Based on this background, this clinical trial was designed to evaluate the safety and
efficacy of Y90-SIRT combined with nivolumab, ipilimumab, and lenvatinib in patients with
unresectable HCC. In addition to assessing short-term efficacy endpoints, such as ORR and
PFS, this trial places particular emphasis on the OS benefit for patients. This study is therefore
both novel and innovative.
2 Methods and design
This
investigator-initiated
phase
Ⅰb/II
trial
adopts
a
multicenter,
single-arm,
prospective design to evaluate the safety and efficacy of Y90-SIRT combined with nivolumab,
ipilimumab, and lenvatinib in patients with unresectable HCC. Enrollment is planned from
January 2026 to June 2026, with a 24-month follow-up period initiated after inclusion of the
final participant. Recognizing the potential biases inherent in single-arm trials, we have
implemented the following measures: (1) blinded adjudication of the ORR(iRecist and
mRecist) by an independent review facility (IRF); (2) propensity score-adjusted sensitivity
analysis
compared
with
historical
control
groups;
(3)
transparent
screening
logs
documenting reasons for exclusion. The structure of the protocol and assessment timelines
are detailed in Figure 1 and Table 1, respectively.
Figure 1: Flowchart of the study protocol.

Table 1: Schedule of clinical assessments for enrolled patients.
Assessments
Pre-enrollment
baseline
( ≤7
days)
Cycle initiation
c
Post-treatment
evalua
tion
(
≤
4
weeksafterfinal
PD-L1 inhibitor
dose)
Follow-up
schedule
Enrollment:
Eligibility screen
a
and
Informed
consent b
√
Baseline
characteristics#
√
Pathological
assessment#
√
Laboratory
tests#
√
√
√
✓
(Year
1:
quarterly;
Years 2 and 3:
biannual)
Imaging
examination#
√
√
√
✓
(Year
1:
quarterly;
Years 2 and 3:
biannual)
Toxicity/adverse
event
monitoring
√
√
✓
(Year
1:
quarterly;
Years 2 and 3:
biannual)
Quality of life
√
√
√
✓
(Year
1:
quarterly;
Years 2 and 3:
biannual)

Relapse
√
√
✓
(Year
1:
quarterly;
Years 2 and 3:
biannual)
Survival
√
√
✓(Year
1:
quarterly;
Years 2 and
3: biannual)
2.1 Main inclusion criteria
Eligible participants must meet the following key criteria: (1) Unresectable HCC
confirmed by clinical and/or pathological diagnosis; The term "unresectable hepatocellular
carcinoma" refers to a clinical state in which radical surgical resection is precluded because
the tumor extent or an inadequate anticipated future liver remnant would prevent R0
removal, or because the procedural risk is prohibitively high, and where surgical intervention
is not expected to yield a survival advantage over non ‑ surgical therapies. (2) No prior
systemic therapy or treatment with Y90; (3) Not suitable for curative treatments, such as
surgical resection, ablation, or transplantation; (4) Child-Pugh class A; (5) ECOG performance
status 0 – 1; (6) No extrahepatic metastasis; (7) Excluding Vp3 and Vp4; (8) Estimated life
expectancy ≥3 months. The complete inclusion and exclusion criteria are detailed in Table
2.
Table 2 Study eligibility criteria.
Inclusion criteria
Exclusion criteria
1. HCC confirmed as unresectable by
imaging or histology, or patients who
refuse surgery. Eligible for Y90-SIRT, with
no evidence of extrahepatic disease on any
available imaging. Lymph node
involvement is permitted. The term
"unresectable hepatocellular carcinoma"
refers to a clinical state in which radical
surgical resection is precluded because the
tumor extent or an inadequate anticipated
future liver remnant would prevent R0
removal, or because the procedural risk is
prohibitively high, and where surgical
intervention is not expected to yield a
survival advantage over non‑surgical
therapies.
1. Diffuse HCC or presence of vascular
invasion or extrahepatic spread, with the
following exceptions: invasion of segmental
portal vein or hepatic vein.
2. Aged between 18 and 80 years at the
time of enrollment
2. Patients with Child-Pugh class C cirrhosis.
3. Participants with Child-Pugh class A.
3. Any contraindication to hepatic arterial

