ORIGINAL RESEARCH

A phase Ib randomized multicenter trial of isolated hepatic perfusion in
combination with ipilimumab and nivolumab for uveal melanoma
metastases (SCANDIUM II trial)5
R. Olofsson Bagge1,2,3y , A. Nelson4,5y , A. Shafazand1,3 , C. Cahlin6 , A. Carneiro7 , H. Helgadottir8, M. Levin4,5 , M. Rizell6 ,G. Ullenhag9 , S. Wirén10 , P. Lindnér6, J. A. Nilsson1,11 & L. Ny4,5
1

Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg; 2Department of Surgery, Sahlgrenska University
Hospital, Gothenburg; 3Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg; 4Department of Oncology, Institute ofClinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Gothenburg; 5Department of Oncology, Sahlgrenska University
Hospital, Gothenburg; 6Transplant Institute, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital,
Gothenburg; 7Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital Comprehensive Cancer Center, Lund; 8Department of Oncology,
Karolinska University Hospital, Stockholm; 9Department of Radiology, Immunology, Genetics, and Pathology, Uppsala University, Uppsala; 10Department of Radiation
Sciences, Umeå University Hospital, Umeå, Sweden; 11Harry Perkins Institute of Medical Research, University of Western Australia, Perth, Australia

Available online 2 July 2024

Background: Uveal melanoma (UM) is a rare malignancy where 50% of patients develop metastatic disease primarily
affecting the liver. Approximately 40% of patients with metastatic UM respond to one-time isolated hepatic perfusion(IHP) with high-dose melphalan. This phase I trial investigates the safety and clinical efﬁcacy of IHP combined with
ipilimumab (IPI) and nivolumab (NIVO).
Patients and methods: Immunotherapy-naïve patients were randomized in this phase I trial to receive either IHP
followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post-operative arm), or one cycle ofpreoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed bymaintenance therapy with NIVO 480 mg for 1 year.
Results: Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/18 patients (6 in the post-operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles
of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was
higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post-operativearm (4/7) and 22% in the pre-post-operative arm (2/9).
Conclusions: Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efﬁcacy of thiscombination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show
potential beneﬁts in terms of safety or efﬁcacy.
Key words: isolated hepatic perfusion, immune checkpoint inhibitor, PD-1, CTLA-4, liver metastases, uveal melanoma

INTRODUCTION
Uveal melanoma (UM) is a rare disease accounting for w3%of all melanomas. Despite effective treatment of the primary tumor, around 50% of patients develop metastases.1
The organ distribution of metastasis is strongly*Correspondence to: Prof. Roger Olofsson Bagge, Department of Surgery,
Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden. Tel: þ46 31 342
0000
E-mail: roger.olofsson.bagge@gu.se (R. Olofsson Bagge).
Twitter handle: @OlofssonBaggeyThese authors are Co-ﬁrst authors.
Note: This study was previously presented at ASCO 2023, Chicago, USA.
2059-7029/© 2024 The Author(s). Published by Elsevier Ltd on behalf ofEuropean Society for Medical Oncology. This is an open access article under the
CC BY license (http://creativecommons.org/licenses/by/4.0/).
5Volume 9 - Issue 7 - 2024

hepatotropic, with isolated liver metastases observed inover half of the patients with metastatic disease. In thissituation, patients have a poor prognosis. The median survival is 4-10 months, and very few patients survive >5years.1,2
Treatment with immune checkpoint inhibitors (ICIs) has
limited clinical efﬁcacy in patients with metastatic UM.
Ipilimumab (IPI) combined with nivolumab (NIVO) has
overall response rates (ORRs) ranging from 10% to 18% andan uncertain impact on overall survival (OS).3,4 The combination of pembrolizumab and epigenetic therapy with ahistone deacetylase inhibitor has resulted in durable
responses in a subset of patients.5 A randomized phase III
trial using tebentafusp, a bispeciﬁc fusion protein linking
melanoma cells with T cells, in human leukocyte antigen
https://doi.org/10.1016/j.esmoop.2024.103623

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R. Olofsson Bagge et al.

