This phase II trial studies how well pembrolizumab works in treating patients with non-squamous non-small cell lung cancer which has spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVES:

I. To correlate circulating tumor DNA (ctDNA) levels measured using cancer personalized profiling by deep sequencing (CAPP-Seq) with radiographic tumor assessments using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria in patients with metastatic non-squamous non-small cell lung cancer (NSCLC) treated with pembrolizumab.

SECONDARY OBJECTIVES:

I. To correlate PD-L1 assessment on pre-treatment tumor samples with objective response using RECIST v1.1 criteria in patients with metastatic non-squamous NSCLC treated with pembrolizumab.

II. To determine the overall response rate (ORR) using RECIST v1.1 criteria in patients with metastatic non-squamous NSCLC treated with pembrolizumab.

III. To determine the progression-free survival (PFS) using RECIST v1.1 in patients with metastatic non-squamous NSCLC treated with pembrolizumab.

IV. To determine the overall survival (OS) in patients with metastatic non-squamous NSCLC treated with pembrolizumab.

V. To determine the safety and tolerability of pembrolizumab in patients with metastatic non-squamous NSCLC.

Inclusion Criteria:

1. Has a pathologically proven recurrent or metastatic non squamous non small cell lung cancer

2. (a) Previously received at least one line of prior systemic therapy for metastatic disease.

   i. If the patient has a sensitizing EGFR mutation or ALK rearrangement, the patient must have received at least one prior targeted therapy for metastatic disease (ie, EGFR TKI therapy or ALK TKI therapy, respectively).

   ii. There is no limit on prior therapies allowed. Patients must have completed previous treatment (including other investigational therapy) in greater than or equal to the following times prior to initiation of trial treatment:

   1. Anti cancer monoclonal antibody (mAb) therapy must be completed ≥ 3 weeks prior to trial treatment
   2. Chemotherapy administered in a daily or weekly schedule must be completed ≥ 1 week prior to trial treatment
   3. Chemotherapy administered in an every 2 week schedule must be completed ≥ 2 weeks prior to trial treatment
   4. Chemotherapy administered in an every 3 week schedule must be completed ≥ 3 weeks prior to trial treatment
   5. Targeted small molecule therapy must be completed ≥ 1 week prior to trial treatment OR (b) Have not received prior systemic therapy for their cancer in recurrent or metastatic setting, AND have a tumor with Tumor Proportion Score (TPS) ≥ 50% as measured by 22C3 PD L1 IHC test, AND no evidence of a sensitizing EGFR mutation or ALK rearrangement.

3. Prior radiation therapy allowed as long as completed in the following times prior to initiation of trial treatment:

   1. Definitive curative intent radiation ≥ 3 weeks prior to trial treatment
   2. Palliative body radiation ≥ 1 week prior to trial treatment
   3. Stereotactic brain radiation ≥ 1 week prior to trial treatment
   4. Whole brain radiation ≥ 2 weeks prior to trial treatment

4. Patients with previously treated (with radiation or surgery) brain metastases that are stable are allowed. Patients with stable or progressing metastases must have metastases ≤ 1.5 cm, be asymptomatic, and either not be on steroids or be on 10 mg prednisone equivalent or less.

5. Has measurable disease based on RECIST v1.1 criteria

6. Is medically able and willing to undergo needle biopsy of a tumor lesion. PD L1 expression is not required to enroll in the trial.

7. Has life expectancy ≥ 3 months

8. Ability to understand and the willingness to sign a written informed consent document.

9. ≥ 18 years of age on day of signing informed consent

10. ECOG performance status of 0 or 1 (Appendix A)

11. Adequate organ function:

    1. Absolute neutrophil count (ANC) ≥ 1,000/mcL
    2. Platelets ≥ 75,000/mcL
    3. Hemoglobin ≥ 8 g/dL
    4. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance ≥ 50 mL/min for patient with creatinine levels > 1.5 x institutional ULN
    5. Serum total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN
    6. AST (SGOT) and ALT (SGPT) ≤ 3 x ULN OR ≤ 5 x ULN for patients with liver metastases

12. Female patients of childbearing potential must have a negative urine or serum pregnancy test prior to the first dose of trial treatment. They must also agree to two barrier methods or a barrier method plus a hormonal method, or agree to abstain from heterosexual activity, for the course of the study through 120 days after the last dose of trial treatment. Females who have been surgically sterilized or are free from menses for > 1 year (postmenopausal) may enroll.

13. Male patients with a female partner of childbearing potential should agree to use a barrier method of contraception, or agree to abstain from heterosexual activity for the course of the study through 120 days after the last dose of trial treatment.

Exclusion Criteria:

1. Is currently receiving another investigational therapy
2. Has received prior anti PD 1 or anti PD L1 therapy
3. Has clinically significant toxicities from previous anti cancer therapy that have not resolved, or have not stabilized at a new baseline
4. Has undergone a surgical procedure involving general anesthesia within 2 weeks of starting trial treatment, or has inadequate healing or recovery from complications of surgery prior to starting trial treatment. This does not apply to low risk procedures such as thoracentesis; paracentesis; chest tube/PleurX catheter placement; line placement; needle biopsy of tumor; and bronchoscopy.
5. Is receiving high dose systemic steroid therapy within 3 days of trial treatment. Topical and intraarticular steroid injections are allowed, as are physiologic doses of systemic steroids (≤ 10 mg of prednisone equivalent daily).
6. Has carcinomatous meningitis as determined by positive CSF cytology
7. Has known active additional malignancy that is undergoing active treatment.
8. Has active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, supra physiologic doses of systemic corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin; or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Asthma; type I diabetes mellitus; hypothyroidism; and vitiligo are allowed.
9. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator. This includes known active tuberculosis; Grade 3 active infection; history of allogeneic bone marrow transplant or solid organ transplant; known history of Human Immunodeficiency Virus (HIV); known active Hepatitis B (eg, Hep B DNA positive in prior 3 months) or known active Hepatitis C (eg, HCV RNA [qualitative] is detected in prior 3 months).
10. Known active interstitial lung disease, or current (non infectious) pneumonitis or history of (non infectious) pneumonitis that required oral steroids.
11. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting

up to 3 years