embolization: Known hepatic arterial reflux;
known portosystemic shunt; coagulopathy
(platelet count < 50 × 10
9/L, INR > 1.5);
renal failure/insufficiency requiring
hemodialysis or peritoneal dialysis; known
severe arteriosclerosis; complete
thrombosis or complete invasion of the
main portal vein.
4. Participants with an ECOG performance
status of 0 or 1 at the time of enrollment
4. History of heart disease: congestive heart
failure > New York Heart Association
(NYHA) class II; active coronary artery
disease (CAD) (myocardial infarction ≥6
months prior to study initiation is
permitted); arrhythmias that are difficult to
control with antiarrhythmic drugs or require
a pacemaker (NCI-CTCAE v5.0 > grade 2);
uncontrolled hypertension; clinically
significant gastrointestinal bleeding within 4
weeks prior to initiation of study drugs.
5. Participants with a lung dose threshold of
30 Gy for yttrium-90 microspheres (each
treatment dose ≤30 Gy), and an
anticipated future liver remnant volume
(FLRV) ≥30% of the total liver volume.
5. Thrombotic or embolic events, such as
cerebrovascular accident (including
transient ischemic attack), deep vein
thrombosis, or pulmonary embolism,
occurring within 6 months prior to the first
administration of study drug, except for
segmental portal vein thrombosis.
6. Participants with one or more
measurable lesions; for those with
segmental or right anterior/posterior portal
vein invasion (Vp1/Vp2), the disease is
confined to a single lobe and suitable for
Y90 microsphere treatment.
6. Receipt of systemic anticancer therapy,
radiotherapy, endocrine therapy,
immunotherapy, or other investigational
drugs within 4 weeks prior to study
initiation.
7. If the patient is co-infected with hepatitis
B virus (HBV) or hepatitis C virus (HCV), the
following criteria must be met: HBV or HCV
viral levels should be monitored during
study participation. Patients with detectable
hepatitis B surface antigen (HBsAg) or HBV
DNA should have HBV DNA < 100 IU/ml
and be managed according to local
treatment guidelines. Most patients with
advanced HCC and HCV have not received
treatment for HCV infection. However, if
antiviral therapy has been completed prior
7. Current or prior use of
immunosuppressive drugs within 28 days
before the first administration of nivolumab
or ipilimumab. Exceptions to this criterion
include: intranasal, inhaled, topical steroids
or local steroid injections (e.g.,
intra-articular injection); physiological
doses of systemic corticosteroids not
exceeding 10 mg/day of prednisone or
equivalent; steroids used for the prevention
of allergic reactions (e.g., premedication for
CT scan).

to the first administration of study drugs,
these patients are considered eligible for
inclusion.
8. No prior systemic therapy or transarterial
radioembolization (Y90 glass microsphere
TARE).
8. Receipt of live attenuated vaccines within
30 days prior to the first administration of
study drug (IP). Note: If the patient is
enrolled, live vaccines should not be
administered during the study drug
treatment period and within 30 days after
the last dose of the study drug.
9. No active autoimmune disease and no
history of chronic or recurrent autoimmune
disease.
9. Major surgery within 4 weeks prior to
study initiation, and the patient must have
recovered from the effects of major
surgery.
10. Adequate hematological, liver, and
renal function as follows: (1) Absolute
neutrophil count ≥1,500/mm³ (2)
Hemoglobin level ≥9.0 g/dL (3) Platelet
count ≥75,000/mm³ (4) Total bilirubin
≤1.5 × ULN (5) AST ≤2.5 × ULN (6)
ALT ≤2.5 × ULN (7) International
normalized ratio (INR) ≤1.25 (8) Albumin
≥31 g/L (9) 24-hour urine collection
creatinine clearance (CL) > 40 mL/min or
calculated creatinine clearance (CL) > 40
mL/min.
10. Patients with a second primary
malignancy, apart from adequately treated
basal cell carcinoma of the skin or
carcinoma in situ of the cervix, unless
disease-free for more than 3 years.
11. Not pregnant and no intention to
conceive before or during treatment.
11. Uncontrolled comorbidities, including
but not limited to persistent or active
infection, symptomatic congestive heart
failure, uncontrolled hypertension, unstable
angina, arrhythmia, interstitial lung disease,
severe chronic gastrointestinal disease
associated with diarrhea, or
psychiatric/social conditions that limit
compliance with study requirements,
significantly increase the risk of adverse
events, or impair the patient’s ability to
provide written informed consent.
12. Written informed consent from the
patient.
12. Active infections, including tuberculosis
(clinical assessment including medical
history, physical examination, and imaging,
as well as tuberculosis testing according to
local practice), hepatitis B (known positive
HBV surface antigen [HBsAg]), and hepatitis

