Percutaneous hepatic perfusion combined with ipilimumab and nivolumab for metastatic uveal melanoma (CHOPIN): a single-centre, open-label, randomised, phase 2 trial.

Immune checkpoint inhibitors ipilimumab and nivolumab show limited activity in uveal melanoma, although retrospective studies suggest improved outcomes when combined with liver-directed therapies.

免疫检查点抑制剂伊匹木单抗和纳武利尤单抗在葡萄膜黑色素瘤中的疗效有限，但回顾性研究提示，与肝脏靶向治疗联合使用时，治疗结果有所改善。

This study aimed to evaluate the efficacy and safety of combining percutaneous hepatic perfusion with ipilimumab and nivolumab.

本研究旨在评估经皮肝灌注联合伊匹木单抗和纳武利尤单抗的疗效和安全性。

Methods

In this investigator-initiated, single-centre, open-label, randomised, phase 2 trial, adults aged 18-80 years with unresectable liver-only or liver-dominant metastatic uveal melanoma, WHO performance status 0-1, and with no previous systemic therapy were randomly assigned (1:1) to receive percutaneous hepatic perfusion alone (perfusion group) or percutaneous hepatic perfusion combined with ipilimumab plus nivolumab (combination group).

在这项由研究者发起的单中心、开放标签、随机、II期试验中，年龄在18-80岁之间、患有不可切除的仅肝转移或肝占优势的葡萄膜黑色素瘤、WHO体能状态评分为0-1、且之前未接受过全身治疗的成人被随机分配（1:1）接受单独经皮肝灌注（灌注组）或经皮肝灌注联合伊匹木单抗加纳武利尤单抗（联合组）。

Two perfusions with melphalan (3 mg/kg; maximum 220 mg) were scheduled in weeks 1 and 7.

计划在第1周和第7周进行两次美法兰灌注（3 mg/kg；最大剂量220 mg）

The combination group also received intravenous ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) once every 3 weeks in weeks 0, 3, 6, and 9 without maintenance therapy.

联合治疗组还将在第0、3、6和9周每3周通过静脉给予伊匹木单抗（1 mg/kg）和纳武单抗（3 mg/kg），无需维持治疗。

The primary endpoint, 1-year progression-free survival, was analysed in the intention-to-treatpopulation; the safety analysis included all treated patients and was prospectively collected and graded using Common Terminology Criteria for Adverse Events version 5.0.

主要终点，1年无进展生存期，在意向治疗人群中进行了分析；安全性分析包括所有接受治疗的患者，并使用不良事件通用术语标准版本5.0前瞻性地收集和分级。

The trial is registered with ClinicalTrials.gov (NCT04283890) and EudraCT (2018-004248-49) and is ongoing but no longer enrolling.

该试验已在ClinicalTrials.gov（NCT04283890）和EudraCT（2018-004248-49）注册，并正在进行中，但不再招募新患者。

Results

Between Dec 10, 2020, and Nov 15, 2024, 80 patients were screened, of whom 76 were eligible and assigned to the combination group (n=38) or perfusion group (n=38), including 49 (64%) men and 27 (36%) women.

在2020年12月10日至2024年11月15日期间，共筛查了80名患者，其中76名符合资格并被分配到联合治疗组（n=38）或灌注组（n=38），包括49名（64%）男性和27名（36%）女性。

Median follow-up was 24·9 months (IQR 15·4-36·0). 1-year progression-free survivalwas 54·7% (95% CI 36·8-69·5) with combination therapy versus 15·8% (5·8-30·1) with perfusion alone (adjusted hazard ratio0·34 [95% CI 0·19-0·60]; p=0·0002).

中位随访时间为24.9个月（四分位数间距15.4-36.0）。联合治疗组的1年无进展生存率为54.7%（95%置信区间36.8-69.5），而单独灌注组为15.8%（5.8-30.1）（调整后的风险比为0.34 [95%置信区间0.19-0.60]；p=0.0002）。

Grade 3-4 treatment-related adverse events occurred in 31 (82%) of 38 patients with combination therapy compared to 15 (41%) of 37 patients with perfusion alone, due to both a higher incidenceof severe perfusion-related events and immunotherapy-related adverse events.

在接受联合治疗的38名患者中，有31名（82%）出现了3-4级治疗相关不良事件，而在仅接受灌注治疗的37名患者中，有15名（41%）出现了3-4级不良事件，这是由于严重灌注相关事件和免疫治疗相关不良事件的发生率均较高。

The most common grade 3-4 adverse events were thrombocytopenia (13 [34%] in the combination group vs five [14%] in the perfusion group), leukopenia (ten [26%] vs five [14%]), γ-glutamyl transferase increase (seven [18%] vs three [8%]), and anaemia (five [13%] vs one [3%]).

最常见的3-4级不良事件是血小板减少症（联合组13名[34%]，灌注组五名[14%]）、白细胞减少症（十名[26%]，五名[14%]）、γ-谷氨酰转移酶升高（七名[18%]，三名[8%]）和贫血（五名[13%]，一名[3%]）。

One treatment-related death (due to triple M syndrome) occurred in the combination group.

联合治疗组中发生了一例与治疗相关的死亡（由于三重M综合征）

interpretation

Adding ipilimumab and nivolumab to percutaneous hepatic perfusion significantly improved progression-free survival, but with a higher rate of adverse events.

将伊匹木单抗和纳武利尤单抗添加到经皮肝灌注中显著改善了无进展生存期，但不良事件的发生率较高。

The combination therapy offers a promising new treatment paradigm for patients with metastatic uveal melanoma.

联合治疗为转移性葡萄膜黑色素瘤患者提供了一个有前景的新治疗范式。

These results would ideally be validated in larger, multicentre randomised trials; however, conducting such studies is challenging due to the low incidenceof uveal melanoma.

这些结果理想情况下应在更大规模的多中心随机试验中得到验证；然而，由于葡萄膜黑色素瘤的发病率低，进行此类研究具有挑战性。

funding

Leiden University Medical Centre, Delcath Systems, and Bristol Myers Squibb.

莱顿大学医学中心、Delcath系统公司和百时美施贵宝公司。