Isolated Hepatic Perfusion With Melphalan for Patients With Isolated Uveal Melanoma Liver Metastases: A Multicenter, Randomized, Open-Label, Phase III Trial (the SCANDIUM Trial)

Roger Olofsson Bagge, Axel Nelson, Amir Shafazand, Charlotta All-Eriksson, Christian Cahlin, Nils Elander, Hildur Helgadottir, Jens Folke Kiilgaard, Sara Kinhult, Ingrid Ljuslinder, Jan Mattsson, Magnus Rizell, Malin Sternby Eilard, Gustav J Ullenhag, Jonas A Nilsson, Lars Ny, Per Lindnér, Roger Olofsson Bagge, Axel Nelson, Amir Shafazand, Charlotta All-Eriksson, Christian Cahlin, Nils Elander, Hildur Helgadottir, Jens Folke Kiilgaard, Sara Kinhult, Ingrid Ljuslinder, Jan Mattsson, Magnus Rizell, Malin Sternby Eilard, Gustav J Ullenhag, Jonas A Nilsson, Lars Ny, Per Lindnér

Abstract

Purpose: About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking.

Methods: In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety.

Results: Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively (P < .0001). The median PFS was 7.4 months versus 3.3 months (P < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months (P < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group.

Conclusion: IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.

Trial registration: ClinicalTrials.gov NCT01785316.

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Lars Ny

Stock and Other Ownership Interests: SATMEG Ventures

Consulting or Advisory Role: Novartis, Pierre Fabre, Sanofi, MSD, Bristol Myers Squibb, Zealth, GlaxoSmithKline

Speakers' Bureau: Pfizer, Novartis, LEO Pharma, Bristol Myers Squibb/Celgene, MSD, GlaxoSmithKline

Research Funding: MSD (Inst), Syndax (Inst)

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
CONSORT diagram. aThree patients were inappropriately enrolled in the IHP arm, two patients because of > 50% of the liver being occupied with metastasis and one patient because of the presence of systemic metastases. bOne patient was inappropriately enrolled in the control arm because liver metastases were not verified by biopsy. cTwo patients did not receive IHP since their tumor burden was estimated to be >50% after laparotomy and perioperative evaluation, so these two patients then crossed over to the control group. IHP, isolated hepatic perfusion.
FIG 2.
FIG 2.
Waterfall plots for the isolated hepatic perfusion and control group. Shown are the best percentage changes from baseline in the sum of the largest diameters of measurable tumors in patients for whom data from both baseline and postbaseline assessments of target lesions by independent central review were available: (A) 38 of 43 patients who received IHP and (B) 39 of 44 of patients who received control treatment. The upper dashed horizontal line indicates a 20% increase in tumor size in the patients who had disease progression, and the lower dashed line indicates a 30% decrease in tumor size (PR). IHP, isolated hepatic perfusion; PR, partial response.
FIG 3.
FIG 3.
Kaplan-Meier estimates of PFS and hPFS comparing isolated hepatic perfusion and control. Kaplan-Meier estimates of (A) PFS and (B) hPFS as assessed by blinded central review in the ITT population. The tick marks indicate censored data. hPFS, hepatic progression-free survival; IHP, isolated hepatic perfusion; ITT, intention-to-treat; PFS, progression-free survival.