ESMO Open(HLA)-A*02:01 serotype patients with metastatic UM
demonstrated a signiﬁcant improvement in OS (22 versus
16 months).6 These trials show that durable responses toimmunotherapy are possible to obtain in some patients, but
a high unmet clinical need still exists.
Isolated hepatic perfusion (IHP) with melphalan is aregional treatment where the liver is completely isolated
from the systemic circulation, allowing for the delivery of ahigh concentration of a chemotherapeutic agent with minimal systemic exposure.7,8 In this treatment the effective
dose exposed to the liver parenchyma is w10 times higher
than the dosing used during myeloablative treatment withmelphalan in hematological malignancies. In a randomized
phase III trial (SCANDIUM), we recently reported a superior
ORR (40% versus 4%) and a 4-month beneﬁt in progressionfree survival (PFS; 7.4 versus 3.3 months) with IHP compared
to best alternative care in treatment-naïve patients withisolated liver metastases of UM.9
While apoptosis classically has been regarded as a silent
type of cell death, there is increasing evidence that certain
types of chemotherapeutic agents trigger a type of cell deathassociated with inﬂammatory signaling and activation of
immunity, i.e. an immunogenic cell death.10 For example,
anthracyclines cause an immunogenic type of apoptosis,
with hallmarks that include surface translocation of calreticulin, serving as an ‘eat me’ signal for phagocytes, and also
release of high-mobility group box 1 protein triggering an
inﬂammatory immune response, leading to the engulfmentof apoptotic bodies by dendritic cells (DCs) and the activation of cytotoxic CD8þ T cells.11 We have previously shownthat upon exposure to melphalan, melanoma cells increased
the expression of immune-related markers, including programmed death-ligand 1, major histocompatibility complex
class I and Hsp70. When peripheral blood mononuclear cells(PBMCs) were co-cultured with these melanoma cells preexposed to melphalan, this triggered an expansion of
CD33þCD14þCD16þ non-classical monocytes as well as
CD8þ T cells in the co-cultured PBMCs.12 The combinationof melphalan with adoptive cell therapy also signiﬁcantly
prolongs survival in mice with advanced B-cell lymphomas orcolorectal cancer, where melphalan enhances immune
response by increasing cytokine release, DC activation andthe potentiation of both endogenous CD8þ T cells andadoptively transferred tumor-speciﬁc CD4þ T cells.13
The hypothesis behind the present trial was that IHP,
beyond providing a direct antitumoral effect, may also
activate the immune system through these immunologicalmechanisms, and that this could be potentiated combining
the treatment with ICIs. This is further supported by earlyclinical data showing that after isolated limb perfusion (ILP)
for melanoma there is an increase in tumor-speciﬁc CD8þ T
cells in blood after 1 month.14 Another study showed thatmelanoma patients with certain immunological proﬁles,including higher expression of HLA-DR on CD8þ T cells aswell as a higher fraction of memory CD45ROþ CD8þ T cells,
were more likely to respond favorably to isolated limb
perfusion, indicating that T cells are important in the clinical2

https://doi.org/10.1016/j.esmoop.2024.103623

effect of this treatment.15 Furthermore, in patients with UMmetastases, higher levels of CD8þ T-cell tumor inﬁltration
correlate positively with survival after IHP.16 Recent evidence has also shown the beneﬁt of a neoadjuvant
approach with ICIs in patients with cutaneous melanoma.17
However, the impact of ICI timing in the setting of IHP is
unknown, which warrants a comparison of a post-operative
versus a pre-post-operative approach.
This phase I trial (SCANDIUM II) investigates the safety,
tolerability and timing of IHP combined with IPI and NIVO asa treatment for patients with liver-dominant metastases of
UM. In this pre-planned analysis, we report the primary
endpoints of safety and clinical efﬁcacy, including ORR andPFS.
PATIENTS AND METHODSPatients
Patients with histologically or cytologically conﬁrmed liver
metastases from UM were eligible if they had measurable
disease according to Response Evaluation Criteria in Solid
Tumors version 1.1 (RECIST 1.1) criteria18 and had liverdominant disease as assessed by the investigator. Prior
treatment with IHP or immunotherapy was not allowed but
previous chemotherapy and/or regional therapy other thanperfusion therapy was accepted. Patients were excluded if
the tumor volume occupied 50% or more of the liver asassessed by computed tomography (CT) or magnetic resonance imaging (MRI); if the patient had a history of significant autoimmune disease; if there was signiﬁcant heart,lung or renal dysfunction; or if the patient had a body massindex >35 kg/m2.
Study design and treatment
This was a prospective, multicenter, open-label, phase Ib
trial randomizing patients in a 1 : 1 ratio to receive either
IHP followed by combination immunotherapy with fourcycles of IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) every
3 weeks (post-operative arm) or one preoperative cycle of
IPI3/NIVO1 before IHP followed by three cycles of IPI3/
NIVO1 (pre-post-operative arm) (Figure 1A). Thereafter,
both arms received monotherapy with NIVO 480 mg every 4
weeks for up to 1 year.
IHP was carried out at Sahlgrenska University Hospital,
Gothenburg, Sweden. The procedure has previously been
described in detail.8 In summary, a shunt was inserted into
the iliac and jugular veins and connected to an external
centrifugal pump shunting blood from the lower extremity
after clamping the inferior vena cava. The vena cava wasisolated infrahepatically above the renal veins and suprahepatically between the liver and the diaphragm. A catheter
was placed in the retrohepatic portion of the vena cava for
perfusion outﬂow and the hepatic artery proper was cannulated for perfusion inﬂow. The portal vein was clamped,
and the catheters were connected to a perfusion system.
Perfusion was carried out with a target ﬂow rate ofVolume 9 - Issue 7 - 2024

