• 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)

‣ NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment

• Hemoglobin \>= 9 g/dL (within 14 days prior to day 1 of protocol therapy)

• Total bilirubin =\< 1.5 X ULN (unless has Gilbert's disease). Total bilirubin \< 3 x ULN in the presence of documented Gilbert's disease (within 14 days prior to day 1 of protocol therapy)

• Aspartate aminotransferase (AST) =\< 2.5 x upper limit of normal (ULN) (if liver metastases are present, then =\< 5 x ULN is allowed) (within 14 days prior to day 1 of protocol therapy)

• Alanine aminotransferase (ALT) =\< 2.5 x ULN if liver metastases are present, then =\< 5 x ULN is allowed) (within 14 days prior to day 1 of protocol therapy)

• Alkaline phosphatase =\< 2.5 x ULN if liver metastases are present, then =\< 5 x ULN is allowed) (within 14 days prior to day 1 of protocol therapy)

• Serum creatinine within normal limits, OR creatinine clearance of \>= 60 mL/min per 24 hour urine test for patients with creatinine levels above ULN (within 14 days prior to day 1 of protocol therapy)

‣ Creatinine clearance (CrCl, by Cockcroft-Gault) is utilized for all patients to allow for evaluation of the effect of CrCl on the minnelide/triptolide exposures

• If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin time (PT) =\< 1.5 x ULN (within 14 days prior to day 1 of protocol therapy)

‣ If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants

• If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN (within 14 days prior to day 1 of protocol therapy)

‣ If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants

• Albumin \>= 3.0 /dL (within 14 days prior to day 1 of protocol therapy)

• Urinalysis - no clinically significant abnormalities (within 14 days prior to day 1 of protocol therapy)

• QT corrected (QTc) =\< 470 ms (using the Bazett's formula)

‣ Note: To be performed within 28 days prior to Day 1 of protocol therapy.

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (within 14 days prior to day 1 of protocol therapy)

‣ If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 weeks after the last dose of protocol therapy. Contraception must be continued following discontinuation of the study drugs for at least five half-lives of both study drugs

‣ Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

⁃ Female patients of childbearing potential must:

• Agree to practice 1 highly effective method of non-hormonal contraception and one additional effective (barrier) method at the same time, 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 is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g. calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

∙ Agree not to donate eggs (ova) during the course of this study or 180 days after receiving their last dose of study drug. Agree not to breast-feed for the duration of treatment through 6 months post treatment.

⁃ Male patients of childbearing potential must:

• Agree to practice effective barrier contraception during the entire study treatment period and 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 \[e.g. calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception. Female and male condoms should not be used together.)

∙ Agree not to donate sperm during the course of this study or within 180 days after receiving their last dose of study drug.

• Patients must be able to swallow and retain oral medications

• Previously tolerant of osimertinib at 80 mg QD