Inclusion Criteria:

          -  Histologically confirmed, stage IV NSCLC, with advanced or metastatic disease

          -  Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in
             combination with other EGFR mutations) as per local assessment of a tissue
             biopsy/cytology specimen. The tissue biopsy must have been obtained since the time of
             disease progression on most recent targeted therapy. "Liquid" biopsies (i.e. blood
             based) biopsies cannot be used for eligibility determination

          -  Patients must have had progressive disease on prior EGFR inhibitor therapy (gefitinib,
             erlotinib, afatinib, or osimertinib). There is no limit to lines of prior tyrosine
             kinase inhibitor (TKI) therapy. Prior AZD9291 (osimertinib) therapy is permitted

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
             x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
             imaging (MRI), or calipers by clinical exam

          -  NSCLC is exceedingly rare in patients < 18 years of age. Because no dosing or adverse
             event (AE) data are currently available on the use of CB-839 HCl (telaglenastat) in
             combination with AZD9291 in patients < 18 years of age, children are excluded from
             this study

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Must be able to swallow pills

          -  Life expectancy > 3 months

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 90 g/L

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) and up to 3 mg/dL
             for patients with Gilbert's disease

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN and =< 5 x institutional ULN for patients with liver
             metastases

          -  Creatinine within 1.5 x ULN OR

          -  Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (measured or calculated by
             Cockcroft and Gault equation) - confirmation of creatinine clearance is only required
             for patients with creatinine levels above institutional upper limit of normal

          -  If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be
             undetectable on suppressive therapy if indicated

          -  If history of hepatitis C virus (HCV) infection, must be treated and have an
             undetectable HCV viral load

          -  Patients with treated brain metastases are eligible if follow-up brain imaging after
             central nervous system (CNS) - directed therapy shows no evidence of progression

          -  Patients with new or progressive brain metastases (active brain metastases) or
             leptomeningeal disease are eligible if the treating physician determines that
             immediate CNS specific treatment is not required and is unlikely to be required during
             the first cycle of therapy. Patients on corticosteroids for the treatment of brain
             metastases will be permitted as long as the dose is =< 10 mg of prednisone-equivalent
             and has not been increased within 2 weeks of screening

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class 2B or better

          -  Ability to understand and the willingness to sign a written informed consent document.
             Participants with impaired decision-making capacity (IDMC) who have a
             legally-authorized representative (LAR) and/or family member available will also be
             eligible

          -  EXPANSION COHORT: Patients must have had progressive disease on prior first line EGFR
             inhibitor therapy with osimertinib

        Exclusion Criteria:

          -  Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have
             residual toxicities > grade 1), with the exception of alopecia

          -  Previous enrollment in the present study

          -  Past medical history of interstitial lung disease, drug-induced interstitial lung
             disease, radiation pneumonitis requiring steroid treatment, or any evidence of
             clinically active interstitial lung disease

          -  Patients who are receiving any other investigational agent within five half-lives of
             the compound or 3 months, whichever is greater. Patients who have received prior
             immunotherapy may be included only if time from last immunotherapy is at least 3
             months (i.e. 90 days)

          -  Spinal cord compression, symptomatic and unstable brain metastases except for those
             patients who have completed definitive therapy, and have had a stable neurological
             status for at least 2 weeks after completion of definitive therapy. Patients may be on
             corticosteroids (=< 10 mg of prednisone-equivalent) to control brain metastases if
             they have been on a stable dose for 2 weeks (14 days) prior to the start of study
             treatment and are clinically asymptomatic

          -  Patients with an uncontrolled intercurrent illness

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to CB-839 HCl (telaglenastat), AZD9291, or other agents used in study.
             Patients with hypersensitivity to any of the inactive excipients thereof should also
             be excluded

          -  Currently receiving (or unable to stop use prior to receiving the first dose of study
             treatment) medications or herbal supplements known to be potent inducers of CYP3A4
             (wash-out periods vary). All patients must try to avoid concomitant use of any
             medications, herbal supplements and/or ingestion of foods with known inducer effects
             on CYP3A4

          -  Pregnant women are excluded from this study because CB-839 HCl (telaglenastat) is a
             glutaminase inhibitor with the potential for teratogenic or abortifacient effects.
             Because there is an unknown but potential risk for AEs in nursing infants secondary to
             treatment of the mother with CB-839 HCl (telaglenastat) and AZD9291, breastfeeding
             should be discontinued if the mother is treated with CB-839 HCl (telaglenastat) and
             AZD9291. Breastfeeding patients will be excluded. These potential risks may also apply
             to other agents used in this study

          -  Patients with a significant history of cardiovascular disease (e.g., myocardial
             infarction [MI], thrombotic or thromboembolic event in the last 6 months)

          -  Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470
                  msec (Fridericia's Criteria for Corrected QT interval [QTc] Calculation:
                  Fridericia's formula QTcF = (QT/RR 0.33). RR is the time from the interval of 1
                  QRS complex to the next measured in seconds and is commonly calculated as (60/HR)

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third
                  degree heart block, second degree heart block)

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, hypokalemia, congenital long QT syndrome, family
                  history of long QT syndrome or unexplained sudden death under 40 years of age in
                  first degree relatives, or any concomitant medication known to prolong the QT
                  interval

               -  Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) as
                  assessed by either multigated acquisition (MUGA) scan or echocardiogram (ECHO)

          -  Patients with active malignancies other than NSCLC or patients with prior curatively
             treated malignancy at high risk of relapse during the study period with the exception
             of localized squamous or basal cell skin cancers, ductal carcinoma in-situ (DCIS), or
             indolent cancer currently on observation (i.e. chronic lymphocytic leukemia [CLL] or
             low-risk prostate cancer)

          -  Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
             hypertension and active bleeding diatheses, which in the investigator's opinion makes
             it undesirable for the patient to participate in the trial or which would jeopardize
             compliance with the protocol, or active infection with human immunodeficiency virus
             (HIV). Screening for chronic conditions is not required

          -  Patients with symptomatic CNS metastases who are neurologically unstable

          -  Patients who are at risk for impaired absorption of oral medication including, but not
             limited to, refractory nausea and vomiting, chronic gastrointestinal diseases,
             inability to swallow the formulated product or previous significant bowel resection
             that would preclude adequate absorption of CB-839 HCl (telaglenastat) and AZD9291

          -  Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and requirements

          -  Involvement in the planning and/or conduct of the study (applies to both investigator
             staff and/or staff at the study site)