Melphalan/Hepatic Delivery System Displays Efficacy in Uveal Melanoma

Treatment with melphalan delivered via a hepatic delivery system (HDS) demonstrated a favorable benefit-risk profile among adult patients with metastatic uveal melanoma, according to findings from the phase 3 FOCUS study (NCT02678572) published in the Journal of Cancer Research and Clinical Oncology.¹

Among 33 patients treated with melphalan, the objective response rate (ORR) was 57.6% (n = 19), with 33.3% of responses occurring between cycles 4 and 6 of treatment. Notably, patients with a baseline hepatic tumor burden below the median had an ORR of 51.1% vs 22.2% among patients with a hepatic tumor burden above the median (P = .008). Additionally, subgroup analyses for ORR did not reveal significant differences in responses based on relevant characteristics such as age, sex, region, extent of liver involvement, or prior number of therapies.

Moreover, a significant difference in median progression-free survival (PFS) was observed among patients with a hepatic tumor burden below the median vs above, at 11.3 months vs 5.8 months, respectively (P = .007). Nonsignificant numerical differences in PFS were also observed among patients enrolled in Europe vs the US (P = .110), those with no extrahepatic tumors at baseline vs those with extrahepatic involvement (P = .164), and those with low or normal vs elevated lactate dehydrogenase (LDH) values at baseline (P = .153).

Furthermore, a significant difference in overall survival (OS) was observed in the below median vs above median hepatic tumor burden groups, at 26.7 months vs 15.4 months (P = .008). Significant differences were also observed among patients with 1% to 25% vs 26% to 50% liver involvement, with median values of 22.4 months vs 16.9 months (P = .030), and those with low or normal vs elevated LDH values at baseline, with median values of 23.5 months vs 15.3 months (P = .019).

“These subgroup analyses provide valuable insights into optimizing treatment with melphalan/HDS for patients with unresectable metastatic uveal melanoma, underscoring the importance of early intervention in patients with lower tumor burden to maximize clinical benefits," Vojislav Vukovic, MD, MSc, PhD, chief medical officer of Delcath, the developer of the HDS, stated in a news release on the findings.² "The consistent efficacy and manageable safety profile across diverse patient groups further validate this liver-directed therapy as a key option in managing this challenging disease."

Investigators of the phase 3 study enrolled adult patients with histologically confirmed unresectable disease with up to 50% liver involvement, 1 or more measurable liver lesions, and an ECOG performance status of 0 or 1 at screening. Those selected for study entry were initially randomly assigned 1:1 to receive melphalan via the HDS or best alternative care, consisting of investigator’s choice of transarterial chemoembolization, pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine. After slow enrollment due to patient reluctance to receive best alternative care treatment, all patients were assigned to receive the melphalan regimen (n = 102).

Those in the study received melphalan at a dose of 3.0 mg/kg at ideal body weight, with a maximum dose of 220 mg in a single treatment. Treatment was given for a maximum of six 6- to 8-week treatment cycles. Liver venous outflow isolated by a double balloon catheter placed into the inferior vena cava was conducted prior to treatment.

Among 91 evaluable patients, 33.0% were 65 years or older, 51.6% were female, and 50.5% were treated in the US. Most patients had 1% to 25% baseline liver involvement (79.1%), no presence of extrahepatic lesions (70.3%), low or normal baseline LDH levels (62.8%), and no receipt of prior therapy for metastatic disease (56.0%). The median hepatic tumor burden was 52.99 mm.

Efficacy end points of the trial included ORR per independent review committee based on RECIST v1.1 criteria, PFS, and OS. Adverse effects (AEs) underwent investigator assessment and were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.0 2009).

Serious AEs (SAEs) occurred in 45.3% of the total population and were generally consistent between relevant patient subgroups. However, a higher of patients with only hepatic lesions experienced SAEs compared with those with extrahepatic lesions, at 53.0% vs 25.9%; in addition to patients with low or normal LDH levels vs those with elevated levels, at 50.9% vs 37.1%.

Grade 3 or 4 AEs occurred in 81.1% of patients and were generally consistent across patient subgroups. A total of 17.9% of this population had AEs leading to treatment discontinuation, and 13.7% experienced AEs leading to a dose reduction. No apparent trends in SAE or grade 3 or 4 AE increases were observed with receipt of multiple cycles of melphalan/HDS.

References

1. Zager JS, Orloff M, Ferrucci PF, et al. Subgroup analyses of the phase 3 FOCUS study of melphalan/hepatic delivery system in patients with unresectable metastatic uveal melanoma. J Cancer Res Clin Oncol. 2026;152(25). doi: 10.1007/s00432-025-06291-x
2. Delcath Systems announces publication of subgroup analyses of the phase 3 FOCUS study of melphalan/hepatic delivery system in patients with unresectable metastatic uveal melanoma. Delcath Systems. News release. December 31, 2025. Accessed January 2, 2026. https://tinyurl.com/4nvad345