Evaluating Modifiable Biomarkers for the Prediction of Immunotherapy Response and Toxicity

Inclusion Criteria:

* Histologically or cytologically confirmed stage IV non-squamous non-small cell lung cancer (NSCLC) (includes M1a, M1b stage disease, and American Joint Committee on Cancer (AJCC) 7th edition. Patients with T4NX disease (stage IIIB) with nodule in ipsilateral lung lobe are eligible if they are not candidates for combined chemotherapy and radiation.
* Formalin-fixed paraffin-embedded tumor tissue from a procedure performed within 6 months prior to registration is available for submission following registration. Formalin-fixed paraffin-embedded tumor tissue within six months of randomization available for analysis.
* PD-L1 expression tumor proportion score (TPS) \>= 1% in tumor cells, using the MERCK Food and Drug Administration (FDA) approved test as performed by local laboratories at the participating institutions.
* Patients must have measurable or non-measurable disease per the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Presence of malignant pleural fluid alone is allowed as study eligibility.
* Age \>=18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
* Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study.
* Absolute neutrophil count (ANC) \>= 1500/mm\^3 (within 14 days of randomization)
* Platelets \>= 100,000/mm\^3 (within 14 days of randomization)
* Prothrombin time (PT)/international normalized ratio (INR) =\< 1.5 (within 14 days of randomization)

  * Or if patient on therapeutic anticoagulation, PT/INR =\< 3.0
* Partial thromboplastin time (PTT) =\< institutional upper limit of normal (ULN) OR, if patient is on therapeutic anticoagulation, PTT must be =\< 1.5 x ULN (within 14 days of randomization)
* Total Bilirubin =\< 1.5 mg/dL (within 14 days of randomization)
* Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) \< 5 X upper limit of normal (ULN) (within 14 days of randomization)
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 5 X upper limit of normal ULN (within 14 days of randomization)
* Calculated creatinine clearance \>= 45ml/min to be eligible to receive pemetrexed (within 14 days prior to randomization).
* Serum creatinine =\< 1.5 X institutional upper limit of normal (ULN) serum creatinine (within 14 days prior to randomization)

Exclusion Criteria:

* Patients must NOT have received the following:

  * Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC. Patients treated with any prior checkpoint inhibitors for lung cancer are ineligible. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy) is allowed if at least 6 months have elapsed since the prior chemotherapy and registration. Local therapy, e.g. palliative radiation, is allowed as long as a period of 14 days has passed since completion.
* Methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 14 days prior to date of registration will be allowed. Other low-dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required.
* Patient with known EGFR mutations (except exon 20 insertion), BRAF mutation (V600) or ALK or ROS1 translocations that can be treated with oral tyrosine kinase inhibitors are excluded.
* Patients with symptomatic brain metastases are excluded. Patients with treated or asymptomatic brain metastases are eligible if off steroids for at least 14 days. Anticonvulsants are allowed.
* Patients with active malignancy within the last 2 years are excluded (adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years are eligible).
* Patients must not have known pre-existing and clinically active interstitial lung disease.
* Patients must not have significant gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption, etc.)
* Patients must not have history of auto-immune condition requiring ongoing or intermittent systemic treatment.
* Patients must not have history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia, or myocardial infarction within 6 months.
* Patients must not have any other concomitant serious illness or organ system dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug.
* Patients must not plan to receive any other investigational agents during the course of therapy.
* Women must not be pregnant or breast-feeding due to potential harm to the fetus or infant from cytotoxic chemotherapy and the unknown risk of pembrolizumab.

  * All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.
  * A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).