FDA Approves HEPZATO KIT for Unresectable Hepatic-Dominant Metastatic Uveal Melanoma


The FDA has approved HEPZATO KIT (melphalan/Hepatic Delivery System) for use in the treatment of select patients with unresectable hepatic-dominant metastatic uveal melanoma.



The FDA has approved HEPZATO KIT (melphalan/hepatic delivery system; HDS) for use in the treatment of adult patients with metastatic uveal melanoma with unresectable hepatic metastases affecting less than half 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.1

The regulatory decision is supported by findings from the phase 3 FOCUS study (NCT02678572). When melphalan (Hepzato) was delivered via the HDS during a percutaneous hepatic perfusion (PHP) procedure, it resulted in objective response rate (ORR) of 36.3% (95% CI, 26.4%-47.0%) in patients with hepatic and extrahepatic lesions (n = 91), which included a 7.7% complete response rate and a 28.6% partial response rate. The median duration of response of 14 months (95% CI, 8.3-17.7). Moreover, the disease control rate (DCR) was 73.6% (95% CI, 63.3%-82.3%).

Notably, the FOCUS patient population included those who were treatment naïve (56%) and previously treated (44%), and patients were enrolled regardless of HLA genotype.

"FDA approval of HEPZATO KIT marks the beginning of a new chapter for Delcath and the culmination of the company's commitment to bring this treatment option to patients suffering from metastatic uveal melanoma," Gerard Michel, chief executive officer of Delcath Systems, Inc., stated in a press release. "We look forward to partnering with cancer centers across the country to build a network of treatment sites trained in the use of this novel therapy."

The HEPZATO KIT administers the chemotherapy agent, melphalan, directly to the liver via the HDS, which allows for higher drug exposure in target tissues without an increase in systemic toxicity. The use of the delivery system allows for the liver to be isolated while the hepatic venous blood is filtered during drug infusion and subsequent washout during a PHP procedure. This procedure leads to locoregional delivery of a relatively high dose of the chemotherapy.

The FOCUS trial enrolled patients 18 years of age or older with 50% or less histologically or cytologically-proven ocular melanoma metastases in the parenchyma of the liver.2 Patients were required to have measurable disease. Those with Child–Pugh B or C cirrhosis, portal hypertension or active cardiac conditions were excluded.

The trial began as a randomized trial that would randomly assign patients in a 1:1 fashion to receive PHP or best alternative care (BAC) which consisted of investigator's choice of transarterial chemoembolization, pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine.3 However, the trial was slow to enroll as patients were hesistant to receive BAC; as such, the design was amended to a single-arm study in which all patients would receive PHP following discussions with the FDA.

PHP treatments were repeated every 6 to 8 weeks, and patients could receive up to 6 total. Those with hepatic or extrahepatic disease progression went off of study treatment and all patients were followed until death. Patients underwent imaging every 12 weeks.

ORR by independent review committee assessment and RECIST v1.1 criteria served as the trial's primary end point.

Earlier data from the trial were presented at the 2022 ASCO Annual Meeting. At the time of the presentation, 144 patients had been enrolled to the trial, with 102 in the PHP arm and 42 in the BAC arm; 91 and 32 patients, respectively, had received treatment.

Investigators reported a significant increase in ORR and DCR with PHP vs BAC in this population. Those in the PHP arm experienced an ORR of 36.3% (95% CI, 26.44%-47.01%) with a DCR of 73.6% (95% CI, 63.35%-82.31%); these rates were 12.5% (95% CI, 3.51%-28.99%) and 37.5% (95% CI, 21.10%-56.31%), respectively, in the BAC arm. The median DOR with PHP was 14 months (95% CI, 8.31-17.74) vs not calculable (NC; 95% CI, 6.93-NC) with BAC.

Those given PHP also experienced prolonged progression-free survival (PFS) and overall survival (OS) compared with BAC, although the data were still maturing and patients would continue to be followed for about 18 months. In the PHP arm, the median PFS was 9.03 months (95% CI, 6.34-11.56) vs 3.12 months (95% CI, 2.89-5.65) in the BAC arm (P = .0003). The median OS in the investigative and control arms were 19.25 months (95% CI, 16.72-24.35) and 14.49 months (95% CI, 11.10-19.78), respectively.

In the patients evaluated for safety (n = 94) following PHP treatment, 42.6% had a serious treatment-emergent adverse effect (TEAE). Most of these toxicities were hematological, transient, and were noted to resolve. The serious TEAEs experienced by more than 5% in the PHP arm included bone marrow suppression (22.3%), thromboctyopenia (14.9%), neutropenia (10.9%), respiratory and thoracic disorders (6.4%), cardiac disorders (5.3%), and leukopenia (4.2%).

Notably, no treatment-related deaths occurred.

"HEPZATO KIT is the only liver-directed therapy that can treat the whole liver," Vojislav Vukovic, chief medical officer of Delcath Systems, Inc., added in the pres release.1 "Scientific literature supports that HEPZATO KIT may have broad applicability in other tumor types, and we intend to expand our development efforts beyond uveal melanoma given the high incidence of unresectable hepatic dominant tumors."


  1. Delcath Systems, Inc. announces FDA approval of HEPZATO KIT for the treatment of adult patients with unresectable hepatic-dominant metastatic uveal melanoma. News release. Delcath Systems, Inc. August 14, 2023. Accessed August 15, 2023. https://www.prnewswire.com/news-releases/delcath-systems-inc-announces-fda-approval-of-hepzato-kit-for-the-treatment-of-adult-patients-with-unresectable-hepatic-dominant-metastatic-uveal-melanoma-301900346.html
  2. Percutaneous hepatic perfusion in patients with hepatic-dominant occular melanoma (FOCUS). ClinicalTrials.gov. Updated September 28, 2020. Accessed August 15, 2023. https://clinicaltrials.gov/ct2/show/NCT02678572
  3. Zager JS, Orloff MM, Ferrucci PF, et al. 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. 2022;40(suppl 16):9510. doi:10.1200/JCO.2022.40.16_suppl.9510
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