KEAPSAKE: A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC

Inclusion Criteria: 1. Histologically or cytologically documented non-squamous NSCLC 2. Stage IV (M1a-c, AJCC 8th Edition, Amin 2017) disease not previously treated with systemic therapy for metastatic NSCLC a. Patients who received adjuvant or neo-adjuvant therapy (with or without immunotherapy) for localized NSCLC are eligible if all adjuvant/neo-adjuvant therapy (including immunotherapy) was completed at least 6 months prior to the development of metastatic disease. 3. No known actionable mutation in EGFR, ALK, ROS1, BRAF, NTRK or other known actionable mutation for which there is approved therapy in the first-line lung cancer setting 4. Must have at least one radiographically measurable lesion per RECIST v1.1 defined as a lesion that is ≥ 10 mm in longest diameter or lymph node that is ≥ 15 mm in short axis imaged by computed tomography (CT) scan or magnetic resonance imaging (MRI) a. Target lesions situated in a previously irradiated area may be considered measurable if progression has been demonstrated subsequent to radiation therapy 5. Age ≥ 18 years on the day of signing informed consent 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 7. Estimated life expectancy of at least 3 months 8. Recovery to baseline or ≤ grade 1 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 from toxicities related to the prior treatment, unless after discussion with the medical monitor, the AE(s) are deemed clinically non-significant and/or stable on supportive therapy 9. Has sponsor-approved eligible mutation in KEAP1 or NRF2 documented by NGS from a CAP-accredited and/or CLIA-certified laboratory (study-provided NGS or other NGS) and STK11 mutation status is known for the purpose of stratification. 10. Adequate organ function laboratory findings (defined per protocol) 11. Reproductive status: a. A female patient of childbearing potential must: i. Have a negative serum pregnancy test within 7 days prior to randomization ii. Agree to use methods of contraception outlined in Section 8.1.2 during the study through 120 days following the last dose of telaglenastat or pembrolizumab, or through 180 days following the last dose of chemotherapeutic drugs iii. Postmenopausal females (no menses for \> 1 year without an alternate medical cause) and surgically sterilized females are exempt from these requirements b. Male patients who are sexually active with heterosexual partners of childbearing potential must agree to contraceptive requirements outlined in Section 8.1.2 and refrain from donating sperm during the study through 120 days following the last dose of telaglenastat or pembrolizumab, or through 180 days following the last dose of chemotherapeutic drugs Exclusion Criteria: 1. Squamous cell histology and mixed histology tumors with any small-cell/neuroendocrine component (other mixed histology should be reviewed with the medical monitor for eligibility) 2. Any other concurrent malignancy requiring local or systemic therapy. Patients with other previously treated malignancy(ies) are allowed if the specific neoplasm, in the opinion of the principal investigator and with the agreement of the medical monitor, is not expected to interfere with study-specific endpoints 3. Radiation therapy to the lung \> 30 Gy within 6 months prior to randomization 4. Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, abdominal carcinomatosis 5. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs) a. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 6. Treatment with chronic systemic steroids greater than 10 mg equivalent of prednisone per day 7. Unstable/inadequate cardiac function, defined as the following: 1. Myocardial infarction or symptomatic ischemia within 6 months prior to randomization 2. Uncontrolled or clinically significant conduction abnormalities (e.g., patients with ventricular tachycardia on anti-arrhythmics are excluded; patients with 1st degree atrioventricular \[AV\] block or asymptomatic left anterior fascicular block \[LAFB\]/right bundle branch block \[RBBB\] are eligible) 3. Congestive heart failure (New York Heart Association class III to IV) 8. Unable to swallow oral medications 9. Known sensitivity to any component of the study treatment (pembrolizumab, carboplatin, pemetrexed, and/or telaglenastat) or previous severe hypersensitivity to another monoclonal antibody (mAb) 10. Unable or unwilling to take folic acid or vitamin B12 supplementation (per pemetrexed label) 11. Unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) as specified in pemetrexed label 12. Interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoid treatment 13. Unable or unwilling to discontinue proton pump inhibitor (PPI) use ≥ 5 days prior to randomization 14. Patient known to be positive for Human Immunodeficiency Virus (HIV) 15. Known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hepatitis C antibody result and known quantitative Hepatitis C virus RNA results greater than the lower limits of detection of the assay. Patients receiving antiviral therapy for Hepatitis B or C also are not eligible 16. Any condition including social, psychiatric or medical (including uncontrolled significant concurrent illness) that in the opinion of the Investigator could interfere with treatment or protocol-related procedures 17. Regular use of illicit drugs or history (within past year) of substance abuse (including alcohol) 18. Patients who are pregnant or lactating 19. Major surgery \< 3 weeks prior to randomization. In addition, patients with ongoing clinically relevant complications from prior surgery are not eligible and they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment 20. Any radiation therapy within 2 weeks prior to randomization (with exception of SRS for brain metastases). In addition, patients with ongoing clinically relevant complications from prior radiation therapy, patients requiring corticosteroids to treat radiation toxicity and patients who developed radiation pneumonitis are not eligible. 21. Symptomatic ascites or pleural effusion. Patients who are clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) are eligible 22. Refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, significant small bowel resection or gastric bypass surgery, use of feeding tubes or other situation that may preclude adequate absorption or oral study drug 23. Infection requiring more than 5 days of parenteral antibiotics, antivirals, or antifungals within two weeks prior to randomization. Anti-infective therapy must be completed at least 7 days before randomization 24. Patients with active and/or untreated central nervous system metastasis including carcinomatous meningitis (leptomeningeal disease) are not eligible. Patients with previously treated brain metastases are eligible if they meet the following criteria: 1. Received definitive treatment with stereotactic radiosurgery (SRS) or surgery to all known central nervous system (CNS) lesions (whole brain radiotherapy is not an eligible modality) 2. Be at least 4 weeks post-surgical resection of CNS disease, symptomatically stable and off steroids before randomization 25. Any live-virus vaccination within 28 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist ®) are live attenuated vaccines and are not allowed 26. Has had an allogeneic tissue/solid organ transplant