Anti-PD-1 Monoclonal Antibody in Advanced, Trastuzumab-resistant, HER2-positive Breast Cancer

Inclusion criteria for screening:

• Female gender
• Age ≥ 18 years
• Histologically confirmed breast adenocarcinoma that is unresectable loco-regional, or metastatic.
• Locally confirmed HER2-positivity (immunohistochemistry score 3+) or ERBB2-amplification (Ratio ERBB2/centromeres ≥2.0 or mean gene copy number ≥ 6) of primary tumor or of biopsy from metastatic or unresectable loco-regional lesion.
• Trastuzumab resistant disease, defined by:
• progression of disease while on-treatment with trastuzumab
• recurrence while on adjuvant trastuzumab or within 12 months of completing adjuvant trastuzumab
• Any number of prior lines of anti-HER2 therapy acceptable. Patients for whom the treatment with the current first-line combination of trastuzumab, pertuzumab and taxanes is not an option can be considered for enrollment
• If a patient has received a subsequent anti-HER2 therapy, she must also have progressed on the subsequent therapy.
• Presence of at least one measurable lesion (RECIST 1.1)
• LVEF ≥50%
• Patient agrees to submit an FFPE tumor biopsy for central confirmation of HER2 positivity and central assessment of PD-L1 status.
• Written Informed Consent (IC) for screening procedures and trial participation must be signed and dated by the patient and the Investigator prior to screening.
• Written consent to biological material submission, indicating the patient has been informed of and agrees to tissue and blood material use, transfer and handling, must be signed and dated by the patient and the investigator prior to any procedures specific for this trial, including consent to translational research on FFPE and fresh frozen tumor biopsies in case the patient is enrolled into the trial.
• The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
• Life expectancy >3 months.
• Hematopoietic status:
• Absolute neutrophil count ≥ 1.5 × 109/L,
• Platelet count ≥ 100 × 109/L,
• Hemoglobin ≥ 9 g/dL
• Hepatic status:
• Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin ( 60 ml/min
• Proteinuria <1 g/day
• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT (partial thromboplastin time) is within therapeutic range of intended use of anticoagulant.

Inclusion criteria for enrollment:

All inclusion criteria for screening, plus:

• Central lab confirmation on a metastatic biopsy (or biopsy from unresectable loco-regional disease) of:
• HER2-positivity (immunohistochemistry score 3+) or ERBB2- amplification (Ratio ERBB2/centromeres ≥2.0 or mean gene copy number ≥ 6),
• Presence of PD-L1 expression assessed by IHC (during the phase II portion of the trial a parallel, secondary cohort of 15 patients with PD-L1 negative disease will be enrolled)
• Patient agrees to submit tumor tissue for translational research:
• tissue biopsy from unresectable loco-regional or metastatic disease obtained ≤1 year prior to enrollment or new tissue material from a recently obtained surgical or diagnostic biopsy. For patients who have presented with stage 4 disease de novo, a biopsy taken from the presumed primary breast lesion is acceptable (provided this was taken ≤1 year prior to enrollment).
• if available: FFPE tumor block from primary surgery or diagnostic biopsy.
• if available: pre-treatment fresh frozen tumor biopsy.
• if feasible: FFPE tumor block from post-treatment biopsy will be taken at time of disease progression or end of all treatment if ended prior to progression. This re-biopsy is strongly advised.
• if feasible: fresh frozen tumor biopsy from post-treatment biopsy will be taken at time of disease progression or end of all treatment if ended prior to progression.
• Patient agrees to submit baseline (pre-treatment) blood and seri