• Patients must have histologically confirmed stage IV non-small cell lung cancer.

• Male or female patients \>=18 years of age

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

• Documented activating EGFR mutation (Exon 19 deletion, Exon 19 insertion, E709K, G719X, S768I, V769L, T790M, L833F, L833V, V834L, H835L, L858R, A859S, K860I, L861Q, A871E, V843I, or H870R) on tumor sample or cell-free DNA sample performed in Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory.

• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

• Clinical laboratory values as specified below within 7 days before the first dose of study drug (if applicable):

∙ Absolute neutrophil count (ANC) \> 1500/mm\^3

‣ Absolute lymphocyte count \> 500 mm\^3

‣ Platelets \> 100,000/mm\^3

‣ Hemoglobin (Hgb) \> 9 g/dL. Values must be obtained without need for red blood cell transfusion support within 14 days. However, erythrocyte growth factor is allowed as per published American Society of Clinical Oncology (ASCO) guidelines.

‣ Total bilirubin ≤ 1.5 x upper limit of normal (ULN). Patients with Gilbert's syndrome may be allowed on study if total bilirubin is \<= 3 x upper limit of normal (ULN) if direct bilirubin is \<= 1.5 x upper limit of normal (ULN).

‣ Serum glutamic-oxaloacetic transaminase (SGOT) / aspartate aminotransferase (AST) and serum glutamic-pyruvic transaminase (SGPT) / alanine aminotransferase (ALT) \< 2.5 x ULN. AST and/or ALT may be up to 5 x ULN if with known liver metastases.

‣ Renal function as defined by calculated creatinine clearance \>=30 ml/min (Cockcroft-Gault Formula).

• Willing to provide blood and tissue for correlative research purposes.

• Willing to undergo pre-treatment research biopsy, OR donate archived tissue from a biopsy performed within 60 days of the first dose of study drug is available.

• Female patients who:

∙ Are postmenopausal (see Appendix 6) for at least 1 year before the screening visit, OR

‣ Are surgically sterile, OR

‣ If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time (see Appendix 6), from the time of signing the informed consent through 180 days after the last dose of study drug, OR

‣ Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

⁃ Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

• Agree to practice effective barrier contraception during the entire study treatment period and through 120 after the last dose of study drug, OR

∙ Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

⁃ Voluntary written consent must be given before performance of any study-related procedure not part of standard of care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

⁃ Currently receiving and tolerating osimertinib 80 mg PO daily with no current grade 2 or greater AE attributable to osimertinib.

⁃ Evidence of disease progression on imaging (computerized tomography (CT) scan, magnetic resonance imaging (MRI), or Positron Emission Tomography (PET) CT within the last 30 days.

⁃ Resolution of all acute toxic effects of prior chemotherapy, immunotherapy, radiotherapy or surgical procedures to less than or equal to grade 2 per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

⁃ Patients must have received no more than one additional line of systemic therapy to treat lung cancer other than osimertinib (re-treatment with osimertinib after other systemic lung cancer therapy will not count as a line of therapy). A line of therapy equals at least one month of treatment with discontinuation of therapy due to disease progression or intolerability. Patients who have received adjuvant or neoadjuvant osimertinib, chemotherapy, or immunotherapy for surgically resectable NSCLC, or chemotherapy + radiation +/- immunotherapy for locally advanced NSCLC, will not be considered a line of therapy if it is equal to or greater than 12 months since completing their treatment.

⁃ Patients must be currently receiving osimertinib 80 mg for the treatment of metastatic disease or have evidence of metastatic disease recurrence while receiving adjuvant osimertinib therapy.

⁃ Currently receiving osimertinib 80 mg as 1st line therapy for metastatic NSCLC. Patients who have received adjuvant or neoadjuvant, chemotherapy, or immunotherapy for surgically resectable NSCLC, or chemotherapy + radiation +/- immunotherapy for locally advanced NSCLC, will be allowed if it is equal to or greater than 12 months since completing their treatment.

⁃ Meet RECIST 1.1 criteria for PR or SD to osimertinib, including a confirmation scan.

⁃ Have received osimertinib 80 mg for a minimum of 90 days, but no more than 180 days.

⁃ Willing to undergo pre-treatment research biopsy, if deemed safe by the investigator, or willing to donate archived tissue from a biopsy performed within 60 days prior to the first dose of study drug. Note: Pre-treatment tissue is mandatory for Cohort C and will be used for a CLIA-approved TP53 mutation test during screening. To be eligible for Cohort C, patients must not have a known TP53 missense mutation, nonsense mutation, frameshift mutation, in frame deletion, or whole gene deletion (see also exclusion criterion #22).