Pembrolizumab And Stereotactic Radiosurgery (Srs) Of Selected Brain Metastases In Breast Cancer Patients

Patients with metastatic breast cancer with at least 2 brain metastases, eligible to receive
SRS. Patients will complete radiation therapy within 1 week and Pembrolizumab may be
continued every 3 weeks until evidence of brain progression or serious adverse toxicity.
Patients will be followed until death.

Pembrolizumab will be infused the day before SRS, at the standard dose of 200mg IV over 30
minutes and repeated every 3 weeks until disease progression or unacceptable toxicity.

Inclusion Criteria:

- Age older than 18

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Neurological function status 0, 1, 2

- Pre- or post-menopausal women with metastatic breast cancer, and at least 2
intracranial untreated metastases

- A diagnostic contrast enhanced MRI demonstrating at least 2 and no more than 10
measurable lesions, (>5mm in size), performed within two weeks prior to treatment

- Maximum diameter of treated lesions should be <4cm in size

- Have measurable disease based on RECIST 1.1. Lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated in such
lesions.

- Patient needs to be able to understand and demonstrate willingness to sign a written
informed consent document

- Prior SRS is permitted, however the lesions targeted for treatment on trial need to be
previously untreated by SRS

- Enrolled patients should have a two-week washout period from last systemic treatment

- Patients who have undergone prior subtotal resection are eligible providing that
residual disease is <4cm in maximum diameter

- Continuing a concurrent use of hormonal therapy or HER2neu-targeted therapy is
allowed, if the patient exhibits brain metastases progression during these treatments

- The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.

- Contraception duration of 120 days

- Adequate bone marrow reserve and liver function

Exclusion Criteria:

- Active connective tissue disorders, such as lupus or scleroderma requiring flare
therapy

- Current use of systemic chemotherapy

- Has received 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).

- Patients who have undergone complete resection of all known brain metastases

- Inability to obtain histologic proof of breast cancer

- Target lesion metastasis within 5mm of the optic apparatus so that some portion of the
optic nerve or chiasm would be included in the SRS field

- Prior whole brain irradiation

- Has received prior radiotherapy within 2 weeks of start of study treatment.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

- 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-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, 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 the first dose of study drug.

- Has a known additional malignancy (second primary) 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. cervical
cancer in situ) that have undergone potentially curative therapy are not excluded.

- 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 that required steroids or has current
pneumonitis.

- Has an active infection requiring systemic therapy.Has a known history of Human
Immunodeficiency Virus (HIV). Note: No HIV testing is 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: no testing for Hepatitis B and Hepatitis C is required
unless mandated by local health authority.

- Has a known history of active TB (Bacillus Tuberculosis). Note: optional based on
country.

- 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.