Melphalan/HDS Shows Favorable Results in Patients with Low Hepatic Tumor Burden

A subgroup analysis of the phase 3 FOCUS study (NCT02678572) shows that the Melphalan/Hepatic Delivery System (HDS; HEPZATO KIT) has a favorable benefit-risk profile for patients with metastatic uveal melanoma (mUM), specifically in patients with a lower hepatic tumor burden.^1,2

In August 2023, the FDA approved the melphalan/HDS for patients with mUM with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation. This decision was supported by results from the FOCUS study.

The analysis confirmed consistent tumor response across most demographic subgroups but revealed that baseline hepatic tumor burden is the most significant predictor of treatment success.

Patients with lower hepatic tumor burden at baseline experienced markedly and statistically significant superior outcomes across all primary efficacy end points.

The overall response rate (ORR) was 51.1% in patients below the median hepatic tumor burden (n = 45) vs 22.2% in patients above the median hepatic tumor burden (n = 45). The median progression-free survival (PFS) was 11.33 vs 5.82 months, respectively. The median overall survival (OS) was 26.71 vs 15.44 months.

Patients with 1% to 25% liver involvement had a significantly longer median OS than those with 26-50% involvement (22.4 vs 16.9 months, P =.030).

Patients with low or normal baseline lactate dehydrogenase levels(LDH) had a significantly higher median OS than those with elevated LDH (23.5 vs 15.3 months, P =.019).

Melphalan/HDS demonstrated robust efficacy irrespective of prior treatment history or the presence of limited extrahepatic disease, supporting its broad utility.

The treatment was effective in patients both with and without extrahepatic lesions, with similar response rates and survival. The ORR was 37.5% in patients with hepatic-only lesions, and 33.3% in patients with hepatic and extrahepatic lesions. The OS was 20.8 vs 18.9 months. The median PFS was numerically longer in patients with hepatic-only lesions (9.3 vs 6.2 months), though not statistically significant.

“One possible explanation is ‘leakage’ of melphalan due to anatomical variations in hepatic veins and due to filtration efficiency of up to 86%, which results in a systemic melphalan dose of typically 20–40 mg and therefore the potential of direct antitumor effects in extrahepatic lesions,” noted Zager et al in the Journal of Cancer Research and Clinical Oncology on the similarity of the ORRs between both patient types.

Efficacy outcomes were nearly identical between treatment-naive patients and those who had received prior therapies for mUM, including immune checkpoint inhibitors. In patients who were treatment-naive vs those who had been previously treated, the ORR was 35.3% vs 37.5%. The median PFS was 9.0 vs 9.18 months. The median OS was 20.53 vs 20.83 months.

While a majority of objective responses occurred early, a substantial portion emerged in later cycles, supporting the protocol of completing multiple treatments.

• Cycles 1–2: 57.6% of all objective responses were first observed.
• Cycles 4–6: 33.3% of all objective responses were first observed.

Safety and Tolerability Profile

The overall safety profile was consistent with previous reports, characterized primarily by hematological toxicity, and was similar across the analyzed subgroups without evidence of cumulative toxicity. Serious adverse events (AEs) occurred in 45.3% of patients. Grade 3/4 AEs occurred in 81.1% of patients, and the most common AEs were thrombocytopenia and neutropenia. Of the total patients, 17.9% discontinued treatment due to AEs. No treatment-related deaths occurred.

Analysis of AEs by treatment cycle showed no trend toward an increase in the rate of serious AEs or grade 3/4 AEs with successive treatments, indicating a lack of cumulative toxicity.

A higher incidence of serious AEs was observed in patients with only hepatic lesions compared to those with extrahepatic lesions (53.0% vs 25.9%), driven by differing rates of serious thrombocytopenia and leukopenia.

A higher incidence of AEs leading to dose reduction occurred in male patients compared to female patients (23.4% vs 4.2%).

Study Design and Patient Population

The FOCUS study was a multicenter, open-label trial. The analysis was conducted with a heterogeneous population of 91 treated patients with unresectable mUM.

Patients received melphalan (3.0 mg/kg ideal body weight) administered via the HDS once every 6 to 8 weeks for a maximum of 6 cycles.

Eligible patients were adults (≥18 years) with histologically verified unresectable mUM, up to 50% liver tumor involvement, and an ECOG performance status of 0 or 1. The population included both treatment-naive and previously treated patients.

Post hoc analyses were conducted based on age, sex, geographic region, extent of liver involvement, presence of extrahepatic tumors, baseline LDH, number of prior therapies, and hepatic tumor burden at baseline.

Most of the patients were younger than 65 years old and 51.6% were female vs 48.4% male. Of the total patients, 56.0% were treatment-naive and 44.0% had received ≥1 prior therapy.

This comprehensive subgroup analysis of the phase 3 FOCUS study reinforces the clinical benefit of melphalan/HDS in a heterogeneous population of patients with unresectable metastatic uveal melanoma.

REFERENCES

1.Zager J, Orloff M, Ferrucci P 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 152, 25 (2026). doi: 10.1007/s00432-025-06291-x

2.Percutaneous hepatic perfusion in patients with hepatic-dominant ocular melanoma (FOCUS). ClinicalTrials.gov. Updated December 21, 2023. Accessed January 6, 2026. https://clinicaltrials.gov/study/NCT02678572