This phase I trial studies the side effects and best dose of anti-PD-L1/TGFbetaRII fusion protein M7824 (M7824) when given together with radiation therapy in treating patients with hormone receptor positive, HER2 negative breast cancer that has spread to other parts of the body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. M7824 is a drug that targets specific proteins on immune cells in order to activate immune responses against tumor cells. Giving M7824 together with radiation therapy may work better in treating patients with breast cancer.

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) of M7824 and radiation therapy in patients with metastatic hormone receptor positive (HR+)/HER2 negative (-) breast cancer.

II. To evaluate the safety and tolerability of M7824 and radiation therapy in patients with metastatic HR+/HER2- breast cancer.

SECONDARY OBJECTIVES:

I. To assess immunologic/molecular responses, specifically percentage (%) change in tumor-infiltrating lymphocytes (TIL) pre and post therapy to M7824 and radiation therapy in patients with HR+/HER2- metastatic breast cancer.

II. To explore progression free survival (PFS) and overall survival (OS) to power future definitive trial.

III. To evaluate the in-field and abscopal effect of treatment with anti-PD-L1/TGF-beta trap (M7824) and radiation therapy.

EXPLORATORY OBJECTIVES:

I. To characterize the effect of anti-PD-L1/TGF-beta trap (M7824) and radiation therapy on immune biomarkers including PD-L1 expression and fibrosis changes in tumor microenvironment in tumor tissue obtained from subjects pre- and post-treatment.

II. To characterize circulating immune cell populations and cytokine profiles in tumor and circulation following treatment with M7824.

III. To conduct ribonucleic acid sequencing (RNAseq), RNA Scope, whole exome sequencing (WES) targeted sequencing and tissue IO gene expression.

OUTLINE:

Patients receive M7824 intravenously (IV) over 1 hour every 14 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Beginning within 3 days after second dose of M7824, patients undergo radiation therapy once a day (QD) for 5-10 days depending on the site of disease in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 90 days.

Inclusion Criteria:

• Is willing and able to provide written informed consent for the trial and has signed the appropriate written informed consent form, approved by the investigator's Institutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to the performance of any trial activities.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Highly effective contraception for both male and female subjects if the risk of conception exists. Highly effective contraception must be used 30 days prior to first trial administration, for the duration of trial treatment, and at least for 4 months after stopping trial treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately.
• Has confirmed HR+ and HER2 negative breast cancer with known metastatic disease. HR defined as positive if expression greater than 10% by immunohistochemistry (IHC). HER2 negative or non-amplified is determined by the current American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) criteria which are as follows: HER2 testing by IHC as 0 or 1+. If HER2 is 2+, ISH (in situ hybridization) must be performed. HER2 is positive if: i. IHC 3+ based on circumferential membrane staining that is a. complete, intense ii. ISH positive based on: a. single-probe average HER2 copy number >= 6.0 signals/cell. b. Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number >= 4.0 signals/cell c. Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number < 4.0 signals/cell d. Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell.
• Has at least 2 identified sites of metastatic disease by imaging.
• Has received no more than 5 previous lines of chemotherapy and has received at least one line of therapy with an endocrine therapy or endocrine therapy combination.
• White blood cell (WBC) count >= 3 x 10^9/L.
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.
• Lymphocyte count >= 0.5 x 10^9/L.
• Platelet count >= 100 x 10^9/L.
• Hemoglobin (Hgb) >= 9 g/dL.
• Total bilirubin level =< 1.5 x the upper limit of normal (ULN).
• Aspartate aminotransferase (AST) level =< 2.5 x ULN.
• Alanine aminotransferase (ALT) level =< 2.5 x ULN.
• International normalized ratio (INR) < 1.5.
• Adequate renal function defined by an estimated creatinine clearance > 30 mL/min according to the Cockcroft-Gault formula or be measure for creatinine clearance from 24 hour urine collection.
• Has not had major surgery within 28 days prior to starting study treatment. Central venous access surgeries and/or placements would not be considered as major surgery.
• Is eligible for palliative radiotherapy as determined by the treating radiation oncologist.

Exclusion Criteria:

• Anticancer treatment within 14 days before the start of trial treatment (e.g., cytoreductive therapy, radiotherapy [with the exception of palliative radiotherapy delivered in a normal organ-sparing technique], immune therapy, or cytokine therapy).
• Major surgery as determined by the investigator within 28 days before the start of trial treatment (prior diagnostic biopsy is permitted).
• Systemic therapy with immunosuppressive agents within 7 days before the start of treatment; or use of any investigational drug within 28 days before the start of trial treatment.
• Subjects with active central nervous system (CNS) metastases with significant neurological compromise or symptoms are excluded. Subjects with a history of treated CNS metastases (by surgery or radiation therapy), who show no evolving new neurological symptoms are eligible for the study.
• Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
• Significant acute or chronic infections including, among others: a. Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. b. Active hepatitis B virus (HBV) (HBV surface antigen positive) or hepatitis C virus (HCV) (HCV RNA positive). c. Subjects with known active tuberculosis (history of exposure or history of positive tuberculosis test plus presence of clinical symptoms, physical or radiographic findings).
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: a. subjects with type I diabetes, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible b. subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses 10 mg of prednisone or equivalent per day.
• Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association classification class > II), or serious cardiac arrhythmia.
• Clinically relevant diseases (for example, inflammatory bowel disease) and /or uncontrolled medical conditions, which, in the opinion of the investigator, might impair the subject's tolerance or ability to participate in the trial.
• Vaccine administration within 4 weeks of M7824 administration. Vaccination with live vaccines while on trial is prohibited. Administration of inactivated vaccines is allowed (for example, inactivated influenza vaccines).
• Pregnancy and breast feeding.
• History of conditions associated with bleeding diatheses.