BMS-986156 是糖皮质激素诱导的肿瘤坏死因子受体 (TNFR) 相关蛋白 (GITR) 的激动剂，可促进效应 T 细胞激活。联合抗 GITR、抗程序性死亡 1、抗细胞毒性 T 淋巴细胞相关蛋白 4 抗体和放射治疗可改善临床前研究中的肿瘤控制。在此，我们描述了 BMS-986156 ipilimumab 或 nivolumab 联合/不联合立体定向消融放疗 (SABR) 对晚期实体癌患者 (NCT04021043) 的安全性和有效性结果。这项开放标签、多组、单中心 I/II 期研究研究纳入了经组织学证实对标准治疗耐药的 IV 期实体癌患者。第 1 组（G1，n=20）接受四个周期的 ipilimumab (3 mg/kg) 加 BMS-986156（30 mg 作为剂量水平 1 (L1) 或 100 mg 作为剂量水平 2 (L2)），每 3 周一次（ Q3W）。第 2 组（G2，n=10）接受四个周期的 ipilimumab (3 mg/kg) 加 BMS-986156（剂量在 G1、Q3W 中确定）和 SABR（50 Gy/4 fx 或 60-70 Gy/10 fx）第 3 组（G3，n=20）接受四个周期的纳武单抗（480 毫克）加 BMS-986156（30 毫克），每 4 周使用 SABR 维持一次，最长可达 2 年。使用免疫相关反应标准每 1-3 个月进行一次评估，直至进展。2019 年 10 月至 2021 年 12 月期间纳入了 50 名患者，中位数为 3 个（IQR 2-4.25）初始治疗周期。 986156 与 ipilimumab 的耐受性良好。5 名患者因治疗相关不良事件 (TRAE) 而停用 BMS-986156，其中 22 名患者分别为 3 名 G1/L1、1 名 G1/L2 和 1 名 G2。经历过 1-3 级 TRAE（G1/L1、G1/L2、G2、G3 的 6、4、5、7 名患者）有 6 名 (12%) 经历过 3 级 TRAE（G1/L1 为 2、2、1、1 名患者）。 、G1/L2、G2、G3），最常见的是丙氨酸转氨酶升高（n=3，G1/L2、G2 和 G3）和天冬氨酸转氨酶升高（n=2，G2 和 G3）。没有 4-5 级 TRAE。总体而言，19/39 (48.7%) 符合疗效分析的患者病情稳定，3 例 (7.7%) 达到部分缓解。场外（远隔）疾病控制率（ACR）和场外（远隔）缓解率（ARR）分别为38.5％和7.7％，其中ACR最高（50％，9/18）和G3.BMS-986156 中的 ARR (11.1%, 2/18) 对 ipilimumab、nivolumab（联合或不联合 SABR）具有良好的耐受性。该人群的结果令人鼓舞，因为超过一半的患者疾病稳定/部分缓解。© 作者（或其雇主）2024。CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

BMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and radiotherapy improve tumor control in preclinical studies. Herein we describe the results of the safety and efficacy of BMS-986156+ipilimumab or nivolumab with/without stereotactic ablative radiotherapy (SABR) in patients with advanced solid cancers (NCT04021043).This open-label, multigroup, single-center phase I/II study enrolled patients with histologically-confirmed stage IV solid cancers resistant to standard treatments. Group 1 (G1, n=20) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (30 mg as dose level 1 (L1) or 100 mg as dose level 2 (L2)), every 3 weeks (Q3W). Group 2 (G2, n=10) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (dose as determined in G1, Q3W) with SABR (50 Gy/4 fx or 60-70 Gy/10 fx to liver/lung lesions. Group 3 (G3, n=20) received four cycles of nivolumab (480 mg) plus BMS-986156 (30 mg), every 4 weeks with SABR. Maintenance nivolumab could be given up to 2 years. Tumor responses were assessed every 1-3 months until progression, using immune-related response criteria.50 patients were enrolled between 10/2019 and 12/2021. Patients received a median of 3 (IQR 2-4.25) initial treatment cycles. 100 mg BMS-986156 with ipilimumab was tolerated well. Five discontinued BMS-986156 with ipilimumab due to treatment-related adverse events (TRAEs), with three in G1/L1, one in G1/L2 and one in G2, respectively. 22 patients (44%) experienced Grade 1-3 TRAEs (6, 4, 5, 7 patients for G1/L1, G1/L2, G2, G3). Six (12%) had Grade 3 TRAEs (2, 2, 1, 1 for G1/L1, G1/L2, G2, G3), with elevated alanine aminotransferase (n=3, in G1/L2, G2 and G3) and aspartate aminotransferase (n=2, in G2 and G3) being the most common. There was no Grade 4-5 TRAEs. Overall, 19/39 (48.7%) patients eligible for efficacy analysis had stable disease and 3 (7.7%) achieved a partial response. Out-of-field (abscopal) disease control rate (ACR) and out-of-field (abscopal) response rate (ARR) were 38.5% and 7.7%, respectively, with the highest ACR (50%, 9/18) and ARR (11.1%, 2/18) in G3.BMS-986156 was well-tolerated with ipilimumab, nivolumab, with or without SABR. Outcomes were encouraging in this population, as more than half of patients had stable disease/partial response.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.