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Randomized Controlled Trial
. 2025 Jul;32(7):4976-4988.
doi: 10.1245/s10434-025-17231-x. Epub 2025 Apr 7.

An Open-label, Randomized Study of Melphalan/Hepatic Delivery System Versus Best Alternative Care in Patients with Unresectable Metastatic Uveal Melanoma

Jonathan S Zager  1   2 , Marlana Orloff  3 , Pier Francesco Ferrucci  4 , Junsung Choi  5   6 , David J Eschelman  3 , Evan S Glazer  7 , Aslam Ejaz  8 , J Harrison Howard  9 , Erika Richtig  10 , Sebastian Ochsenreither  11 , Sunil A Reddy  12 , Michael C Lowe  13 , Georgia M Beasley  14 , Anja Gesierich  15 , Armin Bender  16 , Martin Gschnell  16 , Reinhard Dummer  17 , Michel Rivoire  18 , Ana Arance  19 , Stephen William Fenwick  20 , Joseph J Sacco  21 , Sebastian Haferkamp  22 , Carsten Weishaupt  23 , Johnny John  24 , Matthew Wheater  25 , Christian H Ottensmeier  20
Affiliations
Randomized Controlled Trial

An Open-label, Randomized Study of Melphalan/Hepatic Delivery System Versus Best Alternative Care in Patients with Unresectable Metastatic Uveal Melanoma

Jonathan S Zager et al. Ann Surg Oncol. 2025 Jul.

Abstract

Background: Metastatic uveal melanoma (mUM) has a poor prognosis, with liver metastases typically presenting a therapeutic challenge. Melphalan/Hepatic Delivery System (Melphalan/HDS) is a drug/medical device combination used for liver-directed treatment of unresectable mUM patients. This study assessed efficacy and safety of Melphalan/HDS versus best alternative care (BAC).

Methods: Eligible patients with unresectable mUM were randomized (1:1) to receive Melphalan/HDS (3 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of 6 cycles or BAC. Due to slow enrollment and patient reluctance to receive BAC treatment, the study design was amended to a single-arm Melphalan/HDS study, and all efficacy analyses of the randomized study were treated as exploratory.

Results: The study enrolled 85 patients. Eligible patients were randomized to receive Melphalan/HDS (n = 43) or BAC (n = 42), and 72 patients received study treatment (Melphalan/HDS [n = 40]; BAC [n = 32]). Exploratory analyses of efficacy endpoints showed numerical differences consistently favoring the Melphalan/HDS arm versus BAC (median overall survival: 18.5 vs. 14.5 months; median progression-free survival: 9.1 vs. 3.3 months; objective response rate: 27.5% vs. 9.4%; and disease control rate: 80.0% vs. 46.9%). Serious adverse events (SAEs) occurred in 51.2% of Melphalan/HDS and in 21.9% of BAC patients. The most common (>5%) SAEs included thrombocytopenia (19.5%), neutropenia (9.8%), leukopenia (9.8%) and febrile neutropenia (7.3%) in Melphalan/HDS patients and cholecystitis, nausea and vomiting (6.3% each) in BAC patients. No treatment-related deaths were observed.

Conclusion: Treatment with Melphalan/HDS shows clinically meaningful efficacy and demonstrates a favorable benefit-risk profile in patients with unresectable mUM as compared to BAC.

Keywords: Liver-directed therapy; Melphalan/Hepatic Delivery System; Metastatic uveal melanoma; Ocular melanoma; Percutaneous hepatic perfusion.

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Conflict of interest statement

Disclosure: JZ–global principal investigator in the FOCUS phase 3 study and serves on Delcath Systems Medical Advisory Board. Education and Training grant through Delcath. Has consulting agreements and/or participated on advisory board panels with Merit Medical, Replumune, Merck, Philogen, Castle Biosciences and Menarini Silicon Biosystems. MO–Advisory Board: Delcath, Replimune. Consultant: Immunocore. Steering Committee: Ideaya. Speaker: Immunocore. DE–Consulting fees from Delcath. EG–Institutional funding for conducting the Phase 3 FOCUS study. JH–Consultant: Delcath. ER–Medical University of Graz received payments for conducting the Phase 3 FOCUS study. SO–Advice: Immunocore, Delcath, Janssen. Speakers’ bureau: Immunocore. Honoraria for presentations: MSD, AstraZeneca, Merck; Travel funding: Merck, Pfizer, Ipsen. GB–Clinical trial funding paid to institution from Replimune, Checkmate pharmaceuticals, Philogen, Delcath. Advisory board: BMS. AG–University Hospital Würzburg received institutional payments for conducting the Phase 3 FOCUS study. RD–Consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME. AA–Consulting or advisory role: Pierre Fabre, Novartis, Roche, BMS, MSD, Biontech. Speakers’ Bureau: Pierre Fabre, Novartis, Roche, BMS, MSD. Travel, Accommodations, Expenses: BMS, MSD. SF–Liverpool University Hospitals NHS Trust received institutional support for conducting this Phase 3 FOCUS study from the trial sponsor. JS–Advisory boards: Delcath, Replimune and Immunocore. Grant funding: Astra Zeneca and BMS (paid to institution). Travel and conference attendance: MSD, BMS and Replimune. SH - Speakers Honoraria: BMS, MSD, Pierre Fabre, Sanofi, Immunocore. MW–Institutional (University Hospital Southampton) funding for conducting a commercial trial. Personal funding for participation in advisory board for Delcath. JJ–Employee of Delcath.

Figures

Fig. 1
Fig. 1
CONSORT diagram. Abbreviations: BAC, best alternative care; HDS, Hepatic Delivery System
Fig. 2
Fig. 2
Kaplan–Meier plot of overall survival in patients treated with Melphalan/Hepatic Delivery System or BAC. Abbreviations: BAC, best alternative care; HDS, Hepatic Delivery System
Fig. 3
Fig. 3
Kaplan–Meier plot of progression-free survival in patients treated with Melphalan/Hepatic Delivery System or BAC - Assessed by the investigator. Abbreviations: BAC, best alternative care; HDS, Hepatic Delivery System
See this image and copyright information in PMC

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