Percutaneous Hepatic Perfusion Could Boost Immunotherapy Response in Metastatic Melanoma

The management of advanced-stage melanoma has been transformed by the introduction of immune checkpoint inhibitors (ICIs). Since the FDA approval of ipilimumab (Yervoy) for this indication in 2011, PD-1 inhibitor–based regimens, including pembrolizumab (Keytruda), nivolumab (Opdivo), and combination approaches, have produced substantial and durable improvements in survival.^1,2 Landmark trials, such as the phase 3 CheckMate 067 (NCT01844505) and phase 2/3 RELATIVITY-047 (NCT03470922), have established combination ICI therapy as a preferred first-line strategy for patients with advanced, unresectable melanoma, including those with BRAF V600–mutated tumors.^3,4

Despite advances in ICI therapy, patients with metastatic melanoma and liver metastasis have worse survival outcomes.^5,6 Approximately 30% of patients with melanoma develop liver metastasis at the time of stage IV diagnosis.⁶ When compared head-to-head among patients with melanoma with liver metastasis vs those without liver metastasis, patients with liver metastasis had worse progression-free survival (PFS) and overall survival (OS) outcomes when treated with anti–PD-1 monotherapy or combination ICI therapy.⁶ In a subgroup analysis of CheckMate 067¹, patients with melanoma and baseline liver metastasis had a worse median PFS (4.4 months vs 18.1 months) and worse median OS (28.2 months vs not reached) when treated with nivolumab/ipilimumab compared with patients without liver metastasis.¹

As investigated by Yu et al, liver metastasis creates an immunosuppressive niche that limits systemic immunotherapy efficacy by inducing macrophage-mediated deletion of activated CD8-positive T cells.⁷ These liver-resident macrophages eliminate tumor-specific T cells through antigen-dependent interactions, leading to peripheral immune tolerance and immunotherapy resistance, even against extrahepatic tumors. Disrupting this liver-driven immune sink by depleting macrophages and preventing T-cell clearance restores antitumor immunity and responsiveness to immunotherapy.

Furthermore, Yu and colleagues found that combining liver-directed radiation therapy to select tumors with ICI can deplete macrophages, prevent T-cell clearance, restore antitumor immunity, and promote abscopal/systemic antitumor activity. Currently, the presence of liver metastasis does not inform treatment decisions in clinical practice despite its role as a poor prognostic biomarker. Ongoing efforts are needed to optimize ICI therapy outcomes in patients with metastatic melanoma and liver metastasis.

The FDA has approved percutaneous hepatic perfusion (PHP) with melphalan for the treatment of patients with metastatic uveal melanoma and liver metastasis, based on results from the phase 3 FOCUS trial (NCT02678572).⁸ This trial investigated the efficacy and safety of PHP with melphalan in patients with unresectable metastatic uveal melanoma. Ninety-one patients were treated with PHP with melphalan. Any-grade treatment-emergent adverse effects (TEAEs) occurred in all patients, with grade 3/4 TEAEs in 81.1%. The most common grade 3/4 TEAEs were thrombocytopenia (54.7%), leukopenia (33.7%), anemia (32.6%), and neutropenia (29.5%). Among the patients treated, the overall response rate (ORR) was 36.3% (95% CI, 26.44%-47.01%), with 7.7% of patients achieving a complete response. The disease control rate was 73.6% (95% CI, 63.35%-82.31%), and the median PFS was 9.0 months (95% CI, 6.34-11.56).

Uveal melanoma demonstrates limited responsiveness to ICI, likely due in part to its strong predilection for hepatic metastasis. Historically, treatment with ipilimumab/nivolumab in metastatic uveal melanoma has yielded ORRs of approximately 11% to 18%.⁹ To evaluate the role of overcoming ICI resistance from liver metastasis with liver-directed therapy, the randomized phase 1/2 CHOPIN trial (NCT04283890) evaluated the role of adding ipilimumab/nivolumab to PHP with melphalan vs PHP with melphalan alone.¹⁰

