Background: Mutational activation of the KEAP1/NRF2 pathway occurs in >20% of NSCLC patients (pts). KEAP1/NRF2 activation protects tumor cells from diverse forms of oxidative stress and promotes tumor growth and survival. In pts w/ advanced NSCLC, mutation of the KEAP1/NRF2 pathway is associated w/ dramatically reduced survival and poor outcomes following standard-of-care therapy. These tumors have increased dependence on GLS-mediated conversion of glutamine to glutamate due to upregulation of NRF2 target genes involved in glutamine metabolism. Telaglenastat (CB-839), an investigational, first-in-class, potent, oral GLS inhibitor, has demonstrated preclinical activity in KEAP1/NRF2-mutated NSCLC cell lines and xenograft models. This study will evaluate the safety and efficacy of telaglenastat + standard-of-care pembro and chemotherapy as 1L therapy for KEAP1/NRF2-mutated non-squamous mNSCLC (NCT04265534). Methods: This phase II, randomized, multicenter, double-blind study will enroll ~120 pts with histologically or cytologically documented stage IV non-squamous NSCLC w/ KEAP1 or NRF2 mutation, no prior systemic therapy for mNSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, and no EGFR, ALK, ROS, or other actionable mutation w/ available approved therapy in 1L setting. KEAP1 or NRF2 mutations will be determined by next generation sequencing (NGS), and study-provided liquid biopsy NGS will be available. Pts will be randomized 1:1 to receive telaglenastat (800 mg BID PO) or placebo, in combination with pembro, carboplatin, and pemetrexed at standard doses on day 1 of each 21-day cycle. Pts will be stratified by STK11/LKB1 mutational status and M stage of cancer (M1a-b vs M1c). The study will include an initial safety run-in period (n=12; 1 cycle). Co-primary endpoints are safety and investigator-assessed progression-free survival (RECIST v1.1). Secondary endpoints include overall response rate, duration of response, overall survival, and efficacy analysis in the subgroup of pts w/ biochemical confirmation of KEAP1/NRF2 pathway activation. Findings of this novel NGS biomarker-selected study will inform the efficacy and safety profile of telaglenastat + standard-of-care chemoimmunotherapy for 1L treatment of KEAP1/NRF2-mutated, non-squamous mNSCLC. Clinical trial information: NCT04265534.