Study of Palliative Radiation Combined with Pembrolizumab in Unresectable Metastatic Stage IV Breast Cancer

Inclusion Criteria:

1. Subject has provided informed consent/assent prior to initiation of any studyspecific activities/procedures.

2. Female age ≥ 18 years at the time of informed consent. 3. Histologicallyconfirmed diagnosis of breast cancer. 4. Disease stage: unresectable ormetastatic stage IV breast cancer. 5. Candidate for palliative SBRT independentfrom study enrollment 6. Measurable disease, defined as at least 1 visceral ornodal/soft tissue breast cancer lesion that can be accurately and seriallymeasured in at least 1 dimension and for which the longest diameter is ≥ 10 mmas measured by Computer Tomography scan or Magnetic Resonance Imaging. Lymphnodes must measure ≥ 15 mm in their short axis to be considered measurable byComputer Tomography scan or Magnetic Resonance Imaging or Positron EmissionTomography-CT.

3. If subject received major surgery, must have recovered adequately from toxicityand/or complications from the intervention prior to enrollment.

4. Subject must have received two prior lines of therapy and include a taxane inthe adjuvant/neoadjuvant or metastatic setting.

5. Triple negative breast cancer patients must have received two lines ofchemotherapy in the metastatic setting.

6. ER+/ PR+, ER-/PR+, and ER+/PR- must have received prior Cyclin Dependent Kinase 4/6 Inhibitor in combination with Aromatase Inhibitor or fulvestrant. However,ER+/Her2 overexpressed patients are not required to have received CDK 4/6inhibitor.

7. Her2 overexpressed breast cancer must have had prior trastuzumab/per (in theneoadjuvant/adjuvant or metastatic setting, and prior Ado-trastuzumab TDM1therapy.

8. Adequate organ function determined within 14 days prior to enrollment,defined as follows:

• Absolute neutrophil (ANC) >1.5 x 109/L
• Platelet count>50 x 109/L
• Hemoglobin>8 g/dL
• Serum creatinine <2.0 x upper limit of normal
• Serum bilirubin < 2.0 x ULN OR direct bilirubin ≤ ULN for a subject withtotal bilirubin level > 2.0 x ULN
• Aspartate aminotransferase (AST) <2.5 x ULN OR <5 x ULN for subject withliver metastases
• Alanine aminotransferase (ALT) <2.5 x ULN OR <5 x ULN for subject withliver metastases
• International normalization ratio (INR) or prothrombin time (PT) <1.5 xULN unless the subject is receiving anticoagulant therapy as long as PTand partial thromboplastin time (PTT)/activated PTT (aPTT) is withintherapeutic range of intended use of anticoagulants
• Lactate dehydrogenase (LDH) levels ≤ 1.5 X upper limit of normal (ULN)within 28 days prior to enrollment
• Female subject of childbearing potential must have a negative urine orserum pregnancy test within 72 hours prior to enrollment. If the urinepregnancy test is positive or cannot be confirmed as negative, a serumpregnancy test will be required.
• ECOG performance status of 0, 1 or 2.

Exclusion Criteria:

1. > 4 Clinically active cerebral metastases. Subjects cerebral metastases may beenrolled, provided that there are less than 4 lesions as these may serve as asite of pallative SBRT

2. History or evidence of any other clinically significant disorder, condition ordisease (with the exception of those outlined above) that, in the opinion ofthe investigator would pose a risk to subject safety or interfere with thestudy evaluation, procedures or completion.

3. Any active autoimmune disease that in the judgement of the PI or sub-I could besignificantly worsened by pembrolizumab

4. Evidence of clinically significant immunosuppression such as the following:

• diagnosis of immunodeficiency;
• concurrent opportunistic infection;
• receiving systemic immunosuppressive therapy (> 2 weeks) or within 7 daysprior to the first dose of study treatment, including oral steroid doses > 20 mg/day of prednisone or equivalent Subjects that require intermittentuse of bronchodilators or local steroid injection will not be excludedfrom the study.

5. Subject has known sensitivity to any of the products or components to beadministered during dosing

6. Known human immunodeficiency virus (HIV) disease.

7. Known acute or chronic hepatitis B or hepatitis C infection.

8. Has undergone prior allogeneic hematopoietic stem cell transplantation withinthe last 5 years. Subjects who have had a transplant greater than 5 years agoare eligible as long as there are no symptoms of Graft versus Host Disease.

9. Has a known history of active Bacillus tuberculosis.

10. Has a history of (non-infectious) pneumonitis that required steroids or currentpneumonitis.

11. Those patients who would not otherwise have an indication for palliative SBRT

12. Prior therapy with tumor vaccine (unless administered in the adjuvant setting).

13. Currently receiving treatment in another investigational device or drug study,or less than 28 days since ending treatment on another investigational deviceor drug study.

14. Expected to require other cancer therapy while on study with the exception oflocal radiation treatment to the site of bone and other metastasis forpalliative pain management. Concurrent endocrine therapy or trastuzumab therapyis allowed if clinically indicated. Concurrent bone modifying agents (includingdenosumab or zoledronic acid) is allowed for patients with bone metastases.

15. Female subject is pregnant or breast-feeding, or planning to become pregnantduring study treatment or 4 months after the last dose of pembrolizumab

16. Female subject of childbearing potential who is unwilling to use acceptablemethod(s) of effective contraception during study treatment or 4 months afterthe last dose of pembrolizumab, whichever is later. Note: Women not ofchildbearing potential are defined as:

• postmenopausal (defined as at least 12 months with no menses without analternative medical cause; in women < 45 years of age a high folliclestimulating hormone follicule stimulating hormone [FSH] level in thepostmenopausal range may be used to confirm a post-menopausal state inwomen not using hormonal contraception or hormonal replacement therapy. Inthe absence of 12 months of amenorrhea, a single FSH measurement isinsufficient.); OR
• have had a hysterectomy and/or bilateral oophorectomy, bilateralsalpingectomy or bilateral tubal ligation/occlusion, at least 6 weeksprior to screening; OR
• has a congenital or acquired condition that prevents childbearing.

17. Subject likely to not be available to complete all protocol-required studyvisits or procedures, and/or to comply with all required study procedures (eg,Clinical Outcome Assessments) to the best of the subject and investigator'sknowledge.