The study found that this combination approach significantly improved clinical outcomes compared with melphalan/PHP alone. The primary end point was achieved with a 1-year PFS rate of 54.7% (95% CI, 36.8%-69.5%) in the investigational group (n = 38) vs 15.8% (95% CI, 5.8%-30.1%) with melphalan/PHP alone (n = 38), and a median PFS of 12.8 months (95% CI, 9.2-15.4) vs 8.3 months (95% CI, 6.0-9.6), respectively (HR, 0.34; 95% CI, 0.19-0.60; P < .001). Secondary outcomes also favored the combination arm, including a higher ORR of 76.3% (95% CI, 59.4%-88.0%) vs 39.5% (95% CI, 24.5%-56.5%; P < .001) and longer median OS of 23.1 months (95% CI, 20.2-38.5) vs 19.6 months (95% CI, 15.2-21.8; HR, 0.39; 95% CI, 0.20-0.77; P = .006). Grade 3 or higher treatment-related adverse effects were more common with the combination regimen vs the control regimen (81.6% vs 40.5%) but were considered manageable, with no new safety signals identified.

To further evaluate this combination treatment strategy beyond uveal melanoma, the University of Wisconsin, Madison, opened a phase 1b/2 investigator-initiated trial (NCT07281924) evaluating the safety, tolerability, and preliminary efficacy of combining melphalan/PHP with nivolumab and relatlimab (Opdualag) in the first-line setting in patients with metastatic nonuveal melanoma and liver metastasis.¹¹

The dual ICI regimen of nivolumab/relatlimab was selected over ipilimumab/nivolumab because published indirect treatment comparison results between the 2 regimens demonstrated a numerically higher 2-year PFS rate with nivolumab/relatlimab compared with ipilimumab/nivolumab (37% vs 25%) among subjects with metastatic cutaneous melanoma with liver metastasis.³ We hypothesize that this combination treatment will exert a synergistic effect, leading to superior clinical outcomes, including ORR, PFS, and OS, compared with historically reported outcomes in patients with liver metastasis treated with combination ICI.² The phase 1b/2 trial is currently active and open to enrollment.¹¹

Ma is an assistant professor and a faculty member in the Division of Hematology, Medical Oncology, and Palliative Care within the Department of Medicine at the University of Wisconsin School of Medicine and Public Health in Madison.

References

1. Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al; CheckMate 067 Investigators. Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2025;392(1):11-22. doi:10.1056/NEJMoa2407417
2. Tawbi HA, Hodi FS, Lipson EJ, et al. Three-year overall survival with nivolumab plus relatlimab in advanced melanoma from RELATIVITY-047. J Clin Oncol. 2025;43(13):1546-1552. doi:10.1200/JCO.24.01124
3. Long GV, Lipson EJ, Hodi FS, et al. First-line nivolumab plus relatlimab vs nivolumab plus ipilimumab in advanced melanoma: an indirect treatment comparison using RELATIVITY-047 and CheckMate 067 trial data. J Clin Oncol. 2024;42(33):3926-3934. doi:10.1200/JCO.24.01125
4. Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq: a phase III trial of treatment sequences in BRAFV600-mutant (m) metastatic melanoma (MM)—final clinical results. J Clin Oncol. 2025;43(suppl 16):9506. doi:10.1200/JCO.2025.43.16_suppl.9506
5. Waninger JJ, Ma VT, Chopra Z, Pearson AN, Green MD. Evaluation of the prognostic role of liver metastases on patient outcomes: systematic review and meta-analysis. Cancer J. 2023;29(5):279-284. doi:10.1097/PPO.0000000000000683
6. Ma VT, Griffith K, Waninger J, et al. 241 Clinical outcomes of metastatic melanoma patients with liver metastases treated with anti–PD-1 monotherapy versus combination ipilimumab/nivolumab. J Immunother Cancer. 2020;8(suppl 3). doi:10.1136/jitc-2020-SITC2020.0241
7. Yu J, Green MD, Li S, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021;27(1):152-164. doi:10.1038/S41591-020-1131-x
8. 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
9. Najjar YG, Navrazhina K, Ding F, et al. Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study. J Immunother Cancer. 2020;8(1):e000331. doi:10.1136/jitc-2019-000331
10. Kapiteijn E, Van den Hoek L, Speetjens F, et al. LBA59 combined percutaneous hepatic perfusion with ipilimumab plus nivolumab in metastatic uveal melanoma (CHOPIN): a single-center, open-label, randomized, phase II study. Ann Oncol. 2025;36(suppl 2):S1602. doi:10.1016/j.annonc.2025.09.071
11. Hepzato Kit and Opdualag for metastatic melanoma and liver metastasis. ClinicalTrials.gov. Updated March 2, 2026. Accessed February 10, 2026. https://clinicaltrials.gov/study/NCT07281924