• Event-free Survival (EFS) [ Time Frame: Up to approximately 6 years ]
  EFS is defined as the time from randomization to the first occurrence of any of the following events:

  • Local, regional, or distant recurrence of disease as assessed by:
    • Radiographic recurrence by blinded independent central review (BICR)
    • Positive pathology by local assessment
    • Physical examination by local assessment confirmed by positive pathology and/or radiographic recurrence by BICR OR
  • Death due to any cause. EFS will be presented.
• Overall Survival (OS) [ Time Frame: Up to approximately 6 years ]
  OS is defined as the time from date of randomization to date of death from any cause. OS will be presented.

• Time to Death or Distant Metastases (TDDM) [ Time Frame: Up to approximately 6 years ]
  TTDM is defined as the time from randomization to the first documented distant metastases or death from any cause, whichever occurs first. The TDDM will be presented.
• Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to approximately 6 years ]
  An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE will be presented.
• Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 6 years ]
  An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented.
• Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Score [ Time Frame: Baseline and up to approximately 52 weeks ]
  The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" are scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall outcome. The change from baseline in Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score will be presented.
• Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Cough (Item 31) Score [ Time Frame: Baseline and up to approximately 52 weeks ]
  The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question "How much did you cough?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. The change from baseline in cough (EORTC QLQ LC13 Item 31) score will be presented.
• Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Chest Pain (Item 10) Score [ Time Frame: Baseline and up to approximately 52 weeks ]
  The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question "Have you had pain in your chest?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. The change from baseline in chest pain (EORTC QLQ-LC13 Item 40) score will be presented.
• Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Dyspnea (Item 8) Score [ Time Frame: Baseline and up to approximately 52 weeks ]
  The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question "Were you short of breath?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A lower score indicates a better outcome. The change from baseline in dyspnea (EORTC QLQ-C30 Item 8) score will be presented.
• Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Physical Functioning (Items 1-5) Score [ Time Frame: Baseline and up to approximately 52 weeks ]
  The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score will be presented.

The purpose of this study is to assess the efficacy and safety of stereotactic body radiotherapy (SBRT) plus pembrolizumab (MK-3475) in the treatment of adult participants with unresected stage I or IIA non-small cell lung cancer (NSCLC).

The primary study hypotheses are:

1. SBRT plus pembrolizumab prolongs Event-free Survival (EFS) compared to SBRT plus placebo (normal saline solution), and
2. SBRT plus pembrolizumab prolongs Overall Survival (OS) compared to SBRT plus placebo.

• Radiation: Stereotactic Body Radiotherapy (SBRT)
  SBRT
• Biological: Pembrolizumab
  IV infusion
  Other Names:

  • MK-3475
  • KEYTRUDA®
• Drug: Placebo
  IV infusion
  Other Name: Normal saline solution

• Experimental: SBRT+Pembolizumab
  Participants receive SBRT once every 3 days for 3-5 fractions (dependent on tumor type/location; 45-54 Gray [Gy] total) over approximately 2 weeks PLUS pembrolizumab 200 mg via intravenous (IV) infusion once every 3 weeks for up to 17 cycles (up to approximately 1 year). Each cycle is 21 days.
  Interventions:

  • Radiation: Stereotactic Body Radiotherapy (SBRT)
  • Biological: Pembrolizumab
• Placebo Comparator: SBRT+Placebo
  Participants receive SBRT once every 3 days for 3-5 fractions (dependent on tumor type/location; 45-54 Gy total) over approximately 2 weeks PLUS placebo (normal saline solution) via IV infusion once every 3 weeks for up to 17 cycles (up to approximately 1 year). Each cycle is 21 days.
  Interventions:

  • Radiation: Stereotactic Body Radiotherapy (SBRT)
  • Drug: Placebo

Inclusion Criteria:

• Has previously untreated non-small cell lung cancer (NSCLC) diagnosed by histology or cytology and confirmed as Stage I or IIA NSCLC (American Joint Committee on Cancer, AJCC) by chest computed tomography (CT) and positron emission tomography (PET) scan
• Cannot undergo thoracic surgery due to existing medical illness(es) as determined by the site's multi-disciplinary tumor board. Medically operable participants who decide to treat with stereotactic body radiotherapy (SBRT) as definitive therapy rather than surgery are also eligible, if patient's unwillingness to undergo surgical resection is clearly documented
• Has a Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
• Is able to receive SBRT and does not have an ultra-centrally located tumor
• Has adequate organ function within 7 days prior to the start of study treatment
• A female is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a) not a women of childbearing potential (WOCBP) OR b) A WOCBP who agrees to use study-acceptable contraception during treatment and for at least 120 days after last dose of study treatment
• Has a radiation therapy plan approved by the central radiation therapy quality assurance vendor

Exclusion Criteria:

• Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 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. cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], tumor necrosis factor receptor superfamily member 4 [OX-40], tumor necrosis factor receptor superfamily member 9 [CD137])
• Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or breast
• Has received a live vaccine within 30 days prior to the first dose of study treatment
• 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 the first dose of study treatment
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. A prior NSCLC that occurred and was treated curatively at least 2 years prior to the date of the current diagnosis would be considered a separate primary lung cancer, and therefore an additional malignancy. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast c carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has a known hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has a known history of Hepatitis B or known active Hepatitis C virus infection
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). However, replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency), while systemic, will be permitted for study eligibility.
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
• 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 study treatment
• Has had an allogenic tissue/solid organ transplant