Pembrolizumab versus Observation after Surgery for the Treatment of Stage I Non-small Cell Lung Cancer

Inclusion Criteria

• The participant (or legally acceptable representative if applicable) must provide written informed consent for the study. The participant may also provide consent for future unspecified research samples. However, the participant may participate in the study without participating in the future unspecified research sample collection
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 28 days prior to registration
• Patients must have undergone complete surgical resection of their stage I NSCLC between 4-12 weeks prior to registration and have negative surgical margins (R0). * NOTE: Both squamous and non-squamous histologies are allowed into the study. Cancers with a histology of “adenosquamous” are considered a type of adenocarcinoma and thus “non-squamous histology”. * NOTE: Staging will be according to the American Joint Committee on Cancer (AJCC) 8th edition
• Pathological tumor size must be 1.0 – 4.0 cm in greatest dimension
• Surgery for this lung cancer must be completed at least 28 days prior to registration
• Must have either previous next generation sequencing (NGS) and PD-L1 results available using the Dako 22C3 antibody or have archival tissue of surgical specimen from current diagnosis available to perform analyses. If prior PD-L1 results with Dako 22C3 antibody are not available from a Clinical Laboratory Improvement Act (CLIA)-accredited laboratory, subjects must be able to provide 5 um x 4 unstained slides for prospective analysis to be used for stratification. If NGS results are not available, subjects must be able to provide at least 10 x 10 um unstained and 1 x 4 um hematoxylin and eosin (H&E) slides from current diagnosis for future NGS and/or other genetic analyses
• Absolute neutrophil count (ANC) >= 1500 K/mm^3 (obtained within 28 days prior to registration)
• Hemoglobin (Hgb) >= 9 g/dL or >= 5.6 mmol/L (obtained within 28 days prior to registration) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Platelets >= 100,000/uL (obtained within 28 days prior to registration)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min if creatinine levels > 1.5 x ULN (obtained within 28 days prior to registration) * Creatinine clearance (CrCl) should be calculated per institutional standard
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN. Documented Gilbert syndrome is allowed if total bilirubin =< x ULN (obtained within 28 days prior to registration)
• Aspartate aminotransferase (AST) =< 2.5 x ULN (obtained within 28 days prior to registration)
• Alanine aminotransferase (ALT) =< 2.5 x ULN (obtained within 28 days prior to registration)
• International normalized ratio (INR) or prothrombin time (PT) activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulation as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (obtained within 28 days prior to registration)
• Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. For subjects randomized to the pembrolizumab arm: If there is > 72 hours between the screening test and cycle 1 day 1 (C1D1), another pregnancy test (urine or serum) must be performed and must be negative before the subject may start C1D1. * NOTE: Females are considered of childbearing potential unless: they are postmenopausal; are surgically sterile; or they have a congenital or acquired condition that prevents childbearing * NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP who is using a highly effective contraceptive method (failure rate of < 1% per year), or is abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) during the intervention period and for at least 120 days after the last dose of study drug. The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study drug
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

Exclusion Criteria

• Current lung cancer is < 1 cm or > 4 cm in size or is stage II, III, or IV
• Patients with tumors that are known to harbor actionable EGFR mutations
• Prior chemotherapy, radiation therapy, or immunotherapy for the treatment of this lung cancer
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. * NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma in situ, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
• Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. * Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization
• Has had an allogenic tissue/solid organ transplant
• Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) * Note: HIV testing is not required unless mandated by local health authority
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. * Note: Hepatitis B and hepatitis C testing is not required unless mandated by local health authority
• Has active TB (Bacillus Tuberculosis) infection
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment