PD-1或PD-L1阻断耐药性转移性黑色素瘤中Ipilimumab联合或不联合nivolumab的随机2期试验。
Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial.
发表日期：2023 Aug 17
作者：
Ari VanderWalde, Shay L Bellasea, Kari L Kendra, Nikhil I Khushalani, Katie M Campbell, Philip O Scumpia, Lawrence F Kuklinski, Frances Collichio, Jeffrey A Sosman, Alexandra Ikeguchi, Adrienne I Victor, Thach-Giao Truong, Bartosz Chmielowski, David C Portnoy, Yuanbin Chen, Kim Margolin, Charles Bane, Constantin A Dasanu, Douglas B Johnson, Zeynep Eroglu, Sunandana Chandra, Egmidio Medina, Cynthia R Gonzalez, Ignacio Baselga-Carretero, Agustin Vega-Crespo, Ivan Perez Garcilazo, Elad Sharon, Siwen Hu-Lieskovan, Sapna P Patel, Kenneth F Grossmann, James Moon, Michael C Wu, Antoni Ribas
来源：
NATURE MEDICINE
摘要：
在这个随机的2期试验中，我们测试了将细胞毒性T淋巴细胞蛋白4 (CTLA-4) 的阻断与PD-1抗体治疗同时使用，对转移性黑色素瘤患者进行治疗，这些患者之前接受过第一线的免疫性PD-1治疗或针对细胞死亡程序1配体的治疗，并且他们的肿瘤有进展。该试验旨在将联合使用的尼伐替尼和伊匹单抗与单独使用的伊匹单抗进行比较。共有92名符合条件的患者以3：1的比例被随机分配到接受尼伐替尼和伊匹单抗联合治疗组或接受单独伊匹单抗治疗组。主要终点是无进展生存期。次要终点包括回应和未回应肿瘤中CD8 T细胞浸润的差异、客观反应率、总生存期和毒性。尼伐替尼和伊匹单抗联合治疗组相比于伊匹单抗单独治疗组，在无进展生存期方面表现出统计学上显著的改善（风险比=0.63，90%置信区间=0.41-0.97，单侧P=0.04）。客观反应率分别为28% (90%置信区间=19-38%) 和9% (90%置信区间=2-25%)，单侧P值为0.05。两组患者中发生3级或更高级的治疗相关不良事件分别为57%和35%，这与这些组合方案已知的毒性特征一致。本次分析观察到的肿瘤内CD8 T细胞密度的变化未能达到统计学上的显著性，支持作为次要终点检验的正式假设。总之，联合使用CTLA-4和PD-1阻断可以扭转一些对PD-1阻断治疗的原发性抵抗。Clinicaltrials.gov识别号：NCT03033576。© 2023作者，独家许可给 Springer Nature America, Inc.
In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41-0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19-38%) and 9% (90% CI = 2-25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.