In the multicenter, open-label, phase III FOCUS trial, researchers have found that the Melphalan/Hepatic Delivery System may offer improved disease control compared with best alternative care in patients with unresectable metastatic uveal melanoma. While limited by early termination and reduced statistical power, exploratory analyses from the study suggested that the system may deliver clinically meaningful benefits in this difficult-to-treat patient population.

The researchers enrolled 85 patients with unresectable metastatic uveal melanoma (mUM) and randomly assigned them 1:1 to receive either Melphalan/Hepatic Delivery System (Melphalan/HDS) or investigator-chosen best alternative care (BAC; eg, transarterial chemoembolization [TACE], ipilimumab, pembrolizumab, or dacarbazine). Patients in the Melphalan/HDS arm received hepatic arterial infusions of melphalan every 6 to 8 weeks in up to six cycles. The delivery was followed by extracorporeal filtration to minimize systemic toxicity. Because of patient reluctance to enroll in the BAC arm, the trial was amended to a single-arm study and all efficacy analyses were considered exploratory. Ultimately, 40 patients received Melphalan/HDS and 32 received BAC.

The median overall survival in the Melphalan/HDS group was 18.5 months compared with 14.5 months in the BAC group. Median progression-free survival was notably longer in the Melphalan/HDS arm at 9 months vs 3.1 months with BAC.

The objective response rate was 27.5% in the Melphalan/HDS group—substantially higher compared with the 9.4% rate that was observed in the BAC group. Similarly, the disease control rate reached 80% with Melphalan/HDS compared with 46.9% with BAC. The median duration of response was 14 months in the Melphalan/HDS arm, which was more than double the 5.6 months reported for BAC.

Progression-free survival at 6 months was achieved in 64% of the patients who were treated with Melphalan/HDS, whereas just 32% of the patients in the BAC arm remained progression free at the same time point. At 1 year, progression-free survival was 31% with Melphalan/HDS and 11% with BAC. Overall survival at 1 year was 79% among patients who received Melphalan/HDS vs 67% among those who received BAC. Two-year overall survival rates were similar between the two groups (27% and 26%, respectively).

“Tolerability of Melphalan/HDS is good, as evidenced by a median of 4.5 completed treatment cycles and 45% of the patients completing the planned 6 treatment cycles as per study protocol,” wrote the study authors, led by Jonathan S. Zager, MD, FACS, of the Moffitt Cancer Center and the University of South Florida.

The researchers reported that treatment-emergent adverse events (TEAEs) were common, particularly in the Melphalan/HDS group, though “no new safety signals for Melphalan/HDS were reported,” the study authors wrote:

• Grade 3/4 TEAEs occurred in 85.4% of patients in the Melphalan/HDS group vs 34.4% of patients who received BAC.

• The most frequent severe toxicities in Melphalan/HDS were hematologic: thrombocytopenia (56.1%), leukopenia (36.6%), neutropenia (36.6%), and anemia (34.1%).

• While two deaths occurred in the Melphalan/HDS arm—as a result of acute hepatic failure and bacterial peritonitis—they weren't attributed to treatment or procedure.

• Adverse events in the BAC arm were less frequent and included nausea, vomiting, and hepatic enzyme elevations.

Uveal melanoma, though rare, carries a high risk of liver metastasis, which occurs in about 90% of metastatic cases. Once liver involvement is established, median survival is often less than 1 year. While tebentafusp has shown benefit for HLA-A*02:01-positive patients, treatment options remain limited for the broader mUM population.

Melphalan/HDS—marketed in the U.S. as HEPZATO KIT—is the only U.S. Food and Drug Administration–approved liver-directed therapy for unresectable mUM. The minimally invasive procedure allows for retreatment and full-liver saturation with a chemotherapeutic agent, and addresses limitations seen in other liver-directed approaches such as TACE or surgical hepatic perfusion.

Combination strategies with immunotherapies are under investigation. Early-phase data from a trial combining Melphalan/HDS with ipilimumab and nivolumab showed promising response rates (objective response rate = 86%, disease control rate = 100%), which supported further research into synergistic treatment protocols.

The study authors concluded: “Melphalan/HDS is a promising liver-directed treatment option for unresectable mUM. Additional clinical studies in other tumor types with unresectable hepatic metastases and combinations with immunotherapy are needed to further explore the full clinical potential of this novel treatment approach.”

A full list of author disclosures can be found in the published research.

Source: Annals of Surgical Oncology