Liver-Directed Melphalan Therapy Shows Promise in Advanced Uveal Melanoma, FOCUS Study Confirms
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A novel treatment approach utilizing melphalan delivered via a hepatic delivery system (HDS) has demonstrated a favorable benefit-risk profile for adults battling metastatic uveal melanoma, according to recently published findings from the phase 3 FOCUS study (NCT02678572). The data, released on December 31, 2025, and appearing in the Journal of Cancer Research and Clinical Oncology, offer new hope for patients with this challenging cancer.
Significant Response Rates Observed in FOCUS Trial
Among the 33 patients evaluated, the objective response rate (ORR) reached 57.6% (n = 19). Importantly, a substantial proportion – 33.3% – of these responses were observed between cycles 4 and 6 of treatment, suggesting a sustained benefit with continued therapy.
Hepatic Tumor Burden Predicts Treatment Success
Subgroup analysis revealed a strong correlation between baseline hepatic tumor burden and treatment response. Patients with lower tumor burdens – below the median – experienced an ORR of 51.1%, compared to just 22.2% in those with higher burdens (P = .008). This finding underscores the potential for maximizing treatment efficacy through early intervention in patients with less advanced disease. Notably, responses did not vary significantly based on age, sex, geographic region, the extent of liver involvement, or prior treatment history.
Progression-Free and Overall Survival Significantly Improved
The benefits of melphalan/HDS extended beyond initial response rates. Patients with lower baseline hepatic tumor burdens exhibited a statistically significant improvement in median progression-free survival (PFS), reaching 11.3 months versus 5.8 months for those with higher burdens (P = .007). While PFS differences between European and US patients (P = .110), those with and without extrahepatic tumors (P = .164), and those with varying lactate dehydrogenase (LDH) levels (P = .153) were not statistically significant, numerical differences were observed.
Even more encouragingly, a significant difference in overall survival (OS) was observed between the two hepatic tumor burden groups, with median OS of 26.7 months for those below the median compared to 15.4 months for those above (P = .008). Further analysis showed OS benefits for patients with 1% to 25% liver involvement (22.4 months) versus 26% to 50% involvement (16.9 months, P = .030), and for those with low or normal LDH levels (23.5 months) compared to elevated levels (15.3 months, P = .019).
Expert Commentary Highlights Importance of Early Intervention
“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,” stated a senior official from Delcath, the developer of the HDS, in a company release. “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.”
Study Design and Patient Characteristics
The phase 3 FOCUS study enrolled adult patients with histologically confirmed unresectable disease, limited to up to 50% liver involvement, and at least one measurable liver lesion. Participants had an ECOG performance status of 0 or 1. Initially, patients were randomized 1:1 to receive either melphalan via HDS or best alternative care – including transarterial chemoembolization, pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine. Due to challenges in enrolling patients for the best alternative care arm, all 102 participants ultimately received the melphalan regimen.
Treatment involved a melphalan dose of 3.0 mg/kg at ideal body weight, capped at 220 mg per cycle, administered over a maximum of six 6- to 8-week cycles. Prior to each treatment, liver venous outflow was isolated using a double balloon catheter placed in the inferior vena cava.
The 91 evaluable patients had a median hepatic tumor burden of 52.99 mm. The patient population was largely representative, with 33.0% aged 65 or older, 51.6% female, and 50.5% treated in the United States. A majority (79.1%) had 1% to 25% baseline liver involvement, 70.3% had no extrahepatic lesions, 62.8% had low or normal baseline LDH levels, and 56.0% had not received prior therapy for metastatic disease.
Safety Profile and Adverse Events
Efficacy end points were assessed using RECIST v1.1 criteria for ORR, with PFS and OS also closely monitored. Adverse effects (AEs) were evaluated by investigators 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 patients overall, with patterns generally consistent across subgroups. However, patients with only hepatic lesions experienced a higher rate of SAEs (53.0%) compared to those with extrahepatic involvement (25.9%). Similarly, SAEs were more frequent in patients with low or normal LDH levels (50.9%) versus elevated levels (37.1%).
Grade 3 or 4 AEs were observed in 81.1% of patients, also with consistent patterns across subgroups. Treatment discontinuation due to AEs occurred in 17.9% of patients, and dose reductions were required for 13.7%. Importantly, no increasing trends in SAEs or high-grade AEs were observed with subsequent treatment cycles.
The findings from the FOCUS study provide compelling evidence for the efficacy and safety of melphalan/HDS in the treatment of unresectable metastatic uveal melanoma, particularly in patients identified with lower hepatic tumor burdens, reinforcing its potential as a valuable therapeutic option.
