Melphalan/HDS Shows Benefit in Metastatic Uveal Melanoma
Melphalan/hepatic delivery system showed better survival and response rates than best alternative care in metastatic uveal melanoma in the FOCUS trial.
Artistic depiction of a melanoma cell targeted by shields, illustrating the cellular fight against skin cancer, emphasizing research and cure: © Татьяна Креминская - stock.adobe.com
The combination of melphalan and a hepatic delivery system (HDS) led to clinically meaningful efficacy vs best alternative care (BAC) in patients with unresectable metastatic uveal melanoma, according to data from the phase 3 FOCUS study (NCT02678572).
According to data published in Annals of Surgical Oncology and according to the trial’s efficacy analysis, melphalan and HDS demonstrated a favorable benefit-risk profile in this patient profile. Overall survival (OS), the trial’s primary end point, was numerically higher among those treated with melphalan plus HDS (n = 40) compared with patients treated with BAC (n = 32). In these respective arms, the median OS was 18.5 months vs 14.5 months, and at 1 and 2 years, the OS rates were 79% vs 67% and 27% vs 26%, respectively.
Additional findings showed that the median progression-free survival (PFS) numerically favored the melphalan and HDS group, with a median PFS of 9.1 months compared with 3.3 months with BAC. At 6 months and 1 year, the PFS rates were 71% vs 26% and 34% vs 11% in the respective groups. The objective response rate (ORR) in the melphalan/HDS group was 27.5% vs 9.4% in the BAC arm. The disease control rate (DCR) was 80.0% vs 46.9%, and the median duration of response (DOR) was 14.0 months vs 5.6 months in the melphalan/HDS arm vs BAC arm.
“This therapy offers a treatment option for patients with this rare condition, which is associated with a poor prognosis and limited treatment options,” wrote the study authors. “Overall, the results demonstrate an acceptable benefit-risk profile for melphalan/HDS in this patient population.”
About the FOCUS Study
FOCUS is a single-arm, multicenter, open-label trial evaluating the safety, efficacy, and pharmacokinetics of melphalan plus HDS in patients with hepatic-dominant ocular melanoma.2 Enrollment was open to patients aged 18 years and older with histologically verified unresectable metastatic uveal melanoma who had up to 50% liver tumor involvement.
Additional enrollment criteria required patients to have an ECOG performance status of 0 or 1, adequate hepatic function, and disease in the liver measurable by CT or MRI Evidence of limited extrahepatic disease on preoperative radiological studies was acceptable if the life-threatening component of the disease was in the liver. Patients must not have received chemotherapy, radiotherapy, chemoembolization, radioembolization, or immunoembolization for their malignancy within 30 days before treatment and must have recovered from all adverse events of therapeutic and diagnostic interventions, with some exceptions. Patients who were treated with anti-PD-1 immunotherapy were prompted to wait 8 weeks before being treated with melphalan/HDS.
Initially, once enrolled, patients were randomly assigned to receive melphalan/HDS or BAC. BAC consisted of an investigator’s choice of transarterial chemoembolism (TACE), pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine. However, because patients were enrolling slowly, likely due to not wanting the BAC treatment, the study was changed. It became a single-arm study where all eligible patients then received melphalan/HDS.
In the investigational arm, patients were given melphalan 3 mg/kg at ideal body weight at a maximum dose of 220 mg for a single treatment once every 6 weeks for a maximum of 6 cycles. Patients received melphalan over 30 minutes via an infusion catheter placed in the hepatic artery. This was followed by a 30-minute washout with extracorporeal filtration to reduce further systemic exposure to melphalan. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was also given to patients within 72 hours of the percutaneous hepatic perfusion procedure to mitigate possible neutropenic effects of melphalan. Before treatment, liver venous outflow was isolated by a double-balloon catheter placed into the inferior vena cava.
The secondary end points of the trial consisted of PFS and ORR via RECIST v1.1 criteria. DOR, hepatic PFS, and safety were the exploratory end points of the study.
According to the publication, all efficacy analyses were underpowered and were evaluated as exploratory analyses as a result of the early termination of the randomized study.
Safety Data From the FOCUS Trial
A total of 73 patients were assessed for safety. Among these patients, 14.6% and 7.3% of those in the melphalan/HDS arm had treatment-related adverse events (TEAEs) which resulted in treatment discontinuation or dose reductions. There were no TEAEs reported on the study that led to discontinuation of treatment in the BAC arm. Additionally, no TEAEs led to dose reductions in the BAC arm.1
The 2 deaths in the melphalan/HDS arm were considered related to the study treatment, devices, or procedures.
All patients in the melphalan/HDS group experienced at least 1 TEAE, compared with 93.8% in the BAC group. A higher percentage of patients in the melphalan/HDS group (85.4%) experienced severe (grade 3 or 4) TEAEs compared with the BAC group (34.4%).
In the melphalan/HDS group, severe adverse events occurring in 10% or more of patients included low platelet count (thrombocytopenia, 56.1%), low white blood cell count (leukopenia, 36.6%), low neutrophil count (neutropenia, 36.6%), low red blood cell count (anemia, 34.1%), and low phosphate levels (hypophosphatemia, 14.6%).
The most frequent severe adverse events in the BAC group (occurring in 6.3% of patients each) were elevated alanine aminotransferase, elevated aminotransferase, and high blood pressure (hypertension). Nausea, vomiting, low white blood cell count, abdominal pain, and upper abdominal pain each occurred as severe adverse events in 3.1% of patients in the BAC group.