References

    1. Diener-West M, Earle JD, Fine SL, et al. : The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: Initial mortality findings. COMS report No. 18. Arch Ophthalmol 119:969-982, 2001
    1. Rantala ES, Kivela TT, Hernberg MM: Impact of staging on survival outcomes: A nationwide real-world cohort study of metastatic uveal melanoma. Melanoma Res 31:224-231, 2021
    1. Nathan P, Hassel JC, Rutkowski P, et al. : Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med 385:1196-1206, 2021
    1. Mariani P, Piperno-Neumann S, Servois V, et al. : Surgical management of liver metastases from uveal melanoma: 16 years' experience at the Institut Curie. Eur J Surg Oncol (Ejso) 35:1192-1197, 2009
    1. Huppert PE, Fierlbeck G, Pereira P, et al. : Transarterial chemoembolization of liver metastases in patients with uveal melanoma. Eur J Radiol 74:e38-e44, 2010
    1. Ny L, Jespersen H, Karlsson J, et al. : The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma. Nat Commun 12:5155, 2021
    1. Klingenstein A, Haug AR, Zech CJ, et al. : Radioembolization as locoregional therapy of hepatic metastases in uveal melanoma patients. Cardiovasc Intervent Radiol 36:158-165, 2013
    1. Ausman RK, Aust JB: Isolated perfusion of the liver with HN2. Surg Forum 10:77-79, 1960
    1. Bartlett DL, Libutti SK, Figg WD, et al. : Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer. Surgery 129:176-187, 2001
    1. Grover A, Alexander HR, Jr: The past decade of experience with isolated hepatic perfusion. The Oncologist 9:653-664, 2004
    1. Feldman ED, Wu PC, Beresneva T, et al. : Treatment of patients with unresectable primary hepatic malignancies using hyperthermic isolated hepatic perfusion. J Gastrointest Surg 8:200-207, 2004
    1. Olofsson R, Cahlin C, All-Ericsson C, et al. : Isolated hepatic perfusion for ocular melanoma metastasis: Registry data suggests a survival benefit. Ann Surg Oncol 21:466-472, 2013
    1. Ben-Shabat I, Hansson C, Sternby Eilard M, et al. : Isolated hepatic perfusion as a treatment for liver metastases of uveal melanoma. J Vis Exp 95:52490, 2015
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al. : New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009
    1. Khoja L, Atenafu EG, Suciu S, et al. : Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: An international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol 30:1370-1380, 2019
    1. Pelster MS, Gruschkus SK, Bassett R, et al. : Nivolumab and ipilimumab in metastatic uveal melanoma: Results from a single-arm phase II study. J Clin Oncol 39:599-607, 2021
    1. Piulats JM, Espinosa E, de la Cruz Merino L, et al. : Nivolumab plus ipilimumab for treatment-naive metastatic uveal melanoma: An open-label, multicenter, phase II trial by the Spanish multidisciplinary melanoma group (GEM-1402). J Clin Oncol 39:586-598, 2021
    1. Heppt MV, Amaral T, Kahler KC, et al. : Combined immune checkpoint blockade for metastatic uveal melanoma: A retrospective, multi-center study. J ImmunoTherapy Cancer 7:299, 2019
    1. Alexander HR, Libutti SK, Bartlett DL, et al. : A phase I-II study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver. Clin Cancer Res 6:3062-3070, 2000
    1. Alexander HR, Jr., Libutti SK, Pingpank JF, et al. : Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver. Clin Cancer Res 9:6343-6349, 2003
    1. van Iersel LBJ, Hoekman EJ, Gelderblom H, et al. : Isolated hepatic perfusion with 200 mg melphalan for advanced noncolorectal liver metastases. Ann Surg Oncol 15:1891-1898, 2008
    1. Rizell M, Mattson J, Cahlin C, et al. : Isolated hepatic perfusion for liver metastases of malignant melanoma. Melanoma Res 18:120-126, 2008
    1. Noter SL, Rothbarth J, Pijl MEJ, et al. : Isolated hepatic perfusion with high-dose melphalan for the treatment of uveal melanoma metastases confined to the liver. Melanoma Res 14:67-72, 2004
    1. Ku Y, Saitoh M, Nishiyama H, et al. : Extracorporeal adriamycin-removal following hepatic artery infusion: Use of direct hemoperfusion combined with veno-venous bypass. Nihon Geka Gakkai Zasshi 90:1758-1764, 1989
    1. Curley SA, Newman RA, Dougherty TB, et al. : Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: a phase I study. Ann Surg Oncol 1:389-399, 1994
    1. Beheshti MV, Denny DF, Jr., Glickman MG, et al. : Percutaneous isolated liver perfusion for treatment of hepatic malignancy: Preliminary report. J Vasc Interv Radiol 3:453-458, 1992
    1. Pingpank JF, Hughes MS, Alexander HR, et al. : A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma. J Clin Oncol 28:LBA8512, 2010
    1. Hughes MS, Zager J, Faries M, et al. : Results of a randomized controlled multicenter phase III trial of percutaneous hepatic perfusion compared with best available care for patients with melanoma liver metastases. Ann Surg Oncol 23:1309-1319, 2016
    1. Zager JS, Orloff MM, Ferrucci PF, et al. : FOCUS phase 3 trial results: Percutaneous hepatic perfusion (PHP) with melphalan for patients with ocular melanoma liver metastases (PHP-OCM-301/301A). J Clin Oncol 40:9510, 2022
    1. Bethlehem MS, Katsarelias D, Olofsson Bagge R: Meta-analysis of isolated hepatic perfusion and percutaneous hepatic perfusion as a treatment for uveal melanoma liver metastases. Cancers (Basel) 13:4726, 2021
    1. Johansson J, Siarov J, Kiffin R, et al. : Presence of tumor-infiltrating CD8(+) T cells and macrophages correlates to longer overall survival in patients undergoing isolated hepatic perfusion for uveal melanoma liver metastasis. Oncoimmunology 9:1854519, 2020

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe