This is a phase II therapeutic study of adding exemestane therapy in post-menopausal women with advanced non-small cell lung cancer (NSCLC) who are progressing while on treatment with an immune checkpoint antibody (pembrolizumab, atezolizumab, or nivolumab).

Inclusion Criteria

• Recurrent or progressive advanced stage non-small cell lung cancer (no small cell component) with most recent treatment being an FDA approved immune checkpoint inhibitor (pembrolizumab, atezolizumab, or nivolumab) NOTE: Pathology reports documenting the diagnosis of NSCLC are required to be reviewed to confirm outside diagnosis

• Sufficient tumor tissue available from original diagnosis or subsequent biopsy for analysis of estrogen receptor and aromatase - tumor block or a minimum of 5 unstained slides

• Failed at least 1 prior FDA approved treatment for advanced NSCLC. Patients with EGFR/ALK/ROS1 rearrangements should have received an FDA-approved TKI prior to enrollment on this trial.

• Measureable disease by RECIST version 1.1

• Post-menopausal defined as

  • Age ≥ 55 years and 1 year or more of amenorrhea
  • Age < 55 years and 1 year or more of amenorrhea with an estradiol assay < 20 pg/mL
  • Surgical menopause with bilateral oophorectomy

• ECOG performance status 0, 1 or 2

  * Life expectancy of 3 months or more in the opinion of the enrolling investigator and documented in the medical record

• Adequate organ function within 14 days of study enrollment defined as:

  • Hematology:

    ** Absolute neutrophil count (ANC) ≥ 1500/mm³, Platelets ≥ 100,000/mm³, Hemoglobin ≥ 8 g/dL

  • Biochemistry:

    • Total Bilirubin within normal institutional limits
    • AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN), except if there is known hepatic metastasis, wherein transaminases may be ≤ 5 x institutional ULN.
    • Serum creatinine ≤ 1.5 mg/dl or glomerular filtration rate > 50 ml/min

• Must have recovered to CTCAE v 4 Grade 1 or better from the acute effects of any prior surgery, chemotherapy or radiation therapy. Chronic residual toxicity (i.e. peripheral neuropathy) is permitted.

• A minimum time period must elapse between the end of a previous treatment and start of study therapy:

  • 1 week from the completion of radiation therapy for brain metastases
  • 4 weeks from the completion of chemotherapy or any experimental therapy
  • 4 weeks from prior major surgery (such as open biopsy or significant traumatic injury)

• Voluntary written consent before any research related procedures or therapy

Exclusion Criteria

• Known active CNS disease - If patient has history of brain metastases, the brain lesions must have been treated with radiation and/or surgery - patients should be neurologically stable and requiring ≤10mg oral prednisone equivalence of steroids per day
• Any toxicity from immune-related toxicity from prior immune therapy that would preclude further treatment with anti-PD-1/PDL-1 inhibitor or ongoing IR toxicity ≥ Grade 2
• Requiring > 10 mg prednisone equivalence of steroids per day for immune-related toxicity
• Inability or unwilling to swallow study drug
• Any gastrointestinal condition causing malabsorption or obstruction (eg, celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome)
• Currently using hormone replacement therapy (oral or patch) or/and phytoestrogen supplements (i.e. black cohosh)
• Known hypersensitivity to exemestane or its excipients
• Any serious underlying medical condition that, in the opinion of the enrolling physician, would impair the ability of the patient to receive protocol treatment
• Prior malignancy, with the exception of curatively treated squamous cell or basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-year disease-free interval
• Concomitant use of strong CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's wort as these may significantly reduce the availability of exemestane