• Participants must have histologically confirmed stage IV NSCLC (per AJCC 7th edition) with either the L858R or exon 19 deletion activating EGFR mutation as identified in a CLIA-approved laboratory from tumor tissue.

⁃ -Note: recurrent stage IV disease initially diagnosed at an earlier stage is considered eligible, provided prior treatment criteria is met.

• Participants must have measurable disease at baseline, 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 with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.

• Participants must be aged ≥ 18 years

• Participants must have an ECOG performance status of 0-1 (Appendix A)

• Participants must have normal organ and marrow function as defined below:

‣ absolute neutrophil count ≥1,500/mcL

⁃ platelets ≥100,000/mcL

⁃ hemoglobin \>9.0 g/dL

⁃ total bilirubin \< 1.5 times the ULN if no liver metastases or \< 3 times the ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases

⁃ AST(SGOT)/ALT(SGPT) \<2.5 × institutional upper limit of normal or \<5 times the ULN in the presence of liver metastases

⁃ creatinine ≤ 1.5 x institutional upper limit of normal

‣ \--- OR

⁃ creatinine clearance ≥50 mL/min as determined by the Cockcroft-Gault formula.

⁃ Note: For participants entering study after starting commercial osimertinib, elevations in hepatic transaminases (AST/ALT) and/or total bilirubin \< grade 2 at study entry are acceptable (see protocol Table 2).

• Participants must have biopsy tissue at time of diagnosis available and sufficient for targeted next-generation sequencing. The sequencing can be performed at a commercial vendor such as Foundation Medicine. The testing does not have to be completed prior to study enrollment. If the specimen is insufficient a repeat biopsy will need to be performed.

⁃ -Note: Cytology specimen may be acceptable for baseline NGS if tumor cellular content is sufficient and following PI approval. If there is no cytology specimen or tissue sample available for NGS, plasma-based NGS may be acceptable for enrollment following discussion with PI.

• For participants entering study after starting commercial osimertinib: a tissue sample from the time of diagnosis must be available and sufficient for NGS testing. Participants who have had commercial tumor NGS testing performed on their pre-osimertinib treated specimen do not need NGS repeated as part of this study.

• Participants must be willing to undergo a repeat tumor biopsy during study treatment between cycles 4 and 8 (if considered medically safe) and at the time of disease progression.

• Participants must be ≥2 weeks since any major surgery (excluding vascular access placement, mediastinoscopy, or biopsies performed by an interventional service)

• Male patients should be asked to use barrier contraceptives (i.e., by use of condoms) during sex with all partners who are women of child bearing potential, including pregnant women, during the trial and for a washout period of 4 months. Male patients should avoid procreation for 4 months after completion of trial treatment. Patients should refrain from donating sperm from the start of dosing until 4 months after discontinuing study treatment.

• Female patients (women of child-bearing potential): Willing to use adequate contraception (barrier or abstinence) at least 2 weeks before receiving any study medication, while on treatment with study drug, and for 6 weeks after finishing treatment.

• Female patients: Must not be pregnant or breast-feeding. Women of child-bearing potential must have a negative pregnancy test (urine or serum) prior to start of dosing or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:

‣ a) Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments

⁃ b) Women under 50 years are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution.

⁃ c) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.

• Ability to understand and the willingness to sign a written informed consent document.

• Subjects may enter the study even if they have started their treatment using commercial osimertinib. Subjects may enter the study anytime during the first 3 months of receiving commercial osimertinib therapy (up to 84 days of commercial osimertinib before entering the study). In order to enter the study after starting commercial osimertinib, subjects must meet all eligibility criteria listed above, have baseline and follow up imaging available for review for response assessment, and must not have developed disease progression during the first 3 months of commercial osimertinib therapy.