Pembrolizumab and Fulvestrant in Treating Patients with Hormone Receptor Positive, HER2 Negative Advanced or Metastatic Breast Cancer

Inclusion Criteria

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information * NOTE: HIPAA authorization may be included in the informed consent or obtained separately
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 28 days prior to registration
• Histologic or cytologic diagnosis of metastatic breast cancer who has received no more than one line of prior hormonal therapy (other than fulvestrant) or no more than one line of prior chemotherapy for advanced non-resectable/metastatic disease
• Tumor is estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+), HER-2 negative (HER2-). ER and PR positivity is defined as >1%. HER-2 negative is defined as by immunohistochemistry (IHC) (0, 1+) or fluorescence in situ hybridization (FISH). HER2 positive test result includes: Single-probe average HER2 copy number >= 6.0 signals/cell; Dual-probe HER2/ chromosome enumeration probe 17 (CEP17) ratio >= 2.0 with an average HER2; copy number >= 4.0 signals/cell; Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number < 4.0 signals/cell; or Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell. Equivocal findings for IHC as 2+ should be reflexed to FISH. Equivocal results by FISH may be considered with approval from the sponsor-investigator
• Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 28 days prior to registration * NOTE: Bone-only disease is allowed and biopsy is required
• Be willing to provide tissue from a newly obtained core or excisional biopsy of a metastatic tumor lesion * NOTE: Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to study registration. 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-investigator
• Normal cardiac function as determined by treating physician per institutional standards via multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) performed within 28 days prior to registration
• Prior chemotherapy or targeted therapy, no more than one line, must be completed at least 28 days prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to =< grade 1 or baseline
• No more than one prior hormonal therapy (only aromatase inhibitors with or without ovarian suppression or tamoxifen allowed) or radiation therapy must be completed at least 14 days prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen to =< grade 1 or baseline
• Absolute neutrophil count (ANC) >= 1500/mm^3 (performed within 28 days of study registration)
• Platelets >= 100,000/mcL (performed within 28 days of study registration)
• Hemoglobin (Hgb) >=9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (performed within 28 days of study registration)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (CrCl) (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) >= 30 mL/min for subjects with creatinine levels > 1.5 x institutional ULN (performed within 28 days of study registration) * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 28 days of study registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases (performed within 28 days of study registration)
• Albumin >= 2.5 mg/dL (performed within 28 days of study registration)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 28 days of study registration)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 28 days of study registration)
• Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to study registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * NOTE: Females are considered of child bearing potential unless: they are postmenopausal; are surgically sterile; or they have a congenital or acquired condition that prevents childbearing * NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Females and males of reproductive potential must be willing to abstain from heterosexual activity or agree to use an adequate method of contraception. Hormonal contraceptives are contraindicated in this population and are not allowed. Contraception will begin from the time of informed consent through 120 days after the last dose of study drug(s)

Exclusion Criteria

• Is currently receiving an investigational agent or has received an investigational agent or used an investigational device within 28 days of study registration
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration. Subjects are permitted to enroll if they have 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. * NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has a known history of active TB (Bacillus tuberculosis). NOTE: TB testing is not required
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). NOTE: HIV testing is not required
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) * NOTE: Hepatitis B and hepatitis C testing is not required
• Hypersensitivity to pembrolizumab or any of its excipients
• Has had a prior anti-cancer monoclonal antibody (mAb) within 28 days prior to study registration or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 28 days earlier
• Has had prior chemotherapy, hormone therapy (other than fulvestrant), targeted small molecule therapy, or radiation therapy for metastatic breast cancer within 14 days prior to study registration and who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered therapy. Prior fulvestrant, more than one line of chemotherapy or more than one line of non-fulvestrant hormonal therapy excludes participation * 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 study registration, as determined by the enrolling physician
• 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
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has known history of, or any evidence of active, non-infectious pneumonitis
• Has known history of, or any evidence of active interstitial lung disease, class II-IV congestive heart failure, or myocardial infarction within 6 months from randomization
• 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
• Breastfeeding during the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment * NOTE: breast milk cannot be stored for future use while the mother is being treated on study
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• Has received a live vaccine within 30 days of study registration * 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