Background: Despite past efforts, no targeted therapies exist for squamous cell lung cancer (LUSC) pts. We identified a heretofore untargeted oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~15% of LUSCs. NFE2L2 encodes NRF2, a transcription factor involved in the oxidative stress response and targeted for degradation by KEAP1. NFE2L2 mutations (mut) occur only in an exon 2 hotspot (Neh2 domain), which is the binding site for KEAP1. Mutations in this region disrupt KEAP1 binding, leading to NRF2 nuclear translocation and increased mTOR signaling via RagD. We report translational studies and results from a phase 2 trial of the oral TORC1/2 inhibitor TAK228 in biomarker-selected pts. Methods: Cell line and xenograft experiments were performed using LK-2 LUSC (NFE2L2 E79K mut), A549 ADCL (KRAS G12S + KEAP1 loss), and SK-MES-1 LUSC cells (NFE2L2/KEAP1 WT) treated with TAK-228, everolimus, rapamycin, or deforolimus. Pts with stage IV LUSC harboring NFE2L2 or KEAP1 mut and ADCL harboring KRAS + KEAP1 co-mut were treated on an NCI CTEP phase 2 study of TAK228 3mg po qd (NCT02417701). Primary endpoint: ORR. Secondary endpoint: PFS. The study used a Simon 2-stage design for each cohort with H0 = 5% (N≥1/5 responses), HA = 40% (N≥2/10 responses). Results: TAK228 exhibited differential anti-tumor activity over TORC1 rapalogs in LK-2 and A549 cells. TAK228 alone was cytotoxic at sub-[μM] (IC50 68nM) in LK-2 cells; all other rapalogs had IC50s > 10μM. This was associated with marked decrease in TORC1/2 & MAPK signaling (decreased pS6, pAKT, pERK). Anti-tumor response was seen in LK-2 and A549 xenografts treated with TAK228. No anti-tumor/growth inhibitory responses were seen with any other rapalog. N = 21 evaluable pts have been treated (10 NFE2L2, 6 KEAP1, 5 KRAS+NFE2L2/KEAP1). Median age = 70; median prior lines tx = 2, smokers = 100%, median pack yrs = 39. Most common AEs included hyperglycemia (72%), fatigue (32%), diarrhea (32%), decreased appetite (32%). In NFE2L2 mut LUSC pts, ORR = 20% (2/10 confirmed PR), DCR = 100% with median PFS = 8.9mos (95%CI 7-NR). In KEAP1 mut LUSC pts, ORR = 17% (1/6 confirmed PR), DCR = 67% with PFS range = 1.8-8.6 mos. In KRAS + NFE2L2/KEAP1 mut ADCL pts, ORR = 0% and DCR = 0%. Conclusions: TAK228 is tolerable with differential activity in NFE2L2 (primary endpoint met) and KEAP1 mutant LUSC. A randomized phase 2 trial of TAK228 + docetaxel vs. SoC chemotherapy in advanced LUSC pts with NFE2L2/KEAP1 mut is in development (LungMAP S1900D) as is an NCI CTEP phase 1/1b trial of TAK228 + CB-839 in advanced NSCLC patients with NFE2L2/KEAP1 mut (NCI #10327). Clinical trial information: NCT02417701.