C. Patients with past or resolved HBV
infection (defined as presence of hepatitis B
core antibody [anti-HBc] and absence of
HBsAg) are eligible. Patients who are HCV
antibody-positive are eligible only if HCV
RNA measured by PCR is negative.
13. Expected survival of at least 12 weeks.
13. History of allogeneic organ
transplantation.
14. Psychiatric disorders or altered mental
status that interfere with understanding the
informed consent process and/or
compliance with the study protocol.
15. Symptomatic brain metastases. If
symptoms are present, imaging is required
to confirm the absence of brain metastases.
16. Pregnant or breastfeeding women.
17. Immunocompromised patients, such as
those known to be serologically positive for
human immunodeficiency virus (HIV).
18. Active or previously documented
autoimmune or inflammatory diseases
(including inflammatory bowel disease
[such as colitis or Crohn’s disease],
diverticulitis [excluding diverticulosis],
systemic lupus erythematosus, sarcoidosis,
or Wegener’s granulomatosis
[granulomatosis with polyangiitis], Graves’
disease, rheumatoid arthritis, hypophysitis,
uveitis, among others).
19. Known allergy or hypersensitivity to any
study drug or its components.
20. Currently participating in or previously
participated in a study involving an
investigational drug, or use of an
investigational device within 4 weeks prior
to the first administration of study
treatment.
2.2 Treatment
Assessment of the incidence of dose-limiting toxicity (DLT) in the phase IB exploratory
quadruple regimen:
Enrolled patients will receive the quadruple regimen, starting with selective internal radiation
therapy using Y90-SIRT. Three weeks after Y90-SIRT intervention, patients will be assigned
to one of three dose exploration cohorts:

(1) Nivolumab 1 mg/kg IV Q3W + Ipilimumab 1 mg/kg IV Q3W dual immunotherapy for up
to 4 cycles;
(2) Nivolumab 1 mg/kg IV Q3W + Ipilimumab 2 mg/kg IV Q3W dual immunotherapy for up
to 4 cycles;
(3) Nivolumab 1 mg/kg IV Q3W + Ipilimumab 3 mg/kg IV Q3W dual immunotherapy for up
to 4 cycles.
After completion of the dual immunotherapy treatment, nivolumab 480 mg IV Q4W will be
administered until disease progression, development of unacceptable toxicity, withdrawal of
informed consent, or a maximum treatment duration of 2 years. Lenvatinib will be
administered in combination with nivolumab after discontinuation of ipilimumab, at a dose
of 8 mg (body weight < 60 kg) or 12 mg (body weight ≥60 kg) PO QD, taken at a fixed
time each day, either fasting or with food. Dose adjustment or temporary interruption of
lenvatinib will be permitted during treatment (refer to the prescribing information for
adjustment), with a maximum interruption period of 30 days. Treatment will continue until
disease progression, the development of unacceptable toxicity, or withdrawal of informed
consent. If any drug is discontinued for any reason during treatment, continuation of the
other drugs is allowed.
The phase II study is designed as a single-arm trial, using the dose regimen selected in
phase IB.
2.3 Criteria for study discontinuation
The trial should be stopped immediately in the following cases:
1. The patient requests to terminate the trial, the Ethics Committee demands termination of
the trial, or the drug regulatory department requires termination of the trial.
2. The investigators confirm that the disease has progressed or that continuing treatment
would be of no therapeutic benefit.
3. Participant- or clinician-reported unacceptable AEs.
4. The patient fails to adhere strictly to the treatment protocol.
All withdrawal rationales will be systematically documented in the clinical records of the trial.
2.4 Data collection
1. Baseline patient characteristics:
a. Age, year
b. Sex, male/female
c. Body mass index, kg/m2
d. Personal history of smoking, alcohol consumption, and
medication usage
e. Comorbidities
f. ECOG performance status
g. Child-Pugh class
h. Hepatitis B status
i. Hepatitis C status
2. Laboratory examinations:

a. CA19-9, U/mL
b. CEA, ng/mL
c. Hemoglobin (g/dL)
d. White blood cell count, × 10
9cells/L
e. Absolute neutrophil count,× 10
9 cells/L
f. Platelet count, × 10
9/L
g. Glomerular filtration rate, mL/min
h. Aspartate aminotransferase, U/L
i. Alanine aminotransferase, U/L
j. Bilirubin, µmol/L
k. Creatinine, µmol/L
i. Thyroid function indices
3. Imaging examinations:
a. Liver MRI/CT scans
b. Chest CT scans
c. Isotope bone scans
d. Liver ultrasound
e. Electrocardiography
2.5 Outcome measures
Primary Objectives:
(1) In phase Ib, determination of the incidence of dose-limiting toxicity (DLT) of the
treatment regimen.
(2) In phase II, the primary objective is the ORR (iRecist and mRecist)in the experimental
group.
Secondary Objectives:
Assessment of PFS, OS, disease control rate (DCR) (iRecist and mRecist), duration of
response (DoR), and safety in the experimental group. Additionally, to explore and evaluate
the relationship between biomarkers in tumor tissue and peripheral blood and the treatment
efficacy.
AEs will be systematically classified and documented in compliance with the National
Cancer Institute’s Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0)
2.6 Sample size
(1) All statistical tests will be two-sided, and P-values ≤0.05 will be considered statistically
significant. Continuous data will be described using mean, median, standard deviation,
maximum, minimum, and 25th and 75th percentiles; categorical or ordinal data will be
presented as frequency and percentage.
(2) Statistical analyses will be performed using SAS 8.2 statistical software.
(3) All statistical tests will be two-sided, and P-values ≤0.05 will be considered statistically

significant.
(4) Sample size determination:
Phase IB: Three predefined dose levels of dual immunotherapy will be explored (see dosing
regimen for details). To ensure the reliability of safety assessment and efficiently determine
the recommended phase II dose (RP2D), a “3+3” dose-escalation design will be adopted. At
least 3 evaluable patients for DLT will be enrolled at each dose level. The sample size for this
stage will be 9 patients.
Phase II: All patients will receive treatment at the RP2D determined in phase IB. According to
Simon ’ s two-stage design, and based on historical data from the HIMALAYA study in
hepatocellular carcinoma, the maximum response rate for ineffective treatment is assumed
to be 21%, and the minimum response rate for effective treatment is estimated to be 45%.
Using a two-sided test with α=0.05 and power (1-β)=0.8, the Minimax two-stage design is
selected. In the first stage, 11 patients will be enrolled; if ≤2 responses are observed, the
study will be terminated early. If the study proceeds to the second stage, an additional 13
patients will be enrolled, for a total sample size of 24. At the end of the study, if the total
number of responses is ≤8, the treatment regimen will be rejected.
2.7 Data management and monitoring plan
Data will be collected by trained evaluators using a validated case report form (CRF),
ensuring timeliness, completeness, and accuracy. Two independent investigators responsible
for data entry will input the raw data from the completed CRFs into Epidata (V3.1). An
independent monitoring committee, comprising multidisciplinary experts in oncology,
interventional radiology, pharmacology, and biostatistics, will oversee the integrity of the trial
data and ensure adherence to the protocol. The committee will have the prerogative to halt
the trial prematurely if necessary. Following study closure, all CRFs will undergo archival
storage for a minimum of five years, with the implementation of read-only access to prevent
post-hoc alterations.
2.8 Confidentiality
All research-related data will be stored in a highly secure environment at the study site.
The personal information of the participants will be safeguarded in encrypted digital
databases with restricted access. To maintain participant confidentiality, any identifiable data,
such as laboratory results, questionnaires, data analysis outcomes, and administrative
records, will be labeled solely with anonymous identification codes.
2.9 Patient and public involvement
No participants or the public will be involved in the development of the protocol or
design of the study. The results of the study will be presented at peer-reviewed journals and
international meetings.
3
Discussion
Most Chinese patients with HCC are diagnosed at an intermediate or advanced stage.
While there has been some progress in the use of systemic therapy combined with local
treatment for patients with unresectable intermediate or advanced HCC, significant

