Percutaneous Hepatic Perfusion Plus Ipi/Nivo Improves PFS in Uveal Melanoma

The combination of dual immune checkpoint blockade and liver-directed chemotherapy significantly improved progression-free survival (PFS) in patients with metastatic uveal melanoma (mUM) in the randomized phase 2 CHOPIN trial (NCT04283890), according to results published in The Lancet Oncology.¹

In the single-center study, combining percutaneous hepatic perfusion (PHP) with melphalan and ipilimumab (Yervoy) plus nivolumab (Opdivo) more than tripled 1-year PFS rates compared with PHP alone (54.7% vs 15.8%; adjusted HR, 0.34; 95% CI, 0.19-0.60; P =.0002). Median overall survival (OS) was 23.1 months with the combination vs 19.6 months with PHP alone (HR, 0.39; 95% CI, 0.20-0.77; P =.0065), although the study was not powered primarily for OS.

Given the historically poor prognosis of mUM and the limited activity of systemic immunotherapy in this disease, these findings may inform ongoing discussions about multimodality strategies in liver-dominant disease.

“The detailed analyses in this publication reinforce the synergistic potential of combining PHP with immunotherapy, showing not only superior PFS and OS but also enhanced hepatic control and deeper, more durable responses,” Ellen Kapiteijn, MD, principal investigator and lead author from Leiden University Medical Center’s Department of Medical Oncology, stated in a news release. “This approach represents a significant advancement for patients with this challenging disease, where liver-dominant metastases drive poor outcomes.”

Trial Overview

CHOPIN was an investigator-initiated, open-label, randomized phase 2 trial conducted at Leiden University Medical Center in the Netherlands. A total of 76 patients with metastatic uveal melanoma were randomly assigned 1:1 to receive PHP with melphalan alone (n = 38) or PHP combined with 1 mg/kg ipilimumab plus 3 mg/kg nivolumab (n = 38).

All patients received 2 PHP procedures at weeks 1 and 7. In the combination arm, ipilimumab and nivolumab were administered at weeks 0, 3, 6, and 9, without maintenance therapy. The primary end point was 1-year PFS in the intention-to-treat population.

At a median follow-up of 24.9 months, the 1-year PFS rate was 54.7% with combination therapy vs 15.8% with PHP alone, and median PFS was 12.8 months vs 8.3 months, respectively. The objective response rate (ORR) was 76.3% with the combination compared with 39.5% for PHP alone; complete response rates were 13% vs 3%. Two-year OS rates were 49.6% and 22.1% for the respective arms.

Grade 3 or higher treatment-related adverse events occurred in 82% of patients receiving combination therapy compared with 41% in the PHP-alone arm. The most common high-grade toxicities included thrombocytopenia in 34% vs 14%, leukopenia in 26% vs 14%, γ-glutamyl transferase elevation in 18% vs 8%, and anemia in 13% vs 3%, respectively. One treatment-related death due to immune-related triple M syndrome was reported in the combination arm.

Clinical Context

Uveal melanoma is the most common primary intraocular malignancy in adults, but metastatic disease, most frequently to the liver, remains associated with poor outcomes.² Median OS historically ranges from 12 to 20 months, depending on disease burden and therapeutic approach.^2,3

Unlike cutaneous melanoma, uveal melanoma has shown limited responsiveness to immune checkpoint inhibitors.³ Dual checkpoint blockade with ipilimumab and nivolumab has demonstrated modest activity in small studies, with response rates generally below those observed in cutaneous melanoma.

Liver-directed therapies have therefore played a central role in management. In the United States, the melphalan-based hepatic delivery system (HEPZATO KIT) received approval from the FDA in 2023 for adults with unresectable hepatic metastases from uveal melanoma meeting defined criteria.⁴ The approval was supported by data from the FOCUS trial (NCT02678572), which demonstrated clinically meaningful hepatic response rates with percutaneous melphalan perfusion.⁵

The CHOPIN trial builds on this paradigm by integrating systemic immune checkpoint blockade with locoregional therapy in an effort to enhance both intrahepatic control and systemic immune activation.

Drug and Mechanistic Background

PHP delivers high-dose melphalan directly to the liver while filtering hepatic venous blood to limit systemic exposure.⁴ Melphalan is an alkylating agent that induces DNA crosslinking and tumor cell death.

Ipilimumab and nivolumab target CTLA-4 and PD-1, together augmenting T-cell–mediated antitumor responses. The biological rationale for combination therapy in CHOPIN rests on the hypothesis that tumor antigen release from hepatic cytotoxic therapy may enhance systemic immune priming.¹

Interpretation and Limitations

The study authors concluded that this presents a new treatment paradigm for mUM, although with added toxicities. They suggested that validation in larger randomized trials would be ideal but that this could be challenging due to the rarity of this disease state.

Gerard Michel, chief executive officer of Delcath Systems, stated in the news release that “these results strongly underscore the clinical value of this combination and give us even greater confidence in adoption by treating physicians and patients.” He also stated that the company is encouraged to explore this combination in other cancers with significant occurrence of hepatic tumors.

REFERENCES

1. van den Hoek L, Burgmans M, Tong T, et al. Kapiteijn E, et al. Percutaneous hepatic perfusion combined with ipilimumab and nivolumab for metastatic uveal melanoma (CHOPIN): a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol. 2026.27(3):P372-382. doi:10.1016/S1470-2045(25)00720-X

2. Carvajal RD, Schwartz GK, Tezel T, Marr B, Francis JH, Nathan PD. Metastatic disease from uveal melanoma: treatment options and future prospects. Br J Ophthalmol. 2017;101(1):38-44. doi:10.1136/bjophthalmol-2016-309034

3. Algazi AP, Tsai KK, Shoushtari AN, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016;122(21):3344-3353. doi:10.1002/cncr.30258

4. FDA approves melphalan as a liver-directed treatment for uveal melanoma. FDA. August 14, 2023. Accessed March 3, 2026. https://tinyurl.com/5whcmw7v

5. Meijer TS, Burgmans MC, de Leede EM, et al. Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study. Ann Surg Oncol. 2021;28(2):1130-1141. doi:10.1245/s10434-020-08741-x