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

项目摘要/摘要 转移性肺鳞状细胞癌(LUSC)和DIVE阴性非小细胞肺患者 癌症(非小细胞肺癌)的预后仍然很差，尽管免疫年龄的存活率略有提高 检查点抑制药。这在很大程度上是因为这些患者缺乏针对性的治疗， 在过去15年中对患者预后影响最大的治疗方法。目前的提案 重点是一种新的相互作用，它发生在一种新的非小细胞肺癌基因及其对 肿瘤新陈代谢。NFE2L2，它编码一种转录因子(NRF2)，保护细胞免受氧化 和异种应激，并上调TORC1信号，在20%的LUSC肿瘤中反复突变。 这些突变只发生在单个热点结构域(Neh2)中，该结构域作为其阴性的结合部位 调控因子Keap1本身在20%的LUSC病例中发生突变。这个途径在30%的KRAS中也发生了改变- 突变的肺癌病例，并与预后不良和免疫检查点抑制物耐药有关。 我们的初步临床前和临床数据表明，口服药物对TORC1/2的抑制作用 在这些情况下，TAK228具有抗肿瘤效果，但代谢改变而不是糖酵解(被 对谷氨酰胺代谢的抑制)会导致治疗耐药。我们证明了双抑制作用 突变特异性LUSC和KRAS突变肺环境中的糖酵解(TAK228)和谷氨酰胺分解(CB-839) 产生协同抗肿瘤活性。拟议的第一阶段临床试验基于这样一个假设： 用TAK228和CB-839同时抑制这些通路将是治疗白血病亚群的有效方法。 存在这些改变或NRF2信号激活的非小细胞肺癌患者。我们的第一阶段试验 TAK228+CB-839有三个目的，包括1)确定TAK228的推荐膨胀量 2)建立TAK228+CB-839治疗晚期非小细胞肺癌的初步疗效。 预先选择的基因型/组织学队列；以及3)表征代谢药效标志物 血液，肿瘤，并通过成像。这项试验是我们声称的新靶向治疗的第一步 非小细胞肺癌患者的选择。下一步和更长期的目标是利用这些数据作为理由 以及在更大的眼睛患者队列中进行正式第二阶段疗效测试的假设生成 在更大的合作小组中执行一项研究，如LUNGMAP S1900，这将是唯一的 适合在美国各机构中探索这种结合的方法。

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.