differences in short-term PFS rates have been observed, and, to date, positive results have
not translated into long-term OS benefits, indicating the limitations of this approach. The
exploration of more effective treatment strategies, especially combination therapies for
unresectable intermediate or advanced HCC, is of great clinical significance. Therefore, this
single-arm, multicenter, prospective phase 1b/II study is designed to evaluate the safety and
efficacy of selective internal radiation therapy (SIRT) with Yttrium-90 microspheres in
combination with nivolumab, ipilimumab, and lenvatinib in patients with unresectable HCC,
aiming to address the unmet needs of these patients.
The quadruple therapy strategy of Y90-SIRT combined with nivolumab, ipilimumab, and
lenvatinib integrates three evidence-based therapeutic approaches: (1) the synergistic
advantages of dual immunotherapy
using PD-1/CTLA-4
inhibitors, the synergy
of
immunotherapy and targeted therapy, and the advantages of immunotherapy combined
with Y90-SIRT; (2) the combination of guideline-recommended first-line treatment regimens;
(3) dose exploration and optimization of treatment strategies. The sequential design of the
trial, in which SIRT is given first, followed by administration of PD-1 and CTLA-4 inhibitors
combined with lenvatinib, not only leverages the cytoreductive effect on micrometastases
and increases immunogenicity, but also mitigates synergistic toxicities. To the best of our
knowledge, this is the first phase II clinical trial to investigate a quadruple modality (SIRT
sequential PD-1/CTLA-4 inhibitors and lenvatinib) for treating patients with unresectable
HCC.
One limitation of this study is that, due to the single-arm design, there may be biases in
patient selection and outcome assessment. However, this approach is necessary as the use of
Y90-SIRT in patients with unresectable HCC is rare, and it is not ethically possible to set up
an inactive control group. The pre-planned comparative analyses with propensity score
adjustment partially mitigate this limitation. In addition, this study is expected to yield
exciting results and lay the foundation for subsequent phase III clinical trials. Furthermore,
this clinical trial will be conducted at multiple clinical centers, enabling relatively easy
achievement of the predefined sample sizes, thereby enhancing the statistical reliability of
the study outcomes.
Abbreviations
AE Adverse Event
AUC Area Under Curve
CTLA-4 Cytotoxic T-Lymphocyte Antigen 4
CI Confidence Interval
CR complete response
DoR Duration of response
DCR Disease control rate
ECOG PS Eastern Cooperative Oncology Group – performance status
ORR Objective Response Rate
OS Overall survival
PD-L1/PD-1 Programmed death-1/ligand 1
PFS Progression-free survival
PR partial response

QoL quality of life
RECIST Response Evaluation Criteria in Solid Tumors
SD stable disease
SCC small cell carcinoma
SCLC small cell lung carcinoma
Acknowledgements
Not applicable.
Author contributions
Rui-Hong Daiand Chang Liu designed the study and wrote the original protocol. Rui-Hong
Dai and Fa-Cheng Lu drafted the manuscript. All the other authors directly contributed,
read, and approved the final manuscript.
Funding
The author(s) declare that financial support was received for the research and/or publication
of this article. This study was found by the Chengdu Medical Research Project in 2026
Data availability
The original contributions presented in the study are included in the article or
Supplementary Material. Further inquiries can be directed to the corresponding author
Ethics statement
The ethics committee on Biomedical Research of West China Hospital of Sichuan
University approved this study
All participants will sign written informed consent prior to
participation in any study activities.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or
financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily
represent those of their affiliated organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
References
[1]Bruno Sang Durvalumab with or without bevacizumab with transarterial
chemoembolisation in hepatocellular carcinoma(EMERALD-1): A multiregional randomised

