Study of Pembrolizumab in Metastatic HER2-negative Breast Cancer Patients With APOBEC3B Mutation

Inclusion Criteria:

1. Female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed HER2-negative breast cancer (infiltrating ductal or lobular breast carcinoma) with measurable metastatic disease.
2. Must have received at least one but not more than three (3) prior lines of palliative chemotherapy for metastatic breast cancer.
3. Have received at least one line of hormonal therapy in the metastatic setting, for patients with ER+ (positive) breast cancer.
4. Documented germline APOBEC3B mutation (i.e. germline deletion).
5. Can provide archival tumour tissue sample or willing to provide tissues from a newly obtained core or excisional biopsy of a tumour lesion not previously irradiated. Note: Formalin-fixed, paraffin embedded (FFPE) tissue blocks or slides allowed (10 unstained slides are needed);
6. Have measurable disease based on RECIST 1.1 as determined by local radiology review. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
7. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (assessed within 10 days prior to the start of study treatment).
8. Have life expectancy of at least 3 months.

9. Have adequate organ function, within 10 days prior to the start of study treatment, as defined in the following:

   1. Absolute neutrophil count (ANC) ≥ 1,500/µl.
   2. Hemoglobin (Hb) ≥ 9 g/dL or 5.6mmol/La.
   3. Platelets > 100,000/µl.
   4. Creatinine ≤ 1.5 times ULN.
   5. ALT (SGPT) and AST (SGOT) ≤ 2.5 times the ULN (≤5 times for patients with liver metastases).
   6. Total bilirubin ≤ 1.5 mg/dL.
10. LDH ≤2.0 times the ULNWomen of child-bearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study treatment.
11. Women of child-bearing potential prepared to use adequate contraceptive measures if sexually active for the course of the study through 120 days after the last dose of treatment.
12. Have signed informed consent and able to comply with scheduled visits, treatment plan and other study procedures.

Exclusion Criteria:

1. Has HER2-positive breast cancer (FISH/CISH confirmed status, or 3+ IHC status)
2. Has use of any investigational agent or participation in another therapeutic clinical trial concurrently or in the 30 days prior to inclusion.
3. Has not recovered (e.g. to ≤Grade 1 or to baseline) from AEs due to a previously administrated therapy. Note: Participants with ≤Grade 2 neuropathy may be eligible.
4. Has an active autoimmune disease that has required systemic treatment in the past 2 years (e.g. with the use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systematic treatment.
5. Has a diagnosis of immunodeficiency or is receiving systematic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study treatment.
6. Has a concurrently active second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Subjects with other non-mammary malignancies must have been disease-free for at least 5 years.
7. Has known active CNS metastases and/or carcinomatous meningitis. Previously treated brain metastases may participate provided these remain stable.
8. Has received prior therapy with an anti-PD1, anti-PDL1 or anti-PDL2 agent or with an agent directed to another co-inhibitory T cell receptor (such as CTLA-4, OX-40, and CD137) or has previously participated in pembrolizumab clinical studies.
9. Patient who has received a live vaccine within 30 days of the first dose of study drug.
10. Known hypersensitive or allergy to pembrolizumab and any of its components.
11. Patient who is pregnant or breastfeeding.
12. Patient with an expected life expectancy of less than 3 months.
13. History of significant comorbidities that, in the opinion of the investigator, may interfere with the conduct of the study, the evaluation of response, or with informed consent.
14. Active uncontrolled infection at the time of inclusion.
15. Has a history of class II-IV congestive heart failure or myocardial infraction.
16. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of this study
17. Has evidence of active pneumonitis, or non-infectious pneumonitis requiring treatment with steroids.
18. Has a known history of Human Immunodeficiency Virus (HIV).
19. 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.