A Randomized Two Arm Phase II Trial of Pembrolizumab Alone or Sequentially Following Single Fraction Non-ablative Radiation to One of the Target Lesions, in Previously Treated Patients With Stage IV NSCLC

This is a Phase 2 randomized two arm phase II trial of pembrolizumab alone or sequentially
following focal radiation to one of the target lesions, in previously treated patients with
stage IV Non-Small Cell Lung Cancer (NSCLC). The primary goal of this trial is to compare the
efficacy of focal radiation (RT) to an index lesion as a way of enhancing the anti-tumor
immune response to pembrolizumab to that of pembrolizumab alone. The primary efficacy
endpoint is overall RECIST-defined response outside the radiation field. To accomplish this
goal 66 patients will be randomized 2:1 (stratified by histology (squamous versus
non-squamous) and refractory versus non-refractory disease) to radiation plus pembrolizumab
or pembrolizumab only, respectively.

Primary Objective: To determine the tumor responses outside the radiation field (abscopal
effect) after radiation followed by pembrolizumab in metastatic NSCLC.

Secondary Objectives:

1. To determine the progression-free and overall survival in patients with NSCLC receiving
pembrolizumab, who receive Single Fraction Radiation Therapy (SFRT)

2. To determine the safety and toxicity of the combination of SFRT and pembrolizumab

3. To examine potential predictive biomarkers in tumor samples and peripheral blood in
patients treated with pembrolizumab and SFRT

4. To determine the local control of SFRT in the radiated lesion, when SFRT is given with
pembrolizumab

5. To evaluate the induction of a T-cell response in patients with metastatic NSCLC treated
with radiation and the effect of radiation

Inclusion Criteria:

- Be willing and able to provide written informed consent/assent for the trial.

- Have measurable disease based on RECIST 1.1.

- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)
prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples
cannot be provided (e.g. inaccessible or subject safety concern) may submit an
archived specimen only upon agreement from the Sponsor and primary investigator.

- Have a performance status of ≤1 ECOG Performance Scale.

- Demonstrate adequate organ function

- Absolute neutrophil count (ANC) ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Hemoglobin ≥ 9g/dL

- Serum creatinine or measured ≤1.5 times the upper limit of normal (ULN) or
measured or calculated creatinine clearance ≥ 60 mL/min for subjects with
creatinine levels >1.5 times the institutional ULN

- Serum total bilirubin ≤ 1.5 X ULN or direct bilirubin ≤ ULN for subjects with
total bilirubin levels > 1.5 ULN

- AST (SGOT) and ALT (SGPT) ≤ 2.5 times ULN or ≤ 5 times ULN for subjects with
liver metastases

- Albumin ≥ 2.5 mg/dL

- Have one measurable lesion of at least 1 cm outside the planned radiation field
(defined as not receiving direct beam from any of the treatment portals).

- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.

- Female subjects of childbearing potential must be willing to use an adequate method of
contraception - Contraception, for the course of the study through 120 days after the
last dose of study medication.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject

- Male subjects of childbearing potential must agree to use an adequate method of
contraception- Contraception, starting with the first dose of study therapy through
120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.

Exclusion Criteria:

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.

- Has a known history of active TB (Bacillus Tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients.

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier.

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent.

- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.

- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
therapy.

- Patient who have previously received radiation overlapping with the current planned
radiation treatment fields are ineligible. Overlap is defined as any tissue falling
within the direct path of both prior and current planned radiation fields.

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

- Patients with active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are clinically stable for at least 4 weeks and, have no evidence of new or
enlarging brain metastases and also are off steroids 3 days prior to dosing with study
medication. Stable brain metastases by this definition should be established prior to
the first dose of pembrolizumab.

- Has had prior chemotherapy, within 2 weeks prior to study treatment. Patients on
targeted therapy (tyrosine kinase inhibitor) may go on the study after 5 days off
therapy.

- Patients who have not recovered (i.e., ≤ Grade 2 or at baseline) from adverse events
due to a previously administered agent.

--Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy. 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 history of (non-infectious) pneumonitis that required steroids, evidence of
interstitial lung disease or active, non-infectious pneumonitis.

- Has an active infection requiring systemic therapy.

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, 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 trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C.

- Has received a live vaccine within 30 days of planned start of study therapy.

- Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®)
are live attenuated vaccines, and are not allowed.