R. Olofsson Bagge et al.

ESMO OpenA
Post-operativen = 18

IHP

IPI3/
NIVO1

IPI3/
NIVO1

IPI3/
NIVO1

IPI3/
NIVO1

NIVO

Follow-up

IPI3/
NIVO1

IHP

IPI3/
NIVO1

IPI3/
NIVO1

IPI3/
NIVO1

NIVO

Follow-up

6w

9w

12 w

R
Pre-postoperativeTime–6 to 0 w

0w

3w

18 mo 6 mo 9 mo 12 mo 15 mo 18 mo 21 mo 24 mo

B
Enrollment

Assessed for eligibility (n = 18)

Randomized (n = 18)

Post-operative treatment (n = 9)
Excluded after randomization• Inappropriate enrollment (n = 1)
• Withdrawal of consent (n = 1)

Safety analysis (n = 9)

Randomized

Treatment

Pre-operative treatment (n = 9)

Safety analysis (n = 9)

Follow-up
Efficacy analysis (n = 7)

Efficacy analysis (n = 9)

Figure 1. Study design and CONSORT diagram. (A) Treatment outline and (B) CONSORT diagram.
CONSORT, Consolidated Standards of Reporting Trials; IHP, isolated hepatic perfusion; IPI3/NIVO1, ipilimumab 3 mg/kg and nivolumab 1 mg/kg; NIVO, nivolumab 480
mg ﬁxed dose; mo, months; R, randomization; w, weeks. Created with BioRender.com.

500-1200 ml/min with a target liver temperature of 40 C.
When steady-state conditions in the perfusion circuit were
established, melphalan at a dose of 1 mg/kg body weight
was added to the perfusion system and was divided into
two doses given 30 min apart. Perfusion was continued for
60 min, then discontinued and the liver was irrigated(Ringer’s acetate, Baxter, Kista, Sweden). The shunts and theperfusion circuit were disconnected, and the catheters were
removed.
Study assessments
Clinical and radiological evaluation was carried out every 3months up to 2 years by either CT or MRI of the liver using
the same modality as at the baseline examination, withadditional CT imaging of the thorax. Laboratory values andvital signs were assessed regularly. After IHP, patients wereadmitted to a post-operative unit overnight and thentransferred to a surgical ward. Patients were followed according to routine clinical care procedures, with a length ofstay of w5-7 days if no complications evolved. Treatment
and follow-up with ICI was carried out according to local
clinical routine, with clinical examinations and laboratory
analysis the ﬁrst day in each treatment cycle as a minimum.
Safety was assessed by collecting data for adverse events(AEs), which were graded according to the National Cancer
Institute Common Terminology Criteria for Adverse Events(CTCAE) version 4.0.
Volume 9 - Issue 7 - 2024

Endpoints
The primary endpoint was to determine the incidence andseverity of AEs and serious adverse events (SAEs). The
secondary endpoints were ORR, clinical beneﬁt rate (CBR),
duration of response (DOR), PFS and OS (data immature atdata cut-off and are not presented in this report). AEs wereregistered from the ﬁrst treatment dose until 100 days after
the last treatment or 30 days after the last dose if theparticipant started a new anticancer therapy, whicheveroccurred ﬁrst. Response was graded according to RECIST
1.1.18 ORR was deﬁned as the percentage of patients with abest overall response of complete response (CR) or partial
response (PR). CBR was deﬁned as the percentage of patients with a best overall response of CR, PR or stable disease (SD). DOR was deﬁned as the time from response to
documented progression at any site, or death from any
cause. PFS was deﬁned as the time from randomization to
documented progression at any site, or death from any
cause according to RECIST 1.1 criteria. Efﬁcacy was evaluated in assessable patients in the overall population.

Statistical analysis
The primary aim of this trial was to determine safety of the
combination of IHP using melphalan and IPI3/NIVO1. The
safety of both these treatments on its own is well known,
but the safety of the combined treatment is completely
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R. Olofsson Bagge et al.

