Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
Clin Lung Cancer. 2020 Jul;21(4):384-388. doi: 10.1016/j.cllc.2020.02.019. Epub 2020 Mar 4.
Current strategies to improve clinical outcomes in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog-mutant non-small-cell lung cancer (NSCLC) patients include mitogen-activated protein kinase kinase 1 inhibitor and programmed death (PD) 1 (PD-1)/PD ligand 1 (PD-L1) immune checkpoint blockade combinations. Experience from treatment of melanoma suggests that anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-PD-1/PD-L1 combinations improve outcomes, but similar benefits remain to be seen for treatment of NSCLC. This report describes a single center, investigator-initiated phase I/II clinical trial to compare 2 combination schedules of intermittent or continuous selumetinib (AZD6244, ARRY-142886), tremelimumab (anti-CTLA-4), and durvalumab (anti-PD-L1) treatment with historical controls in patients with previously treated, unresectable NSCLC. Forty patients will be accrued at the University of Texas M.D. Anderson Cancer Center. Primary objectives include maximum tolerated dose (dose escalation phase) and progression-free survival (dose expansion phase). Secondary objectives include response rate according to Response Evaluation Criteria In Solid Tumors version 1.1, disease control rate, overall survival, safety, and duration of response. Exploratory objectives are to assess biomarkers of response and resistance on the basis of biopsies and peripheral blood taken before and after treatment using immune profiling, transcriptome, and protein readouts.
目前，改善 v-Ki-ras2 Kirsten 大鼠肉瘤病毒致癌基因同源突变型非小细胞肺癌（NSCLC）患者临床结局的策略包括丝裂原活化蛋白激酶激酶 1 抑制剂和程序性死亡（PD）1（PD-1）/PD 配体 1（PD-L1）免疫检查点阻断联合治疗。治疗黑色素瘤的经验表明，抗细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）和抗 PD-1/PD-L1 联合治疗可改善结局，但在治疗 NSCLC 方面仍有待观察到类似的获益。本报告描述了一项由研究者发起的、在单中心开展的 I/II 期临床试验，旨在比较间歇性或连续性 selumetinib（AZD6244、ARY-142886）、tremelimumab（抗 CTLA-4）和 durvalumab（抗 PD-L1）联合治疗与历史对照治疗既往接受过治疗、不可切除 NSCLC 患者的两种联合方案。将在德克萨斯大学 MD 安德森癌症中心入组 40 例患者。主要目标包括最大耐受剂量（剂量递增阶段）和无进展生存期（剂量扩展阶段）。次要目标包括根据实体瘤反应评价标准 1.1 评估的缓解率、疾病控制率、总生存期、安全性和缓解持续时间。探索性目标是评估治疗前后基于活检和外周血的免疫谱、转录组和蛋白检测，以评估反应和耐药的生物标志物。
