On August 14, 2023, the Hepzato Kit—melphalan for injection/hepatic delivery system—was approved as a liver-directed treatment for adults with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver.¹ Patients must have either no extrahepatic disease or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lungs that is amenable to resection or radiation.

Supporting Efficacy Data

Approval was based on findings from the multicenter FOCUS study (ClinicalTrials.gov identifier NCT02678572). In this trial, 91 patients with uveal melanoma and unresectable hepatic metastases were treated with 3 mg/kg of melphalan (maximum total dose = 220 mg) given intra-arterially using the hepatic delivery system every 6 to 8 weeks for up to six infusions.

On independent central review committee assessment, objective response was achieved in 33 patients (36.3%, 95% confidence interval [CI] = 26.4%–47%), with a complete response in 7 patients (7.6%). The median response duration was 14 months (95% CI = 8.3–17.7 months).

How It Is Used

Melphalan is administered via the hepatic delivery system, with infusion into the hepatic artery every 6 to 8 weeks for up to six infusions. The recommended melphalan dose is 3 mg/kg based on ideal body weight, with a maximum dose of 220 mg per single treatment.

Safety Profile

Among 97 patients in the FOCUS safety population, the most common adverse events of any grade were fatigue (65%), nausea (57%), musculoskeletal pain (46%), abdominal pain (39%), vomiting (35%), and dyspnea (23%). The most common grade 3 or 4 adverse events included hypotension (3%) and dyspnea (2%). The most common grade 3 or 4 laboratory abnormalities were decreased platelets (55%), leukocytes (34%), hemoglobin (33%), and neutrophils (30%); grade 3 or 4 international normalized ratio increase and activated partial thromboplastin time increase were reported in 8% each.

Serious adverse events were observed in 45% of patients, most commonly thrombocytopenia (10%), neutropenia (8%), febrile neutropenia (7%), platelet count decrease (6%), leukopenia (4.2%), cardiac arrest (3.2%), neutrophil count decrease (2.1%), hypoxia (2.1%), pleural effusion (2.1%), pulmonary edema (2.1%), and deep vein thrombosis (2.1%). Adverse events led to discontinuation of treatment in 18%, most commonly neutropenia (3.2%). Fatal adverse events occurred in three patients, consisting of cardiac arrest, acute hepatic failure, and bacterial peritonitis.

The Hepzato Kit has a boxed warning for severe periprocedural complications (including hemorrhage, hepatocellular injury, and thromboembolic events) and myelosuppression. The Hepzato Kit is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Hezpato Kit REMS.

The Hepzato Kit has warnings or precautions for hypersensitivity reactions; gastrointestinal disturbances; carcinogenic or mutagenic effects; embryofetal toxicity; and infertility. Contraindications to the use of the Hepzato Kit include active intracranial metastases or brain lesions with a propensity to bleed; liver failure, portal hypertension, or known varices at risk for bleeding; surgery or medical treatment of the liver in the previous 4 weeks; active cardiac conditions; and a history of allergies or known hypersensitivity to melphalan or a component or material used within the Hepzato Kit (including natural rubber latex and heparin as well as severe hypersensitivity to iodinated contrast not controlled by antihistamines and steroids). Melphalan should not be used in patients weighing less than 35 kg. 

REFERENCE

1. Hepzato (melphalan) for injection is a component of the Hepzato Kit hepatic delivery system for intra-arterial use. Delcath Systems, Inc. August 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/­label/2023/201848s000lbl.pdf. Accessed September 12, 2023.