ESMO Open
unknown. The number of patients needed to establish thesafety of the treatment combination was discussed thoroughly with regulatory authorities, the Swedish Medical
Product Agency.
With the intent to balance the risk for potential unknown
AEs and potential beneﬁts in patients with a rare cancer
disease, a sample size of 9 patients in each arm (18 patientsin total) was judged reasonable. Randomization using variable block size was carried out using the MediCase eCRF
system. Time-to-event analysis was carried out using the
KaplaneMeier methodology and is reported using medians
together with 95% conﬁdence intervals (CIs). Fisher’s exact
test was used to compare ORR.
Study oversightThis was an investigator-initiated study with the support offree study drugs (IPI and NIVO) from BMS, CA184-587. The
original protocol and all amendments were approved by
the Swedish Medical Products Agency (EudraCT number
2020-003188-24) and the Swedish Ethical Review Authority(Dnr 2021-05391-02) and was registered at ClinicalTrials.
gov (NCT04463368). The study was conducted in accordance with the protocol, Good Clinical Practice guidelines
and the provisions of the Declaration of Helsinki. All patients provided written informed consent before inclusionin the trial. All AEs and SAEs were prospectively andperiodically monitored by an independent data monitoringboard with the authority to recommend termination of thestudy based on safety concern. No hard stopping criteria
were used.

Table 1. Baseline patient characteristics

Age, median (range),
years
Sex, n (%)
FemaleMale
ECOG PS, n (%)
01Previous treatment formetastatic disease, n (%)
No previous treatment
Chemotherapya
Surgical resection
Radiation therapy
Largest metastatic lesion,n (%)
3.0 cm
3.1-8.0 cm
8.1 cm
Mean tumor volume, %(range %)Metastatic sites, n (%)
Isolated liver
metastases
Liver and extrahepatic
metastases
Years since primary
diagnosis, median(range)Lactate dehydrogenase>ULN, n (%)

Post-operative(n [ 9)Pre-post-operative(n [ 9)62 (48-73)

65 (54-70)

1 (11)
8 (89)

5 (56)
4 (44)

9 (100)0 (0)8 (89)
1 (11)

9 (100)0005 (56)
3 (33)
1 (11)
1 (11)

6 (67)
3 (33)0 (0)
11 (1-45)

7 (78)0 (0)2 (22)
11 (5-40)

8 (89)

5 (56)

1 (11)

4 (44)

0.9 (0.2-6.8)

5 (56)

2.2 (0.1-10.9)

5 (56)

ECOG PS, Eastern Cooperative Oncology Group performance status; IQR, interquartile range; ULN, upper limit of normal.
aTemozolomide.

RESULTS
Patients and treatments
From May 2021 to August 2022, 18 patients were screened,and 18 patients were enrolled at six sites in Sweden(Figure 1B). The patients were randomly assigned to thepost-operative arm (nine patients) or the pre-post-operativearm (nine patients). The demographics and baseline diseasecharacteristics of the patients are described in Table 1. The
randomization resulted in the pre-post-operative arm having
more females, higher number of patients who had received
prior systemic therapy and presence of extrahepatic disease
than in the post-operative arm. The median duration offollow-up at the time of data cut-off for this analysis (30 June2023) was 19.1 months (range 11.0-25.6 months). After
treatment initiation, it was found that one patient in the
post-operative arm did not fulﬁll the criteria for measurable
disease according to RECIST 1.1. This patient was evaluatedfor safety but not for efﬁcacy. As seen below, in the ‘Safety’section, one patient in the post-operative arm withdrew
from the trial without receiving any treatment and before
radiological evaluation; this patient was not included in the
efﬁcacy evaluation. Consequently, 7/9 patients in the
post-operative arm and 9/9 patients in the pre-postoperative arm were included in the efﬁcacy analysis.

4

https://doi.org/10.1016/j.esmoop.2024.103623

Eight of nine patients (89%) in the post-operative armand 7/9 patients (78%) in the pre-post-operative arm
received IHP as per protocol. The median IHP operating time
was 5.5 h (range 4.5-10.3 h) in the post-operative arm and5.8 h (range 4.5-7.0 h) in the pre-post-operative arm. The
median inpatient stay time was 8 days (range 5-11 days) inthe post-operative arm and 9 days (range 7-14 days) in the
pre-post-operative arm. The median perioperative liver
temperature was 40.2 C (range 39.7-40.7 C), the medianperfusion ﬂow rate was 600 ml/min (range 50-1300 ml/min)and the median blood loss (including waste) was 775 ml(range 100-2100 ml). Values were similar across the twoarms (not shown). A peroperative assessment of liver tumor
involvement was conducted, showing that the median tumor volume was 5% of the liver volume (range 1%-45%) in
the pre-post-operative group and 5% (range 5%-40%) in the
post-operative group.
In the post-operative arm, patients received a median of
3 cycles (range 1-4 cycles) of IPI3/NIVO1; 3/9 patients (33%)
received all four cycles of IPI3/NIVO1. In the pre-postoperative arm, patients received a median of 3 cycles(range 1-4 cycles) of IPI3/NIVO1; all patients (9/9) received
one cycle of pre-post-operative IPI3/NIVO1 and 3/9 patients

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R. Olofsson Bagge et al.

