Phase 1b/2 trial of melphalan-percutaneous hepatic perfusion (PHP) therapy and nivolumab/relatlimab in patients with metastatic melanoma and liver metastasis.

Abstract

TPS9600 Background: Despite advances with immune checkpoint inhibitors (ICIs), patients with metastatic melanoma and liver metastases (LM) experience poorer outcomes. In the CheckMate-067 subanalysis, patients with LM treated with nivolumab/ipilimumab had shorter median PFS (4.4 vs 18.1 months) and OS (28.2 months vs not reached) than those without LM, confirming its negative prognostic role. Nivolumab/ipilimumab and nivolumab/relatlimab show comparable efficacy; however, the latter is increasingly used for its improved safety profile (grade ≥3 adverse events: 59% vs 21%). Melphalan-PHP (Hepzato), a liver-directed therapy delivering high-dose melphalan through a closed filtration circuit, concentrates treatment in the liver while minimizing systemic exposure. Research by Yu et al. demonstrated that LM reduces peripheral and tumoral CD8+ T cells, creating an immune desert, while combining liver-directed therapy with ICIs can reactivate systemic immune responses. Based on these insights and the CHOPIN trial’s safety data, the proposed Phase 1b/2 study will assess the safety, tolerability, and preliminary efficacy of melphalan-PHP plus nivolumab/relatlimab for first line treatment of metastatic non-uveal melanoma patients with LM. Methods: Phase 1b/2, single-center, single-arm study will use a Simon two-stage (5+10) design (n=15). Patients will receive nivolumab/relatlimab on Day 1 of each 28-day cycle for up to 2 years and receive melphalan-PHP on Day 15 of Cycle 1 and Cycle 3. Eligible participants must have histologically or cytologically confirmed metastatic melanoma involving the liver and be systemic treatment-naïve in the metastatic setting. Prior adjuvant ICI is permitted provided it was completed >6 months prior to study enrollment. Key exclusions include metastatic uveal melanoma, prior treatment with melphalan-PHP or ICI combinations, uncontrolled or symptomatic brain metastases, prior grade 3+ adverse events from ICI requiring treatment discontinuation, ongoing immunosuppressive therapy, contraindications to anesthesia, and significant cardiac, hepatic (Child-Pugh B/C), or pulmonary disease. The co-primary objectives/endpoints in stage 1 are to assess the safety and tolerability as measured by 2 or less DLTs (any treatment-related grade 4+ non-hematologic event lasting >3 days); and preliminary efficacy as measured by 2 or more objective responses in hepatic and non-hepatic lesions. Secondary objectives include: disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and any tumor reduction. Open for enrollment in January 2026. Clinical trial registry number: NCT07281924. Clinical trial information: NCT07281924 .