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

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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.