Granzyme B-PET: Predicting Immunotherapy Efficacy in TNBC

Inclusion Criteria:

1. Age ≥ 18 years.

2. Histologically confirmed unresectable locally advanced or metastatic breast cancer, with immunohistochemistry (IHC) results indicating negativity for ER, PR, and Her-2. If pathology from a metastatic lesion is available, its histology will take precedence.

   ER and PR negativity is defined as: ER <1% positive and PR <1% positive, OR ER <10% with weak positivity and PR <10% with weak positivity.

   Her-2 negativity is defined as: an IHC score of 0 or 1+; or an IHC score of 2+ with a negative FISH test result. For patients with an IHC score of 0 or 1+, a FISH test is optional but must be negative if performed.

3. Decision by the clinician to treat with a regimen containing an immune checkpoint inhibitor (ICI), with the patient scheduled to receive at least 2 cycles of treatment.

   3.1. If the patient intends to participate in an ongoing clinical trial involving an ICI at our department, they must meet the inclusion and exclusion criteria of that specific trial. ICIs involved in clinical trials at our department include, but are not limited to, Pembrolizumab, Sintilimab, Toripalimab, and QL1706.

   3.2. For patients not enrolled in a clinical trial, they must have PD-L1 positive status (CPS ≥ 1), and the intended drug must be Toripalimab, as approved by the National Medical Products Administration (NMPA).

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Evidence of radiological or objective disease progression during or after the most recent systemic therapy prior to study entry, or intolerance to the toxicity of prior treatment.
6. Life expectancy of ≥ 12 weeks at the time of screening.
7. Presence of at least one measurable lesion that has not been previously irradiated. The lesion must have a longest diameter of ≥10 mm at baseline as measured by CT or MRI (for lymph nodes, the short axis must be ≥15 mm). In cases where only bone lesions are present, lytic or mixed lytic-blastic bone lesions that can be assessed by CT, MRI, or X-ray are acceptable.
8. Left Ventricular Ejection Fraction (LVEF) ≥ 50% within 28 days prior to randomization.

9. Adequate organ and bone marrow function within 14 days prior to randomization. The most recently obtained results for all parameters listed below must be used to meet the eligibility criteria:

   1. Hemoglobin ≥ 9 g/dL
   2. Absolute Neutrophil Count (ANC) ≥ 1,500/mm³
   3. Platelet count ≥ 100,000/mm³
   4. At baseline, Total Bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) if no liver metastases are present, or < 3 × ULN for patients with Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases.
   5. ALT and AST ≤ 3 × ULN, or < 5 × ULN for patients with liver metastases.
   6. Serum albumin ≥ 2.5 g/dL
   7. Creatinine clearance ≥ 30 mL/min (calculated using the Cockcroft-Gault formula).
   8. International Normalized Ratio (INR) or Prothrombin Time (PT), and Partial Thromboplastin Time (PTT) or activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN.
10. From the screening period through the entire study treatment period and for 7 months after the last dose of study treatment, female patients must not donate or retrieve oocytes (eggs) for personal use. Breastfeeding must be avoided during this period. If oocyte preservation is desired, it should be completed prior to randomization in this study.

Exclusion Criteria:

1. Uncontrolled concomitant diseases, including but not limited to: persistent or active infection; uncontrolled or significant cardiovascular disease; severe chronic gastrointestinal conditions associated with diarrhea; or psychiatric/social conditions that may limit compliance with study requirements, significantly increase the risk of adverse events (AEs), or impair the patient's ability to provide written informed consent.

2. Uncontrolled or significant cardiovascular disease, including any of the following:

   1. History of myocardial infarction or symptomatic Congestive Heart Failure (CHF) (New York Heart Association [NYHA] Class II to IV) within 6 months prior to randomization. Patients with troponin levels above the upper limit of normal (ULN) (as defined by the manufacturer) at screening without any symptoms related to myocardial infarction should undergo a cardiology consultation prior to randomization to rule out myocardial infarction.
   2. Uncontrolled hypertension.
   3. Uncontrolled and/or clinically significant arrhythmias.
3. History of (non-infectious) interstitial lung disease (ILD)/pneumonitis requiring steroid treatment, current ILD/pneumonitis, or suspected ILD/pneumonitis on imaging at screening that cannot be ruled out.
4. Use of immunosuppressive medications within 14 days prior to the first dose of the study drug, with the exception of intranasal and inhaled corticosteroids, or systemic corticosteroids at a dose of less than 10 mg/day of prednisone or its equivalent.
5. Clinically significant pulmonary-specific comorbidities, including but not limited to any underlying pulmonary disease (e.g., pulmonary embolism within three months prior to randomization, severe asthma, severe Chronic Obstructive Pulmonary Disease [COPD], restrictive lung disease, significant pleural effusion), and/or any autoimmune, connective tissue, or inflammatory diseases with concomitant pulmonary involvement (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis), and/or prior lung resection.
6. Uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals.
7. Spinal cord compression or clinically active central nervous system (CNS) metastases, defined as untreated and symptomatic, or requiring corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be eligible. Subjects may be included if their brain metastases have been treated, they are no longer symptomatic, do not require corticosteroids or anticonvulsants, and have recovered from the acute toxic effects of radiotherapy.
8. Active primary immunodeficiency, known Human Immunodeficiency Virus (HIV) infection, or active Hepatitis B or Hepatitis C infection. For patients with positive Hepatitis C antibody, only those who are negative for HCV RNA by polymerase chain reaction (PCR) are eligible for enrollment.

9. Unresolved toxicity from prior anticancer therapy, defined as toxicity that has not resolved to ≤ Grade 1 or baseline (with the exception of alopecia).

   Note: Subjects with chronic, stable Grade 2 toxicity (defined as not having worsened for at least 3 months prior to enrollment and being manageable with standard therapy) that the investigator deems related to prior anticancer therapy may be enrolled. Examples include chemotherapy-induced neuropathy or fatigue; residual toxicity from prior immunosuppressive therapy such as Grade 1 or 2 endocrinopathy.

10. Female patients who are pregnant or breastfeeding, or are planning to become pregnant.
11. Known history of severe hypersensitivity reaction to the active substance, excipients in the drug formulation, or other monoclonal antibodies.
12. History of another primary malignancy within the last 3 years, with the exception of: adequately resected non-melanoma skin cancer, curatively treated carcinoma in-situ, other solid tumors that have been cured, or contralateral breast cancer.
13. Substance abuse or any other medical condition, such as a psychiatric illness, that in the investigator's judgment could interfere with the patient's participation in or the evaluation of the results of the clinical study.