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Melphalan/HDS produced antitumor activity in metastatic uveal melanoma, including a consistent ORR across key subgroups.
Melphalan hepatic delivery system (melphalan/HDS) generated clinically meaningful antitumor activity in the phase 3 FOCUS study (NCT02678572) evaluating this liver-directed therapy in patients with metastatic uveal melanoma, with responses occurring early in a substantial proportion of treated patients, according to findings from subgroup analyses published in the Journal of Cancer Research and Clinical Oncology.1
Among the 33 patients who achieved an objective response, defined as a complete response or partial response, 19 (57.6%) responded within the first or second cycle of treatment, and 33.3% of responses emerged during cycles 4 through 6, indicating that meaningful tumor regression could occur both early and later during the treatment course.
“Efficacy results in previously treated patients [with uveal melanoma] in the FOCUS study compare favorably with efficacy reported for tebentafusp [Kimmtrak] in previously treated patients with uveal melanoma,” lead study author Jonathan S. Zager, MD, and colleagues wrote in the paper.
Zager is chief academic officer, a surgical oncologist, and a senior member in the Departments of Cutaneous Oncology and Sarcoma, as well as director of Regional Therapies at the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center in Tampa, Florida. He is also chair of the Department of Oncologic Sciences and a professor of surgery at the University of South Florida, Morsani School of Medicine in Tampa.
Baseline hepatic tumor burden appeared to be a notable discriminator of benefit. Patients with baseline hepatic tumor burden levels below the median experienced a significantly higher ORR compared with those who had levels above the median (51.1% vs 22.2%; P = .008). This pattern extended to time-to-event outcomes, with improved median progression-free survival (PFS) among patients with lower hepatic tumor burden (11.3 months vs 5.8 months; P = .007) and improved median overall survival (OS) (26.7 months vs 15.4 months; P = .008), suggesting that extent of intrahepatic disease at baseline may meaningfully shape clinical trajectory in this population.
Additional exploratory signals were observed across other liver-dominant disease features. Patients with 1% to 25% liver involvement at baseline had a longer median OS than those with 26% to 50% involvement (22.4 months vs 16.9 months; P = .030). Similarly, patients with low or normal baseline lactate dehydrogenase (LDH) levels had a longer median OS than those with elevated LDH levels (23.5 months vs 15.3 months; P = .019). Although numerical differences in PFS were noted by region (Europe vs US), extrahepatic involvement (absent vs present), and LDH category, these comparisons were not statistically significant, underscoring hepatic tumor burden as the most consistent prognostic and potentially predictive factor within these subgroup analyses.
The FOCUS study was a multicenter clinical trial conducted across 23 sites in the US and Europe designed to evaluate the efficacy and safety of melphalan/HDS in patients with metastatic uveal melanoma with liver-dominant disease.1,2 The trial was initially conceived as a randomized, controlled, 2-arm study to compare melphalan/HDS with best alternative care.
In the original design, eligible patients were randomly assigned in a 1:1 fashion to receive either melphalan/HDS or investigator’s choice of best alternative care, which included transarterial chemoembolization (TACE), pembrolizumab, ipilimumab, or dacarbazine.1 However, enrollment challenges emerged, largely driven by patient reluctance to be assigned to the control arm. Following discussions with the FDA, the study protocol was amended to a single-arm design in which all subsequently enrolled patients received melphalan/HDS.
After this amendment, a sample size re-estimation was performed, and a comprehensive meta-analysis of historical control data was conducted to contextualize efficacy outcomes. This meta-analysis incorporated 16 published studies composed of 476 patients with metastatic uveal melanoma treated with either monotherapy or combination systemic immunotherapy, establishing an ORR benchmark for comparative purposes. The final study population included patients initially randomly assigned to the melphalan/HDS arm in the 2-arm phase, as well as all patients enrolled following the transition to the single-arm design.
Treatment with melphalan/HDS was administered once every 6 to 8 weeks for up to 6 cycles. Melphalan was dosed at 3.0 mg/kg based on ideal body weight, with a maximum dose of 220 mg per treatment. Each procedure involved isolation of hepatic venous outflow using a double-balloon catheter positioned in the inferior vena cava. Melphalan was infused over 30 minutes via a catheter placed in the hepatic artery, followed by a 30-minute washout period using extracorporeal filtration to minimize systemic exposure.1,2 Procedures were delivered by a multidisciplinary team, including medical or surgical oncologists, interventional radiologists, anesthesiologists, and perfusionists.1
The primary end point was ORR as assessed by an independent review committee according to RECIST 1.1 criteria.1,2 PFS, OS, duration of response, and disease control rate were secondary end points. Tumor response evaluations incorporated both hepatic and extrahepatic disease, with complete and partial responses summarized by treatment cycle.1
The incidence of serious adverse effects (AEs) across patient subgroups was generally consistent with the overall safety population (45.3%; n = 95), although higher serious AE rates were reported in patients with hepatic-only lesions vs those with hepatic and extrahepatic disease (53.0% vs 25.9%), largely reflecting higher rates of serious thrombocytopenia (21.2% vs 3.7%) and leukopenia (7.3% vs 0%). Serious AE incidence was also higher among patients with low/normal baseline LDH levels vs elevated LDH levels (50.9% vs 37.1%), which appeared to be driven by differences in serious thrombocytopenia (20.0% vs 11.4%). Rates of grade 3/4 AEs across subgroups were similar to the rates seen in the overall population (81.1%).
Findings showered that 17.9% of patients in the overall population discontinued study treatment due to AEs, with numerically higher discontinuation rates observed in patients enrolled in Europe vs the US (26.1% vs 10.2%), those with 26% to 50% liver involvement vs 1% to 25% liver involvement (30.0% vs 14.7%), those with hepatic-only vs hepatic and extrahepatic lesions (21.2% vs 11.1%), and those with low/normal vs elevated baseline LDH levels (21.8% vs 8.6%). AEs leading to dose reduction occurred in 13.7% of patients overall, with a higher incidence reported in males vs females (23.4% vs 4.2%).
“Overall, the results demonstrate a favorable benefit-risk profile for melphalan/HDS across multiple clinically relevant subgroups, including patients [who were] previously treated/treatment-naive, patients with and without extrahepatic metastases, and patients with smaller/larger liver tumor burden,” Zager and colleagues concluded.
