Retlirafusp Alfa Combined With Chemotherapy or Fuzuloparib for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the molecular subtype with the poorest prognosis among breast cancers, characterized by high rates of early recurrence, rapid distant metastasis, and short overall survival. Due to the lack of estrogen receptor, progesterone receptor, and HER2 expression, TNBC is insensitive to endocrine therapy and targeted therapy, making chemotherapy the mainstay of systemic treatment for a long time. However, conventional chemotherapy offers limited efficacy, and treatment options become scarce after the development of drug resistance. In recent years, immune checkpoint inhibitors have shown promising prospects in TNBC, particularly in PD-L1-positive patients who may benefit from immunotherapy combined with chemotherapy; nevertheless, a substantial proportion of patients still fail to achieve durable responses. In addition, PARP inhibitors have provided a new therapeutic option for TNBC patients harboring gBRCA mutations, and they exhibit potential synergistic effects with immunotherapy. Retlirafusp alfa (SHR-1701) is a domestically developed bifunctional fusion protein targeting PD-L1 and TGF-β, which can simultaneously block the PD-1/PD-L1 pathway and neutralize TGF-β in the tumor microenvironment, thereby enhancing anti-tumor immune responses. It has demonstrated promising efficacy and manageable safety in tumor types such as gastric cancer. Based on the above background, this study aims to explore the efficacy and safety of Retlirafusp alfa combined with chemotherapy or fluzoparib in early-stage and advanced TNBC, in order to provide novel therapeutic strategies for TNBC patients.

Inclusion criteria

• Age ≥18 years, female;
• Histopathologically confirmed recurrent or metastatic triple-negative breast cancer, defined as ER-negative (IHC ER-positive percentage <1%), PR-negative (IHC PR-positive percentage <1%), and HER2-negative (IHC -/+ or IHC ++ but FISH/CISH -);
• At least one measurable lesion per RECIST version 1.1 criteria;
• Advanced cohort:

Metastatic or unresectable locally advanced TNBC (no prior systemic therapy or completed neoadjuvant/adjuvant therapy ≥12 months); PD-L1 positive with a Combined Positive Score (CPS) ≥1;

Neoadjuvant cohort:

Clinical stage II (T2N0-1M0/T3N0M0) or III (T2N2-3M0/T3N1-3M0) previously untreated breast cancer patients;

• Life expectancy ≥3 months;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
• Available tissue sample for testing, and gBRCA1/2 mutation status must be determined prior to treatment;
• Adequate major organ function meeting the following criteria (no blood transfusion or use of granulocyte colony-stimulating factor or thrombopoietin within 2 weeks prior to screening):

Hematologic: Absolute neutrophil count (ANC) ≥1.5×10⁹/L; platelet count (PLT) ≥90×10⁹/L; hemoglobin (Hb) ≥90 g/L; Biochemical: Total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN); ALT and AST ≤1.5× ULN (≤3× ULN for patients with liver metastases); alkaline phosphatase ≤2.5× ULN; BUN and creatinine ≤1.5× ULN with creatinine clearance ≥50 mL/min (calculated by Cockcroft-Gault formula); Thyroid-stimulating hormone (TSH) ≤ULN (if abnormal, T3 and T4 levels should also be assessed; patients with normal T3 and T4 levels may be enrolled); Echocardiography: Left ventricular ejection fraction (LVEF) ≥50%; 18-lead electrocardiogram: Fridericia-corrected QT interval (QTcF) <480 ms for females;

• Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment and agree to use adequate contraception during the study period and for at least 4 months after the last dose of study drug;
• Willing to participate, capable of providing signed informed consent, and compliant with study procedures.

Exclusion criteria

• Concurrently receiving anti-tumor therapy in another clinical trial;
• Received other anti-tumor therapy within 4 weeks prior to the first dose of study drug;
• Prior treatment with tumor immunotherapy (including but not limited to PD-1, PD-L1, CTLA-4 inhibitors, etc.) or TGF-β inhibitors;
• Prior treatment with PARP inhibitors (except for patients who completed PARP inhibitor therapy for ovarian cancer ≥5 years ago with no recurrence or metastasis);
• Untreated active brain metastases or leptomeningeal metastases;
• Underwent major surgery unrelated to breast cancer within 4 weeks prior to enrollment, or have not fully recovered from such surgery;
• Presence of any active autoimmune disease or history of autoimmune disease (including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism); patients with vitiligo or childhood asthma that has completely resolved and does not require any intervention in adulthood may be included; patients with asthma requiring bronchodilator therapy for medical intervention are excluded;
• Severe cardiac disease or conditions, including but not limited to: documented history of heart failure or systolic dysfunction (LVEF <50%); uncontrolled high-risk arrhythmias, such as atrial tachycardia, resting heart rate >100 bpm, significant ventricular arrhythmias (e.g., ventricular tachycardia), or high-grade atrioventricular block (i.e., Mobitz II second-degree or third-degree atrioventricular block); angina requiring anti-anginal medication; clinically significant valvular heart disease; ECG showing transmural myocardial infarction; poorly controlled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg);
• Congenital or acquired immunodeficiency (e.g., HIV-infected patients);
• Received live vaccine within 4 weeks prior to study drug administration or likely to receive such vaccine during the study period;
• Known hypersensitivity to any component of the study drugs in this protocol;
• Severe concomitant disease or other comorbidities that may interfere with the planned treatment, or any other condition that, in the investigator's opinion, makes the patient unsuitable for participation in this study.