Breast Cancer Study of Preoperative Pembrolizumab + Radiation

With more than 1 million new cases diagnosed yearly worldwide, breast cancer is a global
public health burden. Over the past decade, molecular subtyping of breast cancer has
identified intrinsic subtypes that may be at enhanced risk for both local and distant
recurrence. This study focuses on the immunogenicity of high-risk breast cancer subtypes that
are likely to display a dense lymphocytic infiltration including including TNBC and HR+/HER2-
tumors.

Immune build up via immune co-stimulatory molecules permits the ensuing immune response to
strengthen and destroy cancer systemically. Thus, the effect of the anti-tumor immune
response initiated by the radiation to an intact tumor by combination with checkpoint
blockade is increased.

Pembrolizumab is an optimal immunotherapy agent to study, as this agent has recently been FDA
approved for use in multiple tumor types. It is therefore ready to be tested for efficacy in
other disease sites and in combination with other treatments.

Inclusion Criteria:

- Confirmed histologic diagnosis of invasive adenocarcinoma of the breast, and

- ER, PR and HER2 testing (on outside or Cedars-Sinai biopsy report), and

- High-risk, ER-positive and HER2-negative breast cancer patients. ER-positive
disease is defined as ER>10%, any PR and HER2-negative by ASCO CAP guidelines.
High-risk disease will be defined by the presence of at least 2 of the following
3 criteria: histologic grade II-III, Ki-67 > 20%, ER expression < 75% by IHC)

- TNBC patients (defined as ER<10%, PR<10%, HER2-neu 0-1+ by IHC or FISH-negative;
or as per MD discretion)

- Operable tumor measuring ≥2 cm in maximal diameter as measured by any available
standard of care imaging (mammogram, breast ultrasound, breast MRI)

- Any nodal status

- Multifocal disease is permitted; largest focus must measure ≥2 cm

- Synchronous bilateral invasive breast cancer is permitted

- No indication of distant metastases

- Breast-conserving therapy is planned

- Tumor amenable to preoperative radiation therapy boost as determined by radiation
oncologist

- ECOG performance status score of 0 or 1

- Screening laboratory values must meet the following criteria:

i. White blood cells (WBCs) ≥ 2000/μL ii. Absolute neutrophil count (ANC) ≥ 1500/μL
iii. Platelets ≥ 100 x 103/μL iv. Hemoglobin ≥ 11.0 g/dL v. Serum creatinine ≤ 2 mg/dL
(or glomerular filtration rate ≥ 40 ml/min) vi. AST ≤ 2.5 x upper limit of normal
(ULN) vii. ALT ≤ 2.5 x ULN viii. Bilirubin within normal limits (except subjects with
Gilbert's syndrome, who must have total bilirubin < 3.0 mg/dL) ix. Negative HIV
screening test x. Negative screening tests for Hepatitis B and Hepatitis C.

Patients with positive results that do not indicate true active or chronic infection may
enroll after discussion and consensus agreement by the treating physician and principal
investigator.

- Women of childbearing potential (WOCBP) must be using an acceptable method of
contraception to avoid pregnancy throughout the study and for at least 4 months after
the last dose of pembrolizumab in such a manner that the risk of pregnancy is
minimized. See below for the definition of WOCBP.

- WOCBP must have a negative serum pregnancy test within 14 days prior to the first dose
of pembrolizumab.

- Women must not be breastfeeding.

- Willingness to adhere to the study visit schedule and the prohibitions and
restrictions specified in this protocol.

- Willingness to undergo mandatory Week 4 research biopsy

- Written informed consent obtained from subject and ability for subject to comply with
the requirements of the study.

Exclusion Criteria:

- HER2-positive breast cancer defined as IHC3+ or IHC2+ with FISH>2 AND copy number >4
OR FISH <2 AND copy number >6

- Inflammatory breast cancer

- Contraindication(s) to breast-conserving therapy

- Contraindication to radiation therapy or planned partial breast irradiation

- Patients with cosmetic breast augmentations, specifically sub glandular implants with
altered breast tissue, at the time of diagnosis

- Medical history and concurrent diseases

- Subjects with active, known or suspected autoimmune disease. Subjects with
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external
trigger are permitted to enroll.

- Any serious or uncontrolled medical disorder that, in the opinion of the
investigator, may increase the risk associated with study participation or study
drug administration, impair the ability of the subject to receive protocol
therapy, or interfere with the interpretation of study results.

- Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

- Prohibited Treatments and/or Therapies

- Chronic use of immunosuppressants and/or systemic corticosteroids (used in the
management of cancer or non-cancer-related illnesses). However, use of
corticosteroids is allowed for the treatment of immune related Adverse Events
(irAEs), or adrenal insufficiency.

- Any non-oncology vaccine therapy used for prevention of infectious diseases
within 4 weeks prior to first dose of pembrolizumab.

- Prior treatment with pembrolizumab or other PD-1/PD-L1 inhibitor.