Telaglenastat Hydrochloride and Osimertinib in Treating Patients With EGFR-Mutated Stage IV Non-small Cell Lung Cancer

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 osimertinib (AZD9291) 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
* Age \> 18 years. 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 telaglenastat (CB-839) HCl in combination with osimertinib (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
* Should participants with hepatitis B virus (HBV) infection be included, patients are only eligible if they meet all the following criteria:

  * Demonstrated absence of hepatitis C virus (HCV) co-infection or history of HCV co-infection
  * Demonstrated absence of human immunodeficiency virus (HIV) infection
  * Participants with active HBV infection are eligible if they are:

    * Receiving anti-viral treatment for at least 6 weeks prior to study treatment, HBV DNA is suppressed to \<100 IU/mL and transaminase levels are below ULN. Participants with a resolved or chronic infection HBV are eligible if they are:

      * Negative for hepatitis B surface antigen (HBsAg) and positive for hepatitis B core antibody \[anti-HBc IgG\]. In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment and 6-12 months (To be determined \[TBD\] by hepatologist) post treatment OR
      * Positive for HBsAg, but for \> 6 months have had transaminases levels below ULN and HBV DNA levels below \<100 IU/mL (i.e., are in an inactive carrier state). In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment and 6-12 months (TBD by hepatologist) post treatment
* 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 systemic anti-cancer therapy (i.e., have residual toxicities \> grade 1), with the exception of alopecia. Note: Subjects with irreversible toxicity that in the opinion of the treating physician is not reasonably expected to be exacerbated by the investigational treatment may be included (e.g., hearing loss, hormone deficiency requiring replacement therapy)
* 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 telaglenastat (CB-839) HCl, osimertinib (AZD9291), or other agents used in study. Patients with hypersensitivity to 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 telaglenastat (CB-839) HCl 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 telaglenastat (CB-839) HCl and osimertinib (AZD9291), breastfeeding should be discontinued if the mother is treated with telaglenastat (CB-839) HCl and osimertinib (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, electrolyte abnormalities (including: Serum/plasma potassium \< lower limit of normal (LLN); serum/plasma magnesium \< LLN; serum/plasma calcium \< LLN , 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 and cause Torsades de Pointes
  * 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 telaglenastat (CB-839) HCl and osimertinib (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)