Background: Despite efforts over the past decade, no targeted treatments exist for pts w/ SQCLC. Analyses by TCGA and others (Paik Cancer Disc 2015) have identified a heretofore untargeted, frequently mutated oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~20% of pts w/SQCLC. NFE2L2 encodes Nrf2, a transcription factor involved in the oxidative stress response which is targeted for degradation by Keap1. NFE2L2 mutations occur exclusively in an exon 2 hotspot that encodes the Neh2 domain (aa.1-86), which is the binding site for Keap1. Mutations in this region disrupt Keap1 binding, leading to Nrf2 nuclear translocation and increased mTOR signaling through regulation of RagD (Shibata Cancer Res 2010). We now report translational studies and prelim results from a phase 2 trial of the oral TORC1/2 inhibitor TAK228 in SQCLC pts with these mutations. Methods: Cytotoxicity, signaling, and xenograft experiments were performed using LK-2 SQCLC cells harboring an NFE2L2 E79K mutation treated with TAK228, everolimus, rapamycin, or deforolimus. Pts w/ prev treated stage IV SQCLC w/ NFE2L2 mutations are eligible for an NCI CTEP single-institution phase 2 study of TAK228 3mg po qd (continuous 28 day cycles; NCT02417701). 1⁰ endpoint: ORR. 2⁰ endpoint: PFS. The study utilizes a Simon 2-stage design with H0 = 5% (N≥1/5 responses), HA = 40% (N≥2/10 responses). Results: TAK228 exhibited significantly increased anti-tumor activity over TORC1 rapalogs in LK-2 cells. TAK228 alone was cytotoxic at sub-[μM] (IC50 68nM); all other rapalogs had IC50s > 10μM. This was assoc with an 80% decrease in downstream pS6 . Tumor response (-55% shrinkage) was also seen in an LK-2 xenograft treated with TAK228. No anti-tumor/growth inhibitory response was seen with any other rapalog. N = 4 pts have been treated on the clinical trial (exon 2 del, D29H, F37V, W24C). 2 related-SAEs (G3 hyperglycemia, G3 confusion) were seen; no other > G2 AEs reported. ORR = 25% (1 PR, 3 SD, 0 PD). Prolonged response is present, with DOR = 11mo, 8mo, 5.5mo, and 1mo, all ongoing. Conclusions: TAK228 is well-tolerated w/ evidence of pre-clinical and clinical activity in NFE2L2 mutant SQCLC. The trial has met its first-stage endpoint and has expanded to N = 10 patients. Clinical trial information: NCT02417701