On August 14, 2023, the FDA approved melphalan hydrochloride for injection/Hepatic Delivery System (HDS; Hepzato Kit; Delcath Systems) as a liver-directed treatment for use in adults with uveal melanoma and unresectable hepatic metastases affecting <50% of the liver and no extrahepatic disease, or extrahepatic disease that is limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.
The FDA granted this approval an orphan drug designation.
The approval was based on the efficacy results of the FOCUS study, a single-arm, multicenter, open-label, phase 3 clinical trial that included 91 patients with uveal melanoma and unresectable hepatic metastases. Patients were allowed to have limited extrahepatic disease in the bone, subcutaneous sites, lymph nodes, or lung if the life-threatening component of the uveal melanoma was in the liver and the extrahepatic disease was amenable to resection or radiation. The main exclusion criteria were metastases in ≥50% of the liver parenchyma, Child-Pugh class B or C cirrhosis, or hepatitis B or C infection.
Patients received 3 mg/kg of melphalan hydrochloride/HDS based on ideal body weight (maximum dose, 220 mg), which was administered every 6 to 8 weeks for up to 6 infusions. The median number of infusions administered per patient was 4 (range, 1-6). In all, 37% of the 91 patients in the study received the maximum 6 infusions.
The main efficacy outcomes were objective response rate (ORR) and duration of response (DOR), as assessed by an independent central review committee using RECIST version 1.1. The results showed an ORR of 36.3% (95% confidence interval [CI], 26.4-47) and a median DOR of 14 months (95% CI, 8.3-17.7).
The most common (≥20%) adverse reactions, including laboratory abnormalities, were thrombocytopenia, fatigue, anemia, nausea, musculoskeletal pain, leukopenia, abdominal pain, neutropenia, vomiting, increased alanine aminotransferase, prolonged activated partial thromboplastin time, increased aspartate aminotransferase, increased blood alkaline phosphatase, and dyspnea.
Overall, treatment with melphalan hydrochloride/HDS was permanently discontinued because of adverse events in 18% of the study patients; neutropenia was the most common cause of permanent treatment discontinuation. In addition, 14% of patients had dose reductions, including 6% of patients because of decreased platelet count; 4.2% because of neutropenia; and 2.1%, each, because of anemia or thrombocytopenia.
The prescribing information for melphalan hydrochloride/HDS includes a boxed warning about the risk for severe periprocedural complications, including hemorrhage, hepatocellular injury, and thromboembolic events, as well as for myelosuppression associated with severe infection, bleeding, or symptomatic anemia. Because of these risks, melphalan hydrochloride/HDS is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program called Hepzato Kit REMS.
Melphalan hydrochloride/HDS is contraindicated in patients who have active intracranial metastases or brain lesions with a propensity to bleed; who have liver failure, portal hypertension, or known varices at risk for bleeding; had surgery or medical treatment of the liver in the past 4 weeks; who have uncorrectable coagulopathy, including active cardiac conditions, worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease; who have an inability to safely undergo general anesthesia; who have allergies or hypersensitivity to melphalan; who have allergies to a component or material used in melphalan hydrochloride/HDS, including an allergy to natural rubber latex; who have an allergy or hypersensitivity to heparin or have heparin-induced thrombocytopenia; and who have a severe allergic reaction to iodinated contrast that is not controlled by premedication with antihistamines and steroids.
The recommended dose of melphalan hydrochloride/HDS is 3 mg/kg, based on ideal body weight, with a maximum dose of 220 mg during a single infusion, which is administered every 6 to 8 weeks, for a maximum of 6 infusions.
