On August 14, the U.S. Food and Drug Administration (FDA) approved the HEPZATO KIT, a melphalan hepatic delivery system, as a liver-directed treatment for adult patients with metastatic uveal melanoma and unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.
HEPZATO KIT is a combination product that administers melphalan, a well-known and long-approved chemotherapeutic agent, directly to the liver through the novel hepatic delivery system, which permits higher drug exposure in target tissues while limiting systemic toxicity. The use of the hepatic delivery system allows practitioners to surgically isolate the liver while the hepatic venous blood is filtered during melphalan infusion and subsequent washout during a percutaneous hepatic perfusion procedure. Percutaneous hepatic perfusion results in locoregional delivery of a relatively high melphalan dose.
Metastatic uveal melanoma is a rare and aggressive form of metastatic cancer with an incidence of approximately 1,000 cases per year in the United States. Ninety percent of metastatic uveal melanoma cases involve the liver, and liver failure is often the cause of death. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend liver-directed therapies for patients with metastatic uveal melanoma and liver metastases. HEPZATO KIT is the only liver-directed therapy approved by the FDA for the treatment of metastatic uveal melanoma; percutaneous hepatic perfusion, the procedure enabled by HEPZATO KIT, is already included in the NCCN Guidelines.
The approval of HEPZATO KIT was based primarily on the results of the FOCUS study (ClinicalTrials.gov identifier NCT02678572), a phase III, single-arm, multicenter, open-label study, which administered melphalan via the hepatic delivery system during a percutaneous hepatic perfusion procedure. Ninety-one patients received treatment every 6 to 8 weeks for up to six treatments. The main efficacy endpoints were objective response rate and duration of response as assessed by an independent review committee using Response Evaluation Criteria in Solid Tumors version 1.1. Objective response rate was 36.3% (95% confidence interval [CI] = 26.4%–47.0%) and median duration of response was 14 months (95% CI = 8.3–17.7 months). The disease control rate observed in treated patients was 73.6% (95% CI = 63.3%–82.3%), with 7 complete responses (7.7%), and 26 (28.6%) partial responses reported.
The patient population enrolled in the FOCUS study included patients with hepatic and extrahepatic lesions subject to a treatment plan, as well as both treatment-naive (56.0%) and previously treated (44.0%) patients, irrespective of human leukocyte antigen genotype.
The HEPZATO KIT prescribing information has a Boxed Warning, which includes three sections: toxicity related to the procedure; myelosuppression; and a Risk Evaluation and Mitigation Strategy program, commonly known as REMS, to manage and mitigate these risks. Serious adverse events associated with the percutaneous hepatic perfusion procedure with the HEPZATO KIT—such as hemorrhage, hepatocellular injury, and thromboembolic events—occurred in less than 5% of treated patients. Myelosuppressive adverse events, including thrombocytopenia, anemia, and neutropenia, are well-known and predictable side effects of melphalan and are routinely managed with standard supportive care measures.
The HEPZATO KIT REMS is designed to ensure consistent conduct of the percutaneous hepatic perfusion procedure and that only treatment teams who have received appropriate training perform the percutaneous hepatic perfusion procedure.