Department of Thoracic Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Department of Thoracic Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Immunother Cancer. 2024 Oct 9;12(10):e009975. doi: 10.1136/jitc-2024-009975.
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.
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 细胞的激活增加。在临床前研究中，联合使用抗 GITR、抗程序性死亡-1、抗细胞毒性 T 淋巴细胞相关蛋白 4 抗体和放疗可改善肿瘤控制。在此，我们描述了在晚期实体瘤患者中，BMS-986156+伊匹单抗或纳武单抗联合/不联合立体定向消融放疗（SABR）的安全性和疗效结果（NCT04021043）。
这是一项开放标签、多组、单中心的 I/II 期研究，纳入了对标准治疗耐药的组织学证实的 IV 期晚期实体瘤患者。第 1 组（G1，n=20）接受 4 个周期的伊匹单抗（3mg/kg）加 BMS-986156（剂量水平 1（L1）为 30mg 或剂量水平 2（L2）为 100mg），每 3 周（Q3W）一次。第 2 组（G2，n=10）接受 4 个周期的伊匹单抗（3mg/kg）加 BMS-986156（在 G1 中确定的剂量，Q3W）联合 SABR（肝脏/肺部病变的 50Gy/4fx 或 60-70Gy/10fx）。第 3 组（G3，n=20）接受 4 个周期的纳武单抗（480mg）加 BMS-986156（30mg），每 4 周一次，联合 SABR。可维持纳武单抗治疗长达 2 年。使用免疫相关反应标准，每 1-3 个月评估一次肿瘤反应，直到进展。
2019 年 10 月至 2021 年 12 月期间共入组 50 例患者。患者接受了中位数为 3（IQR 2-4.25）个初始治疗周期。100mg BMS-986156 联合伊匹单抗耐受性良好。由于治疗相关不良事件（TRAEs），5 例患者停用了 BMS-986156 联合伊匹单抗，其中 3 例在 G1/L1，1 例在 G1/L2，1 例在 G2。22 例（44%）患者出现 1-3 级 TRAEs（G1/L1、G1/L2、G2、G3 组各 6、4、5、7 例）。6 例（12%）患者出现 3 级 TRAEs（G1/L1、G1/L2、G2、G3 组各 2、2、1、1 例），最常见的 TRAEs 为丙氨酸氨基转移酶（ALT）升高（n=3，G1/L2、G2、G3 组各 1 例）和天门冬氨酸氨基转移酶（AST）升高（n=2，G2、G3 组各 1 例）。无 4-5 级 TRAEs。总体而言，39 例（48.7%）符合疗效分析条件的患者病情稳定，3 例（7.7%）部分缓解。野外型（远隔效应）疾病控制率（ACR）和野外型（远隔效应）缓解率（ARR）分别为 38.5%和 7.7%，其中 G3 组的 ACR（50%，9/18）和 ARR（11.1%，2/18）最高。
BMS-986156 联合伊匹单抗、纳武单抗，联合或不联合 SABR，耐受性良好。在该人群中，结果令人鼓舞，超过一半的患者病情稳定/部分缓解。
