A phase II randomized study of telaglenastat, a glutaminase (GLS) inhibitor, versus placebo, in combination with pembrolizumab (Pembro) and chemotherapy as first-line treatment for KEAP1/NRF2-mutated nonsquamous metastatic non-small cell lung cancer (mNSCLC)

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‐ofcare 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‐inclass, 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.