ESMO Open(33%) completed all three cycles of post-operative IPI3/
NIVO1.

SafetyThe primary endpoint of the trial was safety for the combined treatment of IHP and IPI3/NIVO1. Among patients inthe post-operative arm, 8/9 patients (89%) had at least one
grade 3 or 4 AE that was deemed by the investigators to berelated to IHP (Table 2). The most frequent grade 1 or 2
events were fever and anemia that were related to IHP(Supplementary Table S1, available at https://doi.org/10.
1016/j.esmoop.2024.103623). One patient (11%) in the
post-operative arm did not receive IHP due toTable 2. Frequency of patients with grade 3-4 adverse events attributed by the treating physician to IHP or IPI and NIVO graded according to CTCAE 4.0 andclassiﬁed according to MedDRA
EventaPost-operative arm

Event attributed to preoperative IPI/NIVO
Immune system disorders
Encephalitis
General disorders and administration site conditions
Pyrexia
Event attributed to IHPBlood and lymphatic system disorders
AnemiaLeukopenia
Cardiac disorders
Syncope
General disorders and administration site conditions
Pyrexia
Hepatobiliary disorders
Hepatic infection bacterial
Injury, poisoning and procedural complications
Artery dissection
Intraoperative arterial injury
Procedural complicationb
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood bilirubin increased
C-reactive protein increased
Renal and urinary disorders
Acute kidney injury
Nephritis
Respiratory, thoracic and mediastinal disorders
Pleural effusion
Pneumonia
Pulmonary embolism
Vascular disorders
Arterial thrombosis
Hypertension
Event attributed to post-operative IPI/NIVO
Blood and lymphatic system disorders
Autoimmune hemolytic anemia
Thrombocytopenia
Endocrine disorders
Diabetes mellitus
Gastrointestinal disorders
ColitisImmune system disorders
Encephalitis
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood alkaline phosphatase increased
Blood bilirubin increased
Nutrition
Decreased appetite
Renal and urinary disorders
Nephritis
Respiratory, thoracic and mediastinal disorders
Pneumonitis

Grade 3

Grade 4

Grade 3

Grade 4

N/A

N/A

1/9

0

N/A
Grade 3

N/A
Grade 41/9
Grade 30Grade 4

1/9
0

0
0

2/7
1/7

0
0

1/9

0

0

0

0

0

1/7

0

1/9

0

0

0

1/9
0
3/9

0
1/9
0

0
0
3/7

0
0
0

5/9
5/9
0
1/9

1/9
1/9
0
0

3/7
2/7
1/7
2/7

0
1/7
0
0

0
0

0
0

1/7
1/7

0
0

0
0
0

0
0
0

1/7
1/7
1/7

0
0
0

1/9
0
Grade 300Grade 40
1/7
Grade 300Grade 4

0
1/8

1/8
0

0
0

0
0

0

0

0

1/8

1/8

0

0

0

1/8

0

0

0

1/8
1/8
0
1/8

0
0
0
0

2/8
2/8
1/8
0

0
0
0
0

1/8

0

0

0

0

0

1/8

0

0

0

1/8

0

Pre-post-operative arm

CTCAE, Common Terminology Criteria for Adverse Events; IHP, isolated hepatic perfusion; IPI, ipilimumab; MedDRA, Medical Dictionary for Regulatory Activities; NIVO, nivolumab.
a
The denominator is variable among the treatment arms due to differences in exposure to the interventions preoperative IPI/NIVO, IHP and post-operative IPI/NIVO.
b
Includes MedDRA terms arterial injury, procedural complication, procedural pain and wound dehiscence.

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R. Olofsson Bagge et al.

