Phase 2 sequential treatment of percutaneous hepatic perfusion with melphalan/hepatic delivery system followed by tebentafusp in the treatment of metastatic uveal melanoma.

Abstract

TPS9605 Background: Metastatic uveal melanoma (mUM) typically has a poor prognosis with limited treatment options. Tebentafusp (TEBE) is the only approved systemic agent for HLA-A*02:01 positive mUM, and percutaneous hepatic perfusion (PHP) is FDA approved for patients with mUM in the liver (solely or predominantly). Combining PHP with nivolumab plus ipilimumab in the randomized phase 2 CHOPIN trial significantly improved overall response (ORR), progression-free survival (PFS) and overall survival (OS) compared to PHP alone, but with significantly higher grade 3 or greater adverse events. In the phase 3 TEBE clinical trial there was a modest ORR of 11%, and improved OS compared to investigator choice therapy. We hypothesize that PHP causes antigen release and changes in the hepatic tumor microenvironment that may enhance response to TEBE. In this investigator-initiated trial, we aim to explore the combination of sequential regional and systemic therapy in HLA-A*02:01 positive mUM patients. Methods: This is a single institution phase 2 clinical trial combining PHP using the melphalan hepatic delivery system for 2 cycles followed sequentially by intravenous TEBE at approved dosage for up to 1 year of therapy. For patients with unequivocal progression on TEBE, up to 4 additional cycles of PHP will be considered if they continue to meet standard eligibility for PHP. The primary objective is to assess the PFS in uveal melanoma patients who have isolated or liver dominant metastases with landmark analyses at 6 months, 12 months and 24 months. Secondary objectives include (1) toxicity, (2) objective response and duration of response, (3) hepatic and extra-hepatic PFS, (4) OS, (5) biomarker discovery, RNA sequencing and spatial immunofluorescence analysis of the tumor microenvironment through core biopsies performed pre-PHP, after PHP number 2, and post-TEBE treatment. Blood samples for immune panel analysis will be collected at these timepoints. Response assessments are undertaken with standard cross-sectional imaging every 12 weeks for 36 months. Planned accrual is 18 patients with an interim futility analysis after 10 patients are treated to assess the 6-month PFS for the cohort. Primary analysis will be performed using the Kaplan-Meier method. Salient eligibility criteria include: (1) age ≥18 years, (2) histologically confirmed metastatic UM, HLA-A*02:01 positive, (3) measurable disease per RECIST v1.1, (4) ECOG performance status of ≤1, (5) adequate marrow, renal and hepatic function; (6) no more than 50% of liver involvement by tumor. Limited extrahepatic disease is allowed. This study opened for enrollment in November 2025, and two patients have been treated to date (NCT07276386). This study is supported by Delcath Systems, Inc. Clinical trial information: NCT07276386 .