NCCN Guidelines Update Includes HEPZATO KIT for Uveal Melanoma

ORR, PFS, and OS in patients with and without extrahepatic metastatic uveal melanoma showed no significant difference when treated with HEPZATO KIT, per findings from the FOCUS trial.

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology to recommend HEPZATO KIT (melphalan for Injection/Hepatic Delivery System [HDS]) as a Category 2A treatment option for patients with hepatic-dominant metastatic uveal melanoma.^1,2

The Guidelines had previously limited the use of HEPZATO KIT to the treatment of patients with liver-confined metastases.¹

“We are encouraged by the NCCN’s decision to expand HEPZATO [KIT]’s recommendation in the guidelines to include patients with extrahepatic disease, recognizing the critical role hepatic progression plays in the course of metastatic uveal melanoma,” Gerard Michel, chief executive officer of Delcath Systems, stated in a news release. “This update underscores the growing recognition of HEPZATO [KIT] as an important treatment option for patients battling this challenging disease.”

This guideline revision also aligns with the HEPZATO KIT label, which states that the liver-directed treatment is indicated for adult patients with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or those with extrahepatic disease that is limited to the lymph nodes, bone, lung, or subcutaneous tissues amenable to radiation or resection.^1,3

A subgroup analysis from the pivotal phase 3 FOCUS trial (NCT02678572) showed no significant differences in objective response rate (ORR), progression-free survival (PFS), or overall survival (OS) between patients with and without extrahepatic metastatic uveal melanoma who were treated with melphalan/HDS.^1,4 The ORRs were 37.5% and 33.3% in patients with hepatic-only and extrahepatic disease, respectively.⁴ The median PFS was 9.3 months and 6.2 months in these respective arms, and the median OS was 20.8 months and 18.9 months, respectively.

Focusing on the FOCUS Trial

FOCUS enrolled 102 patients at least 18 years of age with histologically verified metastatic uveal melanoma metastasized to the liver; liver tumor involvement of up to 50%; at least 1 measurable liver lesion; and an ECOG performance status of 0 or 1.⁴ Patients were permitted to have received prior treatment or be treatment naive, and they could have limited extrahepatic disease that was amenable to radiation or resection.

FOCUS was initiated as a 2-arm, randomized trial, in which eligible patients were randomly assigned 1:1 to receive melphalan/HDS or best available care (BAC). However, due to slow enrollment and patient reluctance to receive BAC, the study design was changed to a single-arm study in which all eligible patients (n = 91) received melphalan/HDS at 3.0 mg/kg once every 6 to 8 weeks for up to 6 cycles.

ORR served as the primary end point. Secondary end points included duration of response (DOR), OS, PFS, and disease control rate (DCR).

Among all treated patients, the ORR was 36.3% (95% CI, 26.44%-47.01%), and 7.7% of patients achieved a complete response. The partial response, stable disease, and progressive disease rates were 28.6%, 37.4%, and 25.3%, respectively. Notably, 1 patient was not evaluable for response. The median time to response was 3.3 months (95% CI, 2.86-5.59), and the hepatic ORR was 41.8% (95% CI, 31.50%-52.57%).

The median DOR was 14.0 months (95% CI, 8.31-17.74), and the DCR was 73.6% (95% CI, 63.35%-82.31%).

The median PFS was 9.0 months (95% CI, 6.34-11.56). The 6- and 12-month PFS rates were 65% (95% CI, 54%-74%) and 38% (95% CI, 27%-48%), respectively. The median hepatic PFS was 13.9 months (95% CI, 9.30-16.66).

The median OS was 20.5 months (95% CI, 16.79-25.26), The 1- and 2-year OS rates were 80% (95% CI, 70%-87%) and 43% (95% CI, 32%-53%), respectively.

Any-grade and grade 3/4 treatment-emergent adverse effects (TEAEs) were observed in 100.0% and 81.1% of safety-evaluable patients (n = 91), respectively. TEAEs led to dose reduction and treatment discontinuation in 17.9% and 13.7% of patients, respectively. Three deaths were reported; none were attributed to treatment with melphalan/HDS.

References

1. Delcath Systems announces update to National Comprehensive Cancer Network Clinical Practice Guidelines for the treatment of metastatic uveal melanoma. News release. Delcath Systems, Inc. February 17, 2025. Accessed February 18, 2025. https://investors.delcath.com/news-releases/news-release-details/delcath-systems-announces-update-national-comprehensive-cancer
2. NCCN. Clinical Practice Guidelines in Oncology. Melanoma: uveal, version 1.2025. Accessed February 18, 2025. https://www.nccn.org/professionals/physician_gls/pdf/uveal.pdf
3. HEPZATO KIT. Prescribing information. Delcath Systems, Inc. Accessed February 18, 2025. https://hepzatokit.com/wp-content/uploads/2024/05/HEPZATO-KIT-Prescribing-Information-120083.A.pdf
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. doi:10.1245/s10434-024-15293-x