Minnelide and Osimertinib for the Treatment of Advanced EGFR Mutated Non-Small Cell Lung Cancer

Inclusion Criteria: * Documented informed consent of the participant and/or legally authorized representative * Assent, when appropriate, will be obtained per institutional guidelines * Agreement to two research biopsies * If tumor is unbiopsiable or not safely biopsied, exceptions may be granted with study principal investigator (PI) approval * Age: \>= 18 years * Karnofsky performance \>= 70% * Histologically confirmed advanced non-small cell lung cancer (NSCLC). Patients with locally advanced NSCLC must not be candidates for surgical resection, radiation, or chemoradiation with curative intent * The tumor harbors 1 of the 2 common epidermal growth factor receptor (EGFR) mutations known to be associated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) sensitivity (Ex19del or L858R), either alone or in combination with other epidermal growth factor receptor (EGFR) mutations, which may include T790M * Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * Tumor progression after receiving standard/approved osimertinib * Fully recovered from the acute toxic effects (except alopecia) to =\< grade 1 to prior anti-cancer therapy. Grade 2 neuropathy is allowed * Absolute neutrophil count (ANC) \>= 1,500/mm\^3 (within 14 days prior to day 1 of protocol therapy) * NOTE: Growth factor is not permitted within 14 days of ANC assessment * Platelets \>= 100,000/mm\^3 (within 14 days prior to day 1 of protocol therapy) * …