A Phase 1 Trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in Advanced NSCLC Patients

项目总结/摘要 转移性肺鳞状细胞癌（LUSC）和驱动程序阴性非小细胞肺癌患者 尽管在免疫时代生存率略有提高，但非小细胞肺癌（NSCLC）的生存率仍然很差。 检查点抑制剂。这在很大程度上是由于缺乏针对这些患者的靶向治疗， 在过去的15年里，这些治疗对病人的健康影响最大。现时的建议 重点关注一种新的相互作用，发生在一个新的特点NSCLC基因型和它的影响， 肿瘤代谢NFE 2L 2，编码一种转录因子（NRF 2），保护细胞免受氧化损伤。 和外源性应激，上调TORC 1信号，在20%的LUSC肿瘤中反复突变。 这些突变仅发生在单个热点结构域（Neh 2）中，该热点结构域充当其阴性结合位点。 调节因子KEAP 1本身在20%的LUSC病例中发生突变。该途径在30%的KRAS中也发生了改变。 突变型肺癌病例，并与预后不良和免疫检查点抑制剂耐药性相关。 我们的初步临床前和临床数据表明，口服药物对TORC 1/2的抑制作用 在这些情况下，TAK 228具有抗肿瘤功效，但是代谢转换远离糖酵解（被糖酵解减弱）， TORC 1/2抑制）对谷氨酰胺代谢的作用导致治疗抗性。我们发现，双重抑制 突变特异性LUSC和KRAS突变型肺环境中的糖酵解（TAK 228）和β-内酰胺酶解（CB-839） 产生协同抗肿瘤活性。拟议的1期临床试验基于以下假设： 用TAK 228和CB-839同时抑制这些通路将是治疗以下亚群的有效疗法： 具有这些改变或具有NRF 2信号传导激活的NSCLC患者。我们的第一阶段试验 TAK 228 + CB-839有三个目的，包括1）确定TAK 228的推荐扩展剂量 + CB-839治疗晚期NSCLC患者; 2）确立TAK 228 + CB-839治疗晚期NSCLC患者的初步疗效 预先选择的基因型/组织学群组;和3）表征所述基因型/组织学群组中的代谢药效学标志物。 血液肿瘤还有成像这项试验是我们声称的新靶向治疗的第一步 NSCLC患者的选择。下一步和长期目标是利用这些数据作为理由 和假设生成，用于在更大的患者队列中进行正式的2期疗效测试， 在LungMAP S1900等更大的合作团体中执行研究，这将是唯一的 适合在美国各机构探索这种组合方法。

Project Summary/Abstract Patients with metastatic squamous cell carcinomas of the lung (LUSC) and driver-negative non-small cell lung cancers (NSCLC) continue to have poor prognoses despite modest gains in survival in the age of immune checkpoint inhibitors. This is, in large part, due to the absence of targeted therapies for these patients, treatments which have had the biggest impact on patient prognoses in the past 15 years. The current proposal focuses on a novel interaction that occurs between a newly characterized NSCLC genotype and its effects on tumor metabolism. NFE2L2, which encodes for a transcription factor (NRF2) that protects cells from oxidative and xenobiotic stress and which upregulates TORC1 signaling, is recurrently mutated in 20% of LUSC tumors. These mutations occur in only a single hotspot domain (Neh2) that serves as the binding site for its negative regulator, KEAP1, which itself is mutated in 20% of LUSC cases. This pathway is also altered in 30% of KRAS- mutant lung cancer cases and is associated with poor prognosis and immune checkpoint inhibitor resistance. Our preliminary pre-clinical and clinical data show that inhibition of TORC1/2 by the orally available drug TAK228 has anti-tumor efficacy in these contexts, but that a metabolic switch away from glycolysis (blunted by TORC1/2 inhibition) to glutamine metabolism causes treatment resistance. We show that dual inhibition of glycolysis (TAK228) and glutaminolysis (CB-839) in mutation-specific LUSC and KRAS-mutant lung contexts yields synergistic anti-tumor activity. The proposed phase 1 clinical trial is based on the hypothesis that concurrent inhibition of these pathways with TAK228 and CB-839 will be an effective therapy for subsets of NSCLC patients who harbor these alterations or have activation of NRF2 signaling. Our phase 1 trial of TAK228 + CB-839 has three aims, including 1) determination of the recommended expansion dose of TAK228 + CB-839 in patients with advanced NSCLC; 2) establishing the preliminary efficacy of TAK228 + CB-839 in pre-selected genotype/histology cohorts; and 3) characterizing the metabolic pharmacodynamic markers in the blood, tumor, and through imaging. This trial is a first step in what we purport will be a new targeted therapy option for patients with NSCLC. The next step and longer term objective is to utilize these data as justification and hypothesis generation for formal phase 2 efficacy testing in a much larger cohort of patients, with an eye towards executing a study in larger cooperative groups such as LungMAP S1900, which would be uniquely suited to exploring this combination approach across institutions in the United States.