ESMO Open
intraoperative damage to the hepatic artery. This AE
resolved without sequelae within 4 weeks, but the patientchose to withdraw from the trial and received treatment
outside of this trial. Among the seven patients in the prepost-operative arm who underwent IHP, ﬁve patients(71%) had at least one grade 3 or 4 AE that was deemed by
the investigators to be related to IHP. One patient did notreceive IHP due to a perioperative observation that >50%of the liver was occupied with metastases and one patient
did not receive IHP due to grade 3 encephalitis following
one cycle of pre-post-operative IPI3/NIVO1. This latter patient received IHP outside of the trial 5 months later.
Eight patients in the post-operative arm received at least
one cycle of post-operative IPI3/NIVO1; three of these patients (38%) had at least one grade 3 or 4 AE that wasdeemed by the investigators to be related to IPI3/NIVO1(Table 2). Five patients (63%) discontinued IPI3/NIVO1 due
to immune-related AEs (irAEs). Among the nine patients inthe pre-post-operative arm who received one cycle ofpreoperative IPI3/NIVO1, two patients (22%) had at least
one grade 3 or 4 AE that was deemed by the investigators
to be related to IPI3/NIVO1. Of the eight patients in the prepost-operative arm who received at least one cycle of postoperative IPI3/NIVO1, six (75%) had at least one grade 3 or
4 AE that was deemed by the investigators to be related to
IPI3/NIVO1. In the pre-post-operative arm, 4/9 patients(45%) discontinued IPI3/NIVO1 due to irAEs.
Among patients who had at least one cycle of IPI3/
NIVO1, 3/8 patients (38%) in the post-operative arm had an
irAE of grade 3 or higher compared to 8/9 patients (89%) in
the pre-post-operative arm, and the incidence of irAEs wasnumerically higher in the pre-post-operative approach(Supplementary Table S2, available at https://doi.org/10.
1016/j.esmoop.2024.103623). A total of 20 SAEs, 10 ineach arm, were reported in 11 patients (5/9 patients in the
post-operative arm and 6/9 patients in the pre-postoperative arm; Supplementary Table S3, available athttps://doi.org/10.1016/j.esmoop.2024.103623).
There
were no treatment-related deaths in either arm.
Response
Among the seven assessable patients in the post-operativearm, four patients (57%) had an objective response,
including two patients (29%) with a CR (Table 3). Among thenine patients in the pre-post-operative arm, two patients(22%) had an objective response, including one patient

Table 3. Best overall response as assessed by RECIST 1.1

Complete response
Partial response
Stable disease
Progressive disease
Overall response rate

Post-operativearma n (%)

Pre-post-operative
arm n (%)

Total n (%)

2 (22)
2 (22)
3 (33)0 (0)4/7 (57)

1 (11)
1 (11)
4 (44)
3 (33)
2/9 (22)

3 (17)
3 (22)
7 (39)
3 (17)
6/16 (38)aTwo of the nine included patients in the post-operative arm were not assessable for
efﬁcacy.

6

https://doi.org/10.1016/j.esmoop.2024.103623(11%) with a CR. The difference in ORR was not statisticallysigniﬁcant (P ¼ 0.3, Fisher’s exact test). CBR, deﬁned as
patients who had a best response of CR, PR or SD, was 7/7
patients (100%) in the post-operative arm and 6/9 patients(67%) in the pre-post-operative arm. Temporal change inthe target lesion diameter from baseline is shown in
Figure 2A and a swimmer plot of treatment and response
timelines is shown in Figure 2B.
At the time of data cut-off, response was maintained in 4/
6 patients with a response (Supplementary Table S4,availableathttps://doi.org/10.1016/j.esmoop.2024.
103623), with a median duration of response of 8.5
months (95% CI 8.5-20.6 months). Of note, one patient in
the pre-post-operative arm was classiﬁed as having PD according to RECIST 1.1 criteria due to a new lesion at ﬁrst
radiological evaluation, which subsequently disappeared.
According to immune-related RECIST, this patient wasclassiﬁed as having PR, lasting for 18 months before progression of disease.
Progression-free survival
For the overall population (n ¼ 16), the median PFS was 6.0
months (95% CI 0-12.4 months), but was longer when patients who did not receive IHP were excluded (median PFS
11.8 months, 95% CI 0-27.8 months, n ¼ 14). PFS wasnumerically longer in the post-operative arm (11.8 months,
95% CI 8.0-15.6 months, n ¼ 7) than in the pre-postoperative arm (6.0 months, 95% CI 5.5-6.5 months,
n ¼ 9) (Figure 2C). In the post-operative arm, there was one
patient with extrahepatic disease at baseline who had
simultaneous hepatic and extrahepatic progression. In the
pre-post-operative arm, there were four patients with hepatic and extrahepatic disease at baseline, three of whom
had progression at data cut-off, one due to hepatic progression, one due to extrahepatic progression and one due
to simultaneous hepatic and extrahepatic progression.
DISCUSSION
In this phase Ib trial in patients with liver metastases of UM,
a one-time treatment with IHP with melphalan combinedwith four cycles of IPI3/NIVO1 post-operatively resulted in
an ORR of 57%. The study also compared this post-operative
approach with a pre-post-operative approach, where patients received one cycle of IPI3/NIVO1 before IHP and thenthree additional cycles of IPI3/NIVO1. The hypothesis wasthat the pre-post-operative approach could increase efﬁcacy at the risk of a higher toxicity rate. The results
conﬁrmed that the post-operative approach was associatedwith a lower rate of toxicity, but interestingly also anumerically higher ORR (57% versus 22%) and longer PFS(11.8 versus 6.0 months) than the pre-post-operative
approach. However, these effects were associated withhigh rates of AEs for this combination treatment, higher
than what historically has been described for the individual
treatments.
In the pre-post-operative arm, 2/9 (22%) patients did
not receive IHP as planneddone patient due toVolume 9 - Issue 7 - 2024

