Medical Policy

This document addresses Hepzato Kit^™ (Delcath^® Systems; Wilmington, DE), a liver-directed therapy designed to administer high-dose melphalan via a hepatic arterial delivery system. This document does not address other injectable administration routes of melphalan (e.g., Alkeran^®; Apotex, Inc, Toronto, Canada) or other hepatic delivery methods for chemotherapy administration.

Note: Please see the following related document for additional information:

• CG-SURG-78 Locoregional Techniques for Treating Primary and Metastatic Liver Malignancies

Medically Necessary:

Liver-directed administration of high-dose melphalan (Hepzato Kit) is considered medically necessary when all of the following criteria are met:

1. 18 years of age or older; and
2. Weight of at least 35 kilograms (77 pounds); and
3. Metastatic uveal melanoma, when all the following criteria are met;
   1. Unresectable hepatic liver metastases, confirmed on imaging (computed tomography [CT] or magnetic resonance imaging [MRI]); and
   2. Liver metastases affect no more than 50% of the liver; and
   3. If extra-hepatic disease is present, it is:
      1. Limited to the bone, lymph nodes, subcutaneous tissues, or lung; and
      2. Amenable to either, resection or radiation; and
4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1; and
5. None of the following concomitant illnesses or conditions at time of treatment initiation:
   1. Active liver infection (such as, Hepatitis B and Hepatitis C infection); or
   2. Any condition which elevates the risk of bleeding from anticoagulation (for example, stroke or other intracranial abnormalities); or
   3. Child-Pugh Class B or C cirrhosis; or
   4. Known varices or lesions at risk of bleeding (such as, medium to large esophageal and gastric varices, active peptic ulcers or active intracranial metastases or brain lesions with a propensity to bleed); or
   5. Uncorrectable coagulopathy or inability to safely tolerate temporary removal from long-term anti-coagulation therapy; or
   6. Portal hypertension.

Note: According to the black box warning in the FDA Product Information Label, Hepzato Kit should be administered at a designated treatment center that has received site certification.

Investigational and Not Medically Necessary:

Liver-directed administration of high-dose melphalan (Hepzato Kit) is considered investigational and not medically necessary when the criteria above are not met, and for all other indications.

Hepzato Kit is a novel, liver-directed therapy, also known as percutaneous hepatic perfusion (PHP), used for the treatment of uveal melanoma that has metastasized to the liver. In 2023, the Food and Drug Administration (FDA) approved Hepzato (high-dose melphalan) as a component of the Hepzato Kit, as a liver-directed treatment for adults (18 or older) diagnosed with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease other than extrahepatic disease present in the bones, lymph nodes, subcutaneous tissues, or lungs that is amenable to resection or radiation (FDA PI Label, 2023).

In 2024, Zager and colleagues published results from the pivotal, phase III, single arm, Focus Trial. The study’s primary endpoint was objective response rate (ORR) based on the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and disease control rate (DCR). Eligible participants were at least 18 years of age, with histologically confirmed metastatic uveal melanoma to the liver (< 50% liver tumor involvement), at least 1 measurable liver lesion on CT or MRI, ECOG score of 0-1, and limited extrahepatic disease amenable to resection or radiation. Eligible participants also demonstrated the following clinical findings: adequate hepatic function as evidenced by a total serum bilirubin ≤ 1.5 x the upper limit of normal, prothrombin time within 2 seconds of the upper normal limit, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤ 2.5 x ULN in addition to the following complete blood count and comprehensive metabolic panel measurements: platelet count > 100,000/µL, hemoglobin ≥ 10.0 gm/dL, white blood cell count (WBC) > 2,000/uL, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, and creatinine as measured by either serum creatinine ≤ 1.5 mg/dL or measured creatinine clearance is > 40 mL/min/1.73 m2. Administration of Hepzato via the Hepzato Kit requires general anesthesia as well as anticoagulation, as such, additional eligibility criteria were designed to minimize the risks associated with the procedure and included the exclusion of individuals with moderate to severe liver cirrhosis, portal hypertension, NYHA Class II-IV status and history of a Whipple procedure. The FOCUS study was originally designed as a two-arm, open-label, randomized controlled trial (RCT), as such, eligible participants were randomized 1:1 to receive Hepzato or ‘best alternative care,’ including immunotherapies (such as, pembrolizumab) and other liver-directed therapies (for example, transarterial chemoembolization [TACE]). As a result of slower than anticipated enrollment and participant’s reluctance to randomization to the control arm, the study design was amended to a single-arm study in which all eligible participants received Hepzato administration via the Hepzato Kit. Treatment was administered once every 6 to 8 weeks for a maximum of 6 cycles. Lesions were assessed via imagining at follow-up every 6 weeks until disease progression. A total of 102 individuals were enrolled; treatment was attempted in 95 participants and 91 received treatment. In the treated population (n=91), the primary objective was met, as the ORR was 36.3 % (95% confidence interval [CI], 26.4 to 47.0; “the lower bound of the 95 % CI for ORR exceeded the upper bound [8.3 %] from the benchmark meta-analysis”). A complete response was achieved in 7.7% (n=7) of study participants. The median DOR was 14 months (95% CI, 8.3 to 17.7; n=33), and the median OS was 20.5 months (95% CI, 16.8 to 25.3) with an OS of 80 % at 1 year (95% CI, 70 to 87%). The median PFS was 9 months (95% CI, 6.3 to 11.6), with a PFS of 65 % at 6 months (95% CI, 54-74%). A post hoc analysis demonstrated a statistically significant relationship between tumor response and survival (p<0.0001). Every participant reported at least one treatment-emergent adverse event (TEAEs) and treatment was discontinued in 17.9% due to TEAEs. Thrombocytopenia and neutropenia were the most commonly reported serious TEAEs (15.8 % and 10.5%, respectively); most were treated on an outpatient basis. During the study, 3 participants died as a result of a cardiac arrest, a case of acute hepatic failure and a bacterial peritonitis infection at 43, 62 and 64 days, respectively following the last study treatment. None of the deaths were determined to be treatment related. Ultimately, 34 participants (37.4%) of the 91 who initiated treatment, completed all 6 cycles. The study authors concluded that “melphalan/HDS [hepatic delivery system] provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM [metastatic uveal melanoma]”.

In 2023, Olofsson and colleagues published results from a multicenter, randomized, open-label, phase III trial of individuals with previously untreated metastatic primary uveal melanoma, with metastases confined to the liver. Exclusion criteria included tumor involvement in more than 50% of the liver, significant heart, lung, or renal dysfunction and a body mass index (BMI) above 35. A total of 87 individuals were enrolled and randomized to either intrahepatic, high-dose melphalan (n=43) or the control group (n=44 [best alternative care]). The study’s primary endpoint was OS at 24 months. Radiologic response was assessed at months 3, 6, 12, 18, and 24 by either CT or MRI of the liver. In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment (other than intrahepatic melphalan). The overall response rates (ORRs) were 40% in the intrahepatic melphalan arm and 4.5% control arm, respectively (p<0.0001). The median PFS was 7.4 months versus 3.3 months (p<0.0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hepatic PFS was 9.1 months versus 3.3 months (p<0.0001), both favoring the intrahepatic melphalan arm. During the study period, there were 11 treatment-related serious adverse events reported in the intrahepatic melphalan group and 7 in the control group, including 1 treatment-related death reported in the intrahepatic melphalan group. In this previously untreated sample with metastatic primary uveal melanoma, confined to the liver, high-dose, intrahepatic melphalan demonstrated favorable efficacy and a reasonable safety profile compared to best alternative care.

In 2021, Bethlehem and colleagues conducted a systematic review and meta-analysis comparing isolated hepatic perfusion (IHP) with melphalan for individuals with liver metastases to PHP with melphalan (for example, Hepzato Kit). A total of 9 articles reporting on 8 studies were included in the analysis. The median OS was 17.1 months for IHP and 17.3 months for PHP. The median PFS was 7.2 months for IHP and 9.6 months for PHP. The median hepatic PFS was 10 months for IHP and 9.5 months for PHP. The complication rate and 30-day mortality rate were 39.1% and 5.5% for IHP and 23.8% and 1.8% for PHP. There was no difference in OS or PFS between IHP and PHP for individuals with uveal melanoma liver metastases, but there was significantly less risk for complications and mortality following PHP. This analysis was not limited to uveal melanoma.

The National Comprehensive Cancer Network^® (NCCN) clinical practice guideline (CPG) for uveal melanoma (V1.2024) has given a 2A recommendation for the administration of melphalan via PHP (i.e., Hepzato Kit) for the treatment of hepatic-dominant metastatic uveal melanoma with < 50% liver involvement.

Hepzato Kit is only available for administration at experienced centers through the HEPZATO KIT REMS program (FDA PI Label, 2023).

Although uveal melanoma is rare, it is the most common primary intraocular malignancy in adults and occurs in approximately 5 to 10 people per million, per year. Less than 3% of cases present with detectable metastatic disease at the time of diagnosis; the most common site of metastasis is the liver (90%) (NCCN, V1.2024).

Liver-directed therapies have largely demonstrated efficacy in hepatic-dominant metastatic uveal melanoma and as such are typically not recommended beyond this setting (NCCN, V1.2024). The purpose of isolating treatments to the liver-alone is the significant reduction in systemic side effects that is typically achieved. Locoreginoal therapies may include, but are not limited to, ablative therapies (such as, microwave ablation or cryosurgical ablation) and arterially directed therapies (such as, transcatheter arterial chemoembolization, immunoembolization, and percutaneous hepatic perfusion).

Hepzato Kit, a novel, liver-directed therapy, also known as percutaneous hepatic perfusion, is indicated for the treatment of uveal melanoma that has metastasized to the liver. The procedure involves the infusion of a well-established chemotherapy drug, melphalan (originally FDA approved in 1964), delivered at a high-dose directly to the liver via the hepatic artery over a 30-minute period. This treatment procedure avoids systemic chemotherapy by temporarily isolating the liver from the body's circulatory system, allowing for high-dose melphalan delivery directly to the liver and filtering the melphalan out of the blood before returning it to systemic circulation. The procedure is repeated every 6 to 8 weeks and can be administered up to 6 times.

Adverse Events and Warnings

Black box warnings from the FDA PI Label (2023) include the following information and recommendations:

• Severe peri-procedural complications including hemorrhage, hepatocellular injury, and thromboembolic events may occur via hepatic intra-arterial administration.
• Myelosuppression with resulting severe infection, bleeding, or symptomatic anemia may occur; monitor hematologic laboratory parameters and delay additional cycles until blood counts have improved.
• Hepzato is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the HEPZATO KIT REMS. The required components of the HEPZATO KIT REMS include:
  • Healthcare settings that dispense and administer HEPZATO KIT must be enrolled, certified, and comply with the REMS requirements.  
  • Certified healthcare facilities must ensure that healthcare providers who perform the Percutaneous Hepatic Perfusion (PHP) procedure are trained on the use of HEPZATO KIT and must only dispense HEPZATO when authorized to do so by the REMS.
  • Certified healthcare facilities must ensure that individuals are assessed for severe peri-procedural complications during the procedure and for at least 72 hours following the procedure.

Additional warnings from the FDA PI Label (2023) include the following information, contraindications and recommendations:

• Hepozato and the Hepzato kit are contraindicated in individuals with any of the following:
  • Active intracranial metastases or brain lesions with a propensity to bleed;
  • Liver failure, portal hypertension, or known varices at risk for bleeding;
  • Uncorrectable coagulopathy;
  • Active cardiac conditions including, but not limited to, unstable coronary syndromes (unstable or severe angina or myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease;
  • History of allergies or known hypersensitivity to melphalan or a component or material utilized within the Hepzato Kit, including natural rubber latex, heparin, and severe hypersensitivity to iodinated contrast not controlled by antihistamines and steroids.
• Hypersensitivity reactions, including anaphylaxis, have occurred in individuals who received an intravenous (IV) formulation of melphalan.
• Melphalan-based chemotherapy regimens have been reported to cause embryo-fetal toxicity and suppression of both ovarian and testicular function.
• Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma, have been reported in individuals with cancer treated with alkylating drugs (including melphalan); melphalan has been shown to cause chromatid or chromosome damage in humans.

Childs-Turcotte-Pugh (CTP): A scoring system for severity of liver disease and likelihood of survival based on the presence of: degenerative disease of the brain (encephalopathy), the escape or accumulation of fluid in the abdominal cavity (ascites), laboratory measures of various substances in the blood (see table below), and the presence of other co-existing diseases; after calculating the CTP score using a table similar to the one below, candidates can be classified into 1 of 3 categories:

• Childs A (5-6 points): 10 year survival 80-90%
• Childs B (7-9 points): 5 year survival 60-80%
• Childs C (10-15 points): 2 year survival less than 50%

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS):  Describes an individual’s level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.).

Extra-hepatic disease: Cancer that is located outside of the liver.

