Phase II Anti-PD1 Epigenetic Therapy Study in NSCLC.

Inclusion Criteria

• Patients must have histologically proven stage IIIB, IV or recurrent non-small cell lung cancer. Patients must be willing to undergo a pre-treatment biopsy, either core needle biopsy or equivalent amount or via excisional specimen. (cytology specimen not acceptable for this purpose).
• Patients must have measurable disease, 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. See Section 11 for the evaluation of measurable disease. A CT scan of the abdomen and pelvis is not required for patients with no disease in these areas.
• Age >18 years. Because no dosing or adverse event data are currently available on the use of azacitidine with entinostat, or of Nivolumab, in patients 6 months after adjuvant or neoadjuvant platinum-based chemotherapy, who also subsequently progressed during or after a platinum-doublet regimen given to treat the recurrences, are eligible and do not count as another line of therapy for advanced disease.
• Subjects who received pemetrexed, bevacizumab, or erlotinib as maintenance therapy (nonprogressors with platinum-based doublet chemotherapy) and subsequently progressed after maintenance therapy, are eligible and do not count as a line of therapy. However, subject who received a tyrosine kinase inhibitor after failure of a prior platinum-based therapy, that tyrosine kinase inhibitor therapy would count as an additional line of therapy.
• Patients who have been treated with prior standard of care PD-1/L1 agents, alone or in combination with chemotherapy, are eligible. Patients previously treated on clinical trials with non PD-1/PD-L1 immunotherapy agents are eligible. Patients who have been treated with a PD-1/L1 agent in more than 1 line of therapy (as standard of care or in clinical trial) are not eligible.
• Arm-specific eligibility criteria
• Arm D: Anti-PD-1/PD-L1 treatment naïve patients only
• Arm E & F: Anti-PD-1/PD-L1 treatment experienced patients: Patients must have had refractory (Arm E=less than 24 weeks from first dose of anti-PD-1/PD-L1) or recurrent (Arm F=more than 24 weeks from first dose of anti-PD-1/PD-L1) disease during or after anti-PD-1 or anti-PD-L1 therapy and, in the opinion of the investigator, must be unlikely to benefit from nivolumab monotherapy.
• Patients must have disease amenable to biopsy at the time of enrollment as biopsies are required for study participation.

Exclusion Criteria

• Any active history of a known autoimmune disease. Subjects with vitiligo, type 1 diabetes mellitus, residual hypothyroidism requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Subjects with a history of interstitial lung disease that has required intubation in the past (i.e. such as Asthma or COPD).
• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.
• Patients who are receiving any other anticancer therapy.
• Patients with uncontrolled brain metastases. Patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks without the use of steroids or on stable or decreasing dose of 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Patients with malabsorption in the small intestine or other conditions that would preclude administration of oral medication.
• Prior therapy with DNA methyl