double-blind placebo-controlled phase 3 study[J] The lancet Jan 2025
[2]Masatoshi Kudo Transarterial chemoembolisation combined with lenvatinib plus
pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular
carcinoma(LEAP-012):A multicentre, randomised, double-blind, phase 3 study
[3]Gaojun Teng, Transarterial chemoembolization(TACE) combined with camrelizumab and
rivoceranib versus TACE alone in the treatment of unresectable hepatocellular carcinoma: A
multicenter, open-lable, randomized, phase 2 study(CARES-005),2025 ASCO GI LBA522
[4] 中国医师协会介入医师分会临床诊疗指南专委会, 中国研究型医院学会肝胆胰外科专业
委员会. 钇-90 微球选择性内放射治疗肝脏恶性肿瘤规范化操作专家共识（2024 版）[J] . 中
华医学杂志, 2024, 104(7) : 486-498.
[5] 中国医师协会介入医师分会临床诊疗指南专委会, 中国研究型医院学会肝胆胰外科专业
委员会. 钇-90 微球选择性内放射治疗肝脏恶性肿瘤规范化操作专家共识（2024 版）[J] . 中
华医学杂志, 2024, 104(7) : 486-498.
[6] Lu W, Zhang T, Xia F, Huang X, Gao F. Transarterial radioembolization versus
chemoembolization for hepatocellular carcinoma: a meta-analysis. Front Oncol.
2025;14:1511210. Published 2025 Jan 17. doi:10.3389/fonc.2024.1511210
[7]Thomas Yau, Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line
treatment for unresectable hepatocellular carcinoma(CheckMate 9DW): an open-lable,
randomised, phase 3 trial
[8]Jia Fan 2025 ESMO poster 1495
[9]Formenti,S.C.,Rudqvist,N.P.,Golden,E.,Cooper,B.,Wennerberg,E.,Lhuillier,C.,Vanpouille-Box,
C.,Friedman,K.,FerrarideAndrade,L.,Wucherpfennig,K.W.,Heguy,A.,Imai,N.,Gnjatic,S.,Emerson,
R.O.,Zhou,X.K.,Zhang,T.,Chachoua,A.,&Demaria,S.(2018).Radiotherapyinducesresponsesoflun
gcancertoCTLA-4blockade.Naturemedicine,24(12),1845–1851.
[10]Grass,G.D.,Krishna,N.,&Kim,S.(2016).The immune mechanismsofabscopal effectin
radiation therapy.Currentproblemsincancer,40(1),10–24
[11]TwymanSaintVictor,C.,Rech,A.J.,Maity,A.,Rengan,R.,Pauken,K.E.,Stelekati,E.,Benci,J.L.,Xu,B.,
Dada,H.,Odorizzi,P.M.,Herati,R.S.,Mansfield,K.D.,Patsch,D.,Amaravadi,R.K.,Schuchter,L.M.,Ishw
aran,H.,Mick,R.,Pryma,D.A.,Xu,X.,Feldman,M.D.,Minn,A.J.(2015).Radiationanddualcheckpointb
lockadeactivatenon-redundantimmunemechanismsincancer.Nature,520(7547),373–377
[12]Craciun,L.,deWind,R.,Demetter,P.,Lucidi,V.,Bohlok,A.,Michiels,S.,Bouazza,F.,Vouche,M.,Tan
credi,I.,Verset,G.,Garaud,S.,Naveaux,C.,Galdon,M.G.,Gallo,K.W.,Hendlisz,A.,Derijckere,I.D.,Flam
en,P.,Larsimont,D.,&Donckier,V.(2020).Retrospectiveanalysisoftheimmunogeniceffectsofintra
arteriallocoregionaltherapiesinhepatocellularcarcinoma:arationaleforcombiningselectiveinter
nalradiationtherapy(SIRT)andimmunotherapy.BMCcancer,20(1),135
[13]DiFederico,A.,Rizzo,A.,Carloni,R.,DeGiglio,A.,Bruno,R.,Ricci,D.,&Brandi,G.(2022).Atezolizu
mab-bevacizumabplusY
90TAREforthetreatmentofhepatocellularcarcinoma:preclinicalrationaleandongoingclinicaltrial
s.Expertopiniononinvestigationaldrugs,
[14] Mejait A, Roux C, Soret M, et al. Enhanced therapeutic outcomes with
atezolizumab-bevacizumab and SIRT combination compared to SIRT alone in unresectable
HCC: A promising approach for improved survival. Clin Res Hepatol Gastroenterol.
2024;48(2):102282.
[15] Zhan C, Ruohoniemi D, Shanbhogue KP, et al. Safety of Combined Yttrium-90

Radioembolization and Immune Checkpoint Inhibitor Immunotherapy for Hepatocellular
Carcinoma. J Vasc Interv Radiol. 2020 Jan;31(1):25-34.
[16] Agrawal et al. Journal for ImmunoTherapy of Cancer (2016) 4:72
[17] Clin Cancer Res; 19(14); 3977–86.
[18] Kudo et al. HCC. Study 117. Phase 1b of lenvatinib + NIVO in unresectable HCC. ASCOGI
2020. Poster