Azacitidine and Entinostat in Treating Patients With Newly Diagnosed Stage IA-IIIA Non-Small Lung Cancer Undergoing Surgery

Inclusion Criteria:

* Undergoing a diagnostic biopsy, including computed tomography (CT)-guided or bronchoscopic for suspected diagnosis of NSCLC
* Able to understand and sign an informed consent discussing the risks and benefits of obtaining a concurrent research biopsy; patients who have a fresh frozen biopsy available secondary to institutional tissue collection protocols may substitute such a biopsy for the study-required pre-treatment biopsy
* Histologically confirmed diagnosis of operable NSCLC that has not been previously treated
* Clinical stage IA-IIIA
* Appropriate candidate for surgical management, in the opinion of the treating thoracic surgeon
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 at the time of initiation of neoadjuvant epigenetic therapy
* Absolute neutrophil count \> 1,000/mcL
* Platelets \> 100,000/mcL
* Total bilirubin \< 1.5 x institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) \< 2.5 x institutional ULN
* Creatinine \< 1.5 x institutional ULN
* Able to understand and sign an informed consent
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
* Inclusion of women and minorities:

  * Both men and women and members of all races and ethnic groups are eligible for this trial; the coordinating center will be responsible for ensuring each participating site is accruing a representative sample consistent with the estimate of population representation in the site's geographical location for race and ethnic groups as determined by the Census Bureau to assure overall target goals are met

Exclusion Criteria:

* Patients who have received prior chemotherapy or radiation for their diagnosis of lung cancer
* Patients may not be receiving any other investigational agent
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat or 5-azacytidine
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated on this protocol
* Any co-morbid condition that' in the view of the attending physician' renders the patient at high risk from treatment complications
* Human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible
* Known or suspected hypersensitivity to azacitidine or mannitol
* Patients with advanced malignant hepatic tumors
* Use of anti-neoplastic or anti-tumor agents that are not part of the study therapy, including chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy, is not permitted while participating in this study; Note: study participants with stage II or III NSCLC, or stage I NSCLC with tumor size greater than 4 cm, should be offered standard adjuvant platinum-based chemotherapy in accordance with local practice (post-operatively)