Overview

This is a Phase 2, randomized, multicenter, double-blind study of the glutaminase inhibitor telaglenastat with standard-of-care pembrolizumab and chemotherapy versus placebo with standard-of-care pembrolizumab and chemotherapy for first line treatment of metastatic disease in patients with KEAP1/NRF2-mutated, stage IV, nonsquamous, non-small cell lung cancer (NSCLC). The study primary endpoints are PFS per RECIST v. 1.1 and safety. KEAP1/NRF2 mutation status (for eligibility) and STK11/LKB1 status (for stratification) will be determined by next generation sequencing. A commercial liquid biopsy (circulating tumor DNA) NGS test will be provided to study participants free of charge.

Eligibility

Inclusion Criteria:

• Histologically or cytologically documented nonsquamous NSCLC
• Stage IV (M1a-c, AJCC 8th Edition) disease not previously treated with systemic therapy for metastatic NSCLC
  1. Patients who received adjuvant or neoadjuvant therapy (with or without immunotherapy) for localized NSCLC are eligible if all adjuvant/neoadjuvant therapy (including immunotherapy) was completed at least 6 months prior to the development of metastatic disease.
• No known actionable mutation in EGFR, ALK, ROS1, BRAF, NTRK or other known actionable mutation for which there is approved therapy.
• Measurable disease per RECIST 1.1.
• Life expectancy of at least 3 months.
• Mutation in KEAP1 or NRF2 documented by NGS from a CAP-accredited and/or CLIA-certified laboratory and STK11/LKB1 mutation status is known for the purpose of stratification.
• Adequate hepatic, renal, cardiac and hematologic function.
• Willingness to use adequate contraception as defined in the study protocol

Exclusion Criteria:

• Squamous cell histology and mixed histology tumors with any small-cell component (other mixed histology and large cell neuroendocrine histology is allowed).
• Known history of malignancy within the past three years except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or other neoplasm that, in the opinion of the principal investigator and with the agreement of the medical monitor, will not interfere with study-specific endpoints.
• Had radiation therapy to the lung > 30 Gy within 6 months prior to randomization.
• Has active autoimmune disease that has required systemic treatment in past 2 years.
• Is currently receiving chronic systemic steroids and/or immunosuppressive drugs.
• Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose 1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
• Unable to swallow oral medications.
• Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb).
• Known positivity for Hepatitis B or C.
• Is unable or unwilling to take folic acid or vitamin B12 supplementation.
• Interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoid treatment.
• Unable or unwilling to discontinue proton pump inhibitors (PPI) at least 5 days before randomization.
• Major surgery within 3 weeks of randomization.
• Symptomatic ascites or pleural effusion.
• Any condition that may preclude adequate absorption of oral study drug.
• 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. Are at least 7 days post SRS and 4 weeks post-surgical resection of CNS disease, symptomatically stable and off steroids before randomization