晚期黑色素瘤患者中 PD-L1 阻断联合 MAPK 致癌信号抑制。
PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma.
机构信息
University of California Los Angeles (UCLA) and Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA.
UCSF Medical Center, San Francisco, CA, USA.
出版信息
Nat Commun. 2020 Dec 7;11(1):6262. doi: 10.1038/s41467-020-19810-w.
Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.
联合 PD-L1 阻断与致癌丝裂原活化蛋白激酶（MAPK）信号抑制可能会使晚期黑色素瘤患者产生持久的反应。这项 1 期、开放标签、剂量递增和扩展研究（NCT02027961）调查了 durvalumab（抗 PD-L1）联合 dabrafenib（BRAF 抑制剂）和 trametinib（MEK 抑制剂）治疗 BRAF 突变黑色素瘤患者（队列 A，n=26），或 durvalumab 和 trametinib 同时（队列 B，n=20）或序贯（队列 C，n=22）治疗 BRAF 野生型黑色素瘤患者的安全性、耐受性和初步疗效。与这些药物单药治疗相比，联合治疗的不良事件和停药率更为常见。在队列 A 中，69.2%的患者出现客观缓解，队列 B 中为 20.0%，队列 C 中为 31.8%，在部分有活检样本的患者中观察到肿瘤免疫浸润改善和持久缓解。总之，联合 MAPK 抑制和抗 PD-L1 治疗可能为晚期黑色素瘤患者提供治疗选择。
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