R. Olofsson Bagge et al.

ESMO OpenA

Treatment timelineB

Pre-post-operative

1
2

*

3
4
5

80%
60%

Post-operative

6

Pre-post-operative

7

not
* Did
receive IHP

40%
20%

*

0%
−20%

8
9

10
11
ICI
12

−40%

Off treatment
13

−60%

IHP

14

First PR

15−80%First CR

16

−100%

PD

17
0

3

6

9

12

15

18

21

24

Post-operative

100%

Patient number

Change in target lesion from baseline (%)

120%

Death

18

Time (months)

0

6

12

18

24

Time since start of treatment (months)

Progression-free survival probability

C
1.0
0.9
0.8

Post-operative

0.7
0.6
0.5
0.4

+
Pre-post-operative

0.3

+

+

0.2

+

0.1
0.0
0

3

6

9

No. at risk

Post-operative
Pre-post-operative

12

15

18

21

24

Months
7

7

5

5

2

1

0

0

0

9

6

3

3

2

2

2

2

1

Figure 2. Response, treatment and patient outcomes. (A) Change in target lesion size from baseline. (B) Treatment and response timeline. (C) Progression-freesurvival. Tick marks indicate censored data.
CR, complete response; ICI, immune checkpoint inhibitor; IHP, isolated hepatic perfusion; PD, progressive disease; PR, partial response.

encephalitis following preoperative administration of IPI3/
NIVO1 and the other patient due to a perioperative ﬁndingof extensive liver metastasis, possibly due to the delay of
preoperative treatment before IHP. This frequency ofdropout is higher than in the SCANDIUM trial of IHP,19
where 41/43 (95%) treatment-naïve patients received IHP
as planned. In the post-operative arm, one patient did notcomplete the IHP procedure due to intraoperative damage
to the hepatic artery. In a similar study, the CHOPIN trial
investigating the combination of IPI1/NIVO3 and percutaneous hepatic perfusion (PHP), all patients received atleast one cycle of PHP which thus seems like a potentially
Volume 9 - Issue 7 - 2024

more tolerable combination.20 In this study, treatment
discontinuation due to toxicity of IPI3/NIVO1 was 63% in
the post-operative arm and 45% in the pre-post-operativearm, which is higher than in previous studies of patientswith metastatic UM treated with IPI3/NIVO1 alone (23%26%).3,4 Taken together, treatment with IHP and postoperative IPI3/NIVO1 was judged to have signiﬁcant
toxicity and treatment discontinuation, particularly in the
pre-post-operative arm. However, it is worth noting that
we observed durable responses in patients who received
only one cycle of IPI3/NIVO1, which is in general agreement with previous studies on number of treatment cycles
https://doi.org/10.1016/j.esmoop.2024.103623

7

R. Olofsson Bagge et al.

ESMO Openwith IPI and NIVO, where the initial two cycles seem tohave a major role for outcome.21-23
The incidence of treatment-related AEs attributed to IHP
was similar in the post-operative and the pre-post-operativearms, but higher than previously reported for IHP alone,both in terms of grade >3 treatment-related AEs andSAEs.9,24 The proportion of grade 3 hepatitis in the postoperative arm was 67% compared to 33% in the pre-postoperative arm. The reason for this difference is not clear
as we had anticipated a higher risk for immune activationand hepatitis in the pre-post-operative arm. There were
three patients with grade 3 artery complications, and one
patient with liver artery thrombosis detected 2 days after
IHP in the post-operative arm. The patient was treated withlow-molecular-weight heparin therapy but ultimately
developed secondary biloma. Two patients had peroperative damage to the hepatic artery that was surgicallyresolved during the intervention; however, one of thesepatients could not receive IHP due to the complication. Thisfrequency of 3/15 patients with vascular complications after
IHP is higher than previously reported,9 without any
obvious reasons. The incidence of grade 3 irAEs was 3/9(33%) in the post-operative arm which is within the samerange as previously reported for IPI/NIVO in the absence of
IHP.3,4 Among patients in the pre-post-operative arm, 8/9
patients (89%) had a grade 3 or higher irAE, which wassubstantially higher than expected. The distribution of irAEs
in relation to type and system organ class was diverse inboth groups and without apparent differences between
groups. However, we observed several rare and serious
grade 3 or higher irAEs including two patients with encephalitis, one autoimmune hemolytic anemia, one pneumonitis, one colitis, one nephritis and three hepatitis cases.
The irAEs were treated according to consensus guidelines
for ICI toxicity. Although there were no treatment-related
deaths, it is clear that irAEs are a clinical concern, particularly in the pre-post-operative approach. Nevertheless,given that only 18 patients were included in the trial, strong
conclusions cannot be drawn concerning the distribution of
toxicities and complications between the two study arms.
The tolerability and toxicity concerns observed in this study
suggest that modiﬁcation to the treatment protocol tomitigate treatment discontinuation and toxicity is recommended, such as PHP with post-operative IPI1/NIVO3.
Of note, the recent approval of tebentafusp for thetreatment of patients with metastatic UM and the HLAA*02:01 haplotype is a major advance.6 No patients in thepresent trial received tebentafusp since it was not available
in Sweden during the inclusion phase. In the tebentafusp
trial, the objective response rate was 9%, while several
phase II trials of IPI and NIVO have reported ORRs ranging
between 10% and 18%.3,4,25 In the SCANDIUM trial19 where
treatment-naïve patients received IHP, the response rate
was 40%, and in the FOCUS trial where patients received
PHP, the response rate was 35%.26 In this trial, ORR was
considerably higher, reaching 57% for patients who received
post-operative IPI3/NIVO1 and IHP. Furthermore, the8

