Melphalan Liver-Directed Therapy Receives FDA Approval for Metastatic Uveal Melanoma

On 14 August 2023, the FDA (US Food and Drug Administration) approved melphalan-containing HEPZATO KIT (melphalan for injection/hepatic delivery system) (HEPZATO, Delcath Systems, Inc.) for adults with uveal melanoma and unresectable liver metastases affecting less than 50% of the liver, or with extrahepatic disease limited to bone, lymph nodes, subcutaneous tissue or the lungs that can be treated with surgery or radiotherapy.

What Is Uveal Melanoma?

Uveal (eye) melanoma is a rare form of the aggressive cancer accounting for about 5% of skin cancers:  malignant melanoma. Uveal melanoma is this rare subtype and begins in the eye’s pigment cells (see the figure below).

Most melanomas arise on the skin, and immunotherapies such as pembrolizumab are effective for many patients with these forms. Their activity is weaker in intraocular melanomas. About 50% of patients with uveal melanoma are  metastatic (stage 4)  at diagnosis, most commonly with metastases in the liver, which is associated with a poor prognosis (disease course).

What Is Melphalan and How Does It Work?

Melphalan is a chemotherapy medicine in the alkylating-agent class and a nitrogen mustard analogue. It disrupts DNA’s double-helical structure and inhibits cell division, stopping cancer cells from growing and multiplying and thus preventing cancer spread.

Melphalan is used particularly to treat multiple myeloma, a type of bone marrow cancer. It has also been used for some types of ovarian cancer. In use since the 1950s, melphalan received FDA approval for multiple myeloma in 1964.

FDA Approval Based on the FOCUS Study

Efficacy was evaluated in the FOCUS study of 91 patients with uveal melanoma and unresectable liver metastases.

• The objective response rate was 36.3% (95% CI: 26.4, 47), and
• median response duration was 14 months (95% CI: 8.3, 17.7).

Melphalan is administered into the hepatic artery using the Hepatic Delivery System (HDS) every 6 to 8 weeks, for a maximum total of 6 infusions.

The recommended melphalan dose is 3 mg/kg based on ideal body weight, with a maximum of 220 mg in a single treatment.

Warnings and Contraindications

HEPZATO KIT’s prescribing information carries a Boxed Warning for serious complications during the procedure, including bleeding, liver cell injury and thromboembolism. A similar warning covers serious infection, bleeding or marked anaemia resulting from bone marrow suppression.

The most common adverse effects or laboratory abnormalities are reduced platelets (thrombocytopenia), fatigue, anaemia, nausea, musculoskeletal pain, reduced white blood cells (leukopenia), abdominal pain, reduced neutrophils (neutropenia), vomiting, increased liver enzymes (alanine aminotransferase), prolonged clotting time (activated partial thromboplastin time), increased aspartate aminotransferase, increased blood alkaline phosphatase and shortness of breath (dyspnoea).

Conclusion

This approval represents an important step in uveal melanoma treatment. Administering melphalan through the hepatic artery and finding it effective may offer new hope for patients. However, associated risks and adverse effects require careful assessment by patients and healthcare professionals.