PDF(Pubmed)
Abstract：
BACKGROUND: Uveal melanoma (UM) is a rare malignancy where 50% of patients develop metastatic disease primarily affecting the liver. Approximately 40% of patients with metastatic UM respond to one-time isolated hepatic perfusion (IHP) with high-dose melphalan. This phase I trial investigates the safety and clinical efficacy of IHP combined with ipilimumab (IPI) and nivolumab (NIVO).
METHODS: Immunotherapy-naïve patients were randomized in this phase I trial to receive either IHP followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post-operative arm), or one cycle of preoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed by maintenance therapy with NIVO 480 mg for 1 year.
RESULTS: Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/18 patients (6 in the post-operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post-operative arm (4/7) and 22% in the pre-post-operative arm (2/9).
CONCLUSIONS: Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efficacy of this combination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show potential benefits in terms of safety or efficacy.
METHODS: Immunotherapy-naïve patients were randomized in this phase I trial to receive either IHP followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post-operative arm), or one cycle of preoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed by maintenance therapy with NIVO 480 mg for 1 year.
RESULTS: Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/18 patients (6 in the post-operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post-operative arm (4/7) and 22% in the pre-post-operative arm (2/9).
CONCLUSIONS: Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efficacy of this combination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show potential benefits in terms of safety or efficacy.
摘要：
背景：葡萄膜黑色素瘤（UM）是一种罕见的恶性肿瘤，其中50％的患者发展为主要影响肝脏的转移性疾病。大约40％的转移性UM患者对高剂量美法仑的一次性隔离肝灌注（IHP）有反应。这项I期试验研究了IHP联合ipilimumab（IPI）和nivolumab（NIVO）的安全性和临床疗效。
方法：在这项I期试验中，未接受免疫治疗的患者随机接受IHP，随后接受IPI3mg/kg和NIVO1mg/kg（IPI3/NIVO1），共四个周期（术后），或术前一个周期的IPI3/NIVO1，IHP，然后三个周期的IPI3/NIVO1（术前术后臂），然后用NIVO480mg维持治疗1年。
结果：18例患者被纳入并随机分组。三名患者未按计划进行IHP。总的来说,11/18名患者（术后臂6名，术后臂5名）未完成计划的IPI3/NIVO1四个周期。两组对IHP的毒性相似，但手术前、术后组的免疫相关不良事件(AE)数量较高.在可评估的患者中，术后组的总有效率为57%(4/7),术前组的总有效率为22%(2/9).
结论：IHP和IPI3/NIVO1联合治疗与严重不良事件相关。这种组合的疗效是令人鼓舞的高反应率。在IHP之前的一个周期的术前IPI/NIVO在安全性或有效性方面没有显示出潜在的益处。
方法：在这项I期试验中，未接受免疫治疗的患者随机接受IHP，随后接受IPI3mg/kg和NIVO1mg/kg（IPI3/NIVO1），共四个周期（术后），或术前一个周期的IPI3/NIVO1，IHP，然后三个周期的IPI3/NIVO1（术前术后臂），然后用NIVO480mg维持治疗1年。
结果：18例患者被纳入并随机分组。三名患者未按计划进行IHP。总的来说,11/18名患者（术后臂6名，术后臂5名）未完成计划的IPI3/NIVO1四个周期。两组对IHP的毒性相似，但手术前、术后组的免疫相关不良事件(AE)数量较高.在可评估的患者中，术后组的总有效率为57%(4/7),术前组的总有效率为22%(2/9).
结论：IHP和IPI3/NIVO1联合治疗与严重不良事件相关。这种组合的疗效是令人鼓舞的高反应率。在IHP之前的一个周期的术前IPI/NIVO在安全性或有效性方面没有显示出潜在的益处。