https://doi.org/10.1016/j.esmoop.2024.103623

median PFS was 11.8 months among assessable patients inthe current trial, compared to 3.3 months for tebentafusp,6
7.4 months for IHP19 and 9.0 months for PHP.26
It is important to acknowledge the limitations inherent inthis trial. Firstly, the relatively small sample size contributes
to uncertainty in the outcomes, as reﬂected in the broad CIs
observed. Additionally, the randomization process resulted
in disparities between the groups in terms of prior treatments, M-stage and the presence of extrahepatic disease.
These disparities are to suggest that the post-operative
group may have exhibited a more favorable prognosis.
In summary, the combination of IHP and post-operative
IPI3/NIVO1 in patients with liver-dominant metastases of
UM was associated with a high rate of grade 3-4 AEs but
without fatal events and with encouraging efﬁcacy. A phase II
trial comparing PHP with post-operative IPI1/NIVO3 comparedwith IPI3/NIVO1 is planned (the SCANDIUM III trial).
ACKNOWLEDGEMENTS
We are grateful for the editing support provided by Nesrin
Vurgun, PhD, at the Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg. Our sincere
gratitude to the patients and their families participating inthis trial, as well as the research nurses, oncologists, surgeons and radiologists, among others, who have contributed in so many different ways to make this study possible.
FUNDING
This was an investigator-initiated study with the support offree study drugs (ipilimumab and nivolumab) from BristolMyers Squibb. This study was supported by grants from theAmerican Association for Cancer Research [grant number 2120-39-OLOF], Assar Gabrielsson Foundation [grant number
BGR20-02], Gothenburg Medical Society, Stiftelsen Handlanden Hjalmar Svenssons forskningsfond [grant number
HERMSV2023001], Knut and Alice Wallenberg Foundation,
Sjöberg Foundation [grant number 20210111:1], Sahlgrenska
University Hospital [grant numbers ALFGBG-965024, NHV977897], Swedish Cancer Society [grant number 22 2355 Pj]
and Swedish Research Council [grant number 2020-02446],
and donations made in memoriam of Karin Lindholm.
DISCLOSURE
ROB has received institutional research grants from BristolMyers Squibb (BMS) and SkyLineDx; speaker honoraria from
Roche and Pﬁzer; has served on advisory boards for Amgen,
BD/BARD, Bristol-Myers Squibb (BMS), Merck Sharp &DohmeMerck Sharp & Dohme (MSD), Novartis, Roche andSanoﬁ Genzyme; and is a shareholder in SATMEG Ventures
AB. LN has received institutional research grants from
Merck and Syndax Pharmaceuticals; speaker honoraria from
BMS, Johnson&Johnson, Leo Pharma, MSD, Novartis, Pﬁzer
and Roche; has served on advisory boards for BMS, MSD,
Novartis, Pierre Fabre, Sanoﬁ Genzyme and Zealth; and is ashareholder in SATMEG Ventures AB. HH has received
speaker honoraria from BMS, MSD and Pierre Fabre and has
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R. Olofsson Bagge et al.

served on advisory boards for MSD and Novartis. ML has
received lecturing fees from Bristol Myers Squibb, MSD,
Roche and Novartis. JAN is a shareholder in SATMEG Ventures AB. GU has during the past 2 years received honoraria
for teaching activities by BMS, MSD, Pierre Fabre andNovartis and for consulting/advising by Incyte, BMS,
Novartis, MSD, Alligator Bioscience, LIDDS and SeqCure
Immunology AB and is a stock owner in ESSITY and Oncopeptides. PL has served on advisory boards for Pierre Fabre.
All other authors have declared no conﬂicts of interest.
DATA SHARINGThe data generated in this study are available upon requestfrom the corresponding author.
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