Isolated hepatic perfusion: A one-time open surgical procedure where the vascular supply to the liver is isolated to allow delivery of high doses of chemotherapy (typically melphalan) directly to liver metastases; IHP is not widely used as the procedure takes many hours to complete, cannot be repeated, and is associated with significant toxicity and prolonged hospital stays.

Metastasis: The spread of cancer from one part of the body (the origin of the cancer) to another part of the body. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

New York Heart Association (NYHA) Definitions:
The NYHA classification of heart failure is a 4-tier system that categorizes subjects based on subjective impression of the degree of functional compromise; the four NYHA functional classes are as follows:

• Class I - cardiac disease but without resulting limitation of physical activity; ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain; symptoms only occur on severe exertion.
• Class II - cardiac disease resulting in slight limitation of physical activity; they are comfortable at rest; ordinary physical activity (e.g., moderate physical exertion such as carrying shopping bags up several flights of stairs) results in fatigue, palpitation, dyspnea, or anginal pain.
• Class III - cardiac disease resulting in marked limitation of physical activity; they are comfortable at rest; less than ordinary activity causes fatigue, palpitation, dyspnea or anginal pain.
• Class IV - cardiac disease resulting in inability to carry on any physical activity without discomfort; symptoms of heart failure or the anginal syndrome may be present even at rest; if any physical activity is undertaken, discomfort is increased.

Percutaneous hepatic perfusion (PHP): A repeatable procedure where chemotherapy (typically melphalan) is administered via percutaneous catheters directly into the liver via the hepatic artery, the venous blood from the liver is then removed from a catheter in the inferior vena cava, filtered extracorporeally to remove the chemotherapy, and then returned into systemic circulation. This process reduces systemic side effects but is associated with its own risks.

Unresectable: Refers to a tumor that cannot safely be removed surgically due to size or location.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Bethlehem MS, Katsarelias D, Olofsson Bagge R. Meta-Analysis of isolated hepatic perfusion and percutaneous hepatic perfusion as a treatment for uveal melanoma liver metastases. Cancers (Basel). 2021; 13(18):4726.
2. Brüning R, Tiede M, Schneider M, et al. Unresectable hepatic metastasis of uveal melanoma: hepatic chemosaturation with high-dose melphalan-long-term overall survival negatively correlates with tumor burden. Radiol Res Pract. 2020. 5672048.
3. Olofsson Bagge R, Nelson A, Shafazand A, et al. Isolated hepatic perfusion with melphalan for patients with isolated uveal melanoma liver metastases: a multicenter, randomized, open-label, phase III trial (the SCANDIUM Trial). J Clin Oncol. 2023; 41(16):3042-3050.
4. Zager JS, Orloff M, Ferrucci PF, et al. Efficacy and safety of the melphalan/hepatic delivery system in patients with unresectable metastatic uveal melanoma: results from an open-label, single-arm, multicenter phase 3 study. Ann Surg Oncol. 2024; 31(8): 5340-5351.  

Government Agency, Medical Society, and Other Authoritative Publications:

1. Delcath Systems Inc. Percutaneous hepatic perfusion in patients with hepatic-dominant ocular melanoma (FOCUS). NCT02678572. Updated December 12, 2023. Available at: https://clinicaltrials.gov/study/NCT02678572?term=focus%20&intr=melphalan&rank=1. Accessed on June 24, 2024.
2. Delcath Systems, Inc. HEPZATO KIT^™ Risk Evaluation and Mitigation Strategy (REMS). Available at: https://hepzatokitrems.com/. Accessed on June 24, 2024.
3. Hepzato Kit [Product Information]. Delcath Systems, Inc. Wilmington, DE; August 2023. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/201848s000lbl.pdf. Accessed on June 26, 2024.
4. National Comprehensive Cancer Network^® (NCCN) Practice Guidelines in Oncology^®. © 2024 National Comprehensive Cancer Network, Inc. For additional information, visit the NCCN website: http://www.nccn.org. Accessed on June 18, 2024.
   • Melanoma: Uveal (V1.2024). Revised May 23, 2024.

1. American Cancer Society. Available at: www.cancer.org. Accessed on June 18, 2024.
2. National Cancer Institute. Cancer topics Available at: http://www.cancer.gov/cancertopics. Accessed on June 18, 2024.
   • Intraocular (Uveal) Melanoma Treatment (PDQ). Last updated May 12, 2023.
3. U.S. National Institutes of Health (NIH). Clinical trials. Available at: https://clinicaltrials.gov/ct2/search. Accessed on June 18, 2024.

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.