A Randomized Phase II Trial of Adjuvant Pembrolizumab versus Observation Following Curative Resection for Stage I Non-Small Cell Lung Cancer (NSCLC) with Primary Tumors between 1-4 cm.

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.

NOTE: Initial informed consent will remain valid throughout the 12-week period between

surgical resection and study registration unless, in the opinion of the treating

investigator, the participant experiences a significant change in medical or mental

status.

- Males and females age ≥ 18 years at the time of consent.

- 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 AJCC 8th edition.

- Pathological tumor size must be 1.0 - 4.0 cm in greatest dimension. NOTE: According to

AJCC 8th edition, subjects with lepidic predominant adenocarcinoma should be staged

based on their invasive tumor size and not their total tumor size (i.e., subjects with

lepidic predominant tumors whose invasive tumor size is less than 1 cm are not

eligible, even if their total tumor size is 1.0 cm or greater).

- Surgery for this lung cancer must be completed at least 28 days prior to registration.

- Must have either previous 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 CLIA-accredited laboratory, subjects must be able to provide 5 x 5µm 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 10µm unstained and 1 x 4µm

H&E slides from current diagnosis for future NGS and/or other genetic analyses.

- Demonstrate adequate organ function as defined in the protocol; all screening labs to

be 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 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. See Section 5.1.4 for definitions.

- 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. See contraceptive guidance in Section 5.1.4 of the protocol.

- 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 active 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 (eg, CTLA-4, OX-40,

CD137).

- Has received a live or live-attenuated vaccine within 30 days prior to the first dose

of study drug. Administration of killed vaccines is 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 (eg., 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/interstitial lung disease that required

steroids or has current pneumonitis/interstitial lung disease.

- 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.