Melphalan Approved for Liver-Directed Treatment for Uveal Melanoma

The FDA has approved melphalan for injection (Hepzato Kit/Hepatic Delivery System), containing melphalan (Hepzato, Delcath Systems, Inc.) as a liver-directed treatment for patients with uveal melanoma with unresectable hepatic metastases affecting ≤50% of the liver. This treatment is permitted for those with no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation. This application was granted orphan drug designation.  

Why it matters: “Ocular melanoma, the most common intraocular malignancy, frequently metastasizes to the liver but to date there is no established standard-of-care for hepatic-dominant ocular melanoma patients,” wrote Jonathan Zager, Chair of the University of South Florida Department of Oncologic Sciences at Moffitt Cancer Center, and colleagues, in their published results of the FOCUS trial (NCT02678572), on which approval was based.

What they studied: Efficacy as studied in the phase 3, open-label, single-arm, multicenter FOCUS trial in which 91 patients with uveal melanoma with unresectable hepatic metastases were treated. If the life-threatening component of the patient’s uveal melanoma was in their liver and the extrahepatic disease was amenable to resection or radiation, limited extrahepatic disease in the bone, subcutaneous sites, lymph nodes, or lung was permitted. The key exclusion criteria included metastases in ≥50% of the liver parenchyma, Child-Pugh Class B or C cirrhosis, or hepatitis B or C infection.

The primary end points studied were objective response rate and duration of response as assessed by an independent central review committee using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

What they found: Of those being treated with melphalan, objective response rate was 36.3% with a median duration of response of 14 months.

Adverse events: The most common adverse events or laboratory abnormalities experienced in ≥20% of those being treated with liver-directed melphalan 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.

What to know: Please refer to the Hepatic Delivery System (Hepzato Kit) prescribing information for a Boxed Warning detailing the risk of severe peri-procedural complications including hemorrhage, hepatocellular injury, and thromboembolic events. As well, the Boxed Warning details the risk of myelosuppression with resulting severe infection, bleeding, or symptomatic anemia. Hepazto Kit is available only under a Risk Evaluation and Mitigation Strategy (REMS) program.

Conclusion: “In this analysis of data from the FOCUS trial, percutaneous hepatic perfusion (PHP) demonstrates superior objective response rate, duration of response, disease control rate, progression-free survival, and overall survival in comparison with best alternative care (BAC) in the treatment of hepatic metastases from ocular melanoma,” concluded Dr. Zager and colleagues. “This therapy offers a potential option for patients with this rare indication that is associated with a poor prognosis and few treatment options.”

Instructions: The recommended dosage is 3 mg/kg of melphalan per ideal body weight. Melphalan is to be administered via the Hepatic Delivery System by infusion into the hepatic artery over 30 minutes followed by a 30-minute washout period every six to eight weeks, for a maximum of six total infusions. Melphalan should not exceed a maximum of 220 mg during any treatment.

For More Information

Zager JS, Orloff MM, Ferrucci, PF, et al (2022). FOCUS phase 3 trial results: Percutaneous hepatic perfusion (PHP) with melphalan for patients with ocular melanoma liver metastases (PHP-OCM-301/301A). J Clin Oncol, 41(suppl_16). Abstract 9510. DOI:10.1200/JCO.2022.40.16_suppl.9510 (2023). Percutaneous hepatic perfusion in patients with hepatic-dominant ocular melanoma (FOCUS). NLM identifier: NCT02678572.

Hepzato (melphalan) prescribing information (2023). Delcath Systems, Inc. Available at:

US Food and Drug Administration (2023). FDA approves melphalan as a liver-directed treatment for uveal melanoma. Available at:

Image credit: Hellerhoff. Licensed under: CC BY-SA 4.0.

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