Efficacy and Safety of Extended-Dose Interval Immunotherapy Versus Standard-Dose Interval Immunotherapy for Advanced Triple-Negative Breast Cancer

Efficacy and Safety of Extended-Dose Interval Immunotherapy Versus Standard-Dose Interval Immunotherapy for Advanced Triple-Negative Breast Cancer: A Multicenter Randomized Controlled Clinical Trial

Triple-negative breast cancer (TNBC), defined by the lack of ER, PR and HER2 expression, is refractory to endocrine therapy and anti-HER2 agents. Chemotherapy was once the mainstay for advanced TNBC, but its limited efficacy necessitates optimized therapeutic strategies. TNBC's high TIL infiltration and elevated PD-L1 expression confer sensitivity to immune checkpoint inhibitors (ICIs), with ICI-chemotherapy combinations initially establishing first-line standard status. Emerging clinical evidence shows that ICI-antibody-drug conjugate (ADC) combinations outperform ICI-chemotherapy regimens, yet immune-related adverse events (irAEs) remain a critical clinical challenge. Expert consensus recommends continuing ICI therapy in advanced TNBC patients achieving CR, PR or SD after ICI-based combination therapy until disease progression or intolerable toxicity. Mechanistically, once ICIs reach target receptor saturation, dose escalation or high-frequency administration fails to boost efficacy but raises toxicity risk. Thus the investigators hypothesize that an ICI maintenance strategy with fixed dose and extended intervals can preserve efficacy, reduce toxicity, improve patient compliance, enhance quality of life and alleviate economic burden for advanced TNBC patients with CR/PR/SD after ICI-chemotherapy or ICI-ADC treatment.

Inclusion Criteria:

1. Voluntary consent to participate in this study and signing of the informed consent form.
2. The age of the signatory of the informed consent form should be ≥18 years old and ≤70 years old.
3. Advanced (locally recurrent inoperable or metastatic) TNBC confirmed by histology or cytology, defined as ER-negative, PR-negative, and HER2-negative.
4. PD-L1 IHC detection in tumor tissue with a CPS score ≥1.
5. Have received first-line standard immunotherapy combined with chemotherapy or immunotherapy combined with ADC and completed 6 cycles, with the last dose administered no more than 28 days before randomization.
6. The therapeutic efficacy was confirmed as CR, PR or SD after 6-cycle standard treatment according to the RECIST v1.1 criteria.
7. Plan to continue receiving immunotherapy.
8. An Eastern Cooperative Oncology Group performance-status score of 0 or 1.
9. The expected survival period exceeds 12 weeks.
10. Adequate organ function:.
11. No mental or intellectual abnormalities.
12. Willing and able to comply with the trial protocol during the trial period.
13. Female subjects of childbearing potential must agree to use highly effective contraceptive measures starting at least 7 days before the first dose and continuing until 24 weeks after the last dose. The serum pregnancy test result must be negative within 7 days prior to the first dose.

Exclusion Criteria:

1. Untreated active brain metastases or meningeal metastases.
2. Concomitant other malignant tumors with progression within the recent 5 years or requiring active treatment (excluding adequately treated and controlled carcinoma in situ and non-melanoma skin cancer).
3. Concomitant severe non-malignant diseases that would affect the patient's compliance or put the patient at risk.
4. Concomitant active infection.
5. Receiving other anti-tumor therapies or participating in other interventional clinical trials.
6. Inflammatory breast cancer.
7. Dementia, intellectual disability, or any mental disorders that hinder the understanding of the informed consent form.
8. History of allergic reactions to any components of the study drugs or existing contraindications to their use.
9. Presence of any active autoimmune diseases or history of autoimmune diseases.
10. Presence of poorly controlled clinical cardiac symptoms or diseases, such as:1) Heart failure of NYHA class II or above;2) Unstable angina pectoris;3) Myocardial infarction occurring within 1 year;4) Clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention.
11. Presence of grade ≥3 toxicities related to prior treatments that restrict the continuation of maintenance therapy.
12. History of immunodeficiency, including HIV positivity, active HBV/HCV infection, other acquired or congenital immunodeficiency diseases, and history of organ or allogeneic stem cell transplantation.
13. Vaccination with live vaccines within 4 weeks prior to the administration of study drugs or planned vaccination during the study period.
14. Prior administration of irinotecan, topotecan, or any other topoisomerase I inhibitors (including investigational topoisomerase I inhibitors), or known history of allergies to the above-mentioned drugs.
15. Use of systemic glucocorticoids at a dose exceeding 10 mg/day of prednisone equivalent within 14 days prior to the administration of study drugs, or planned long-term use of the above dose during the study period (topical, inhaled, or short-term (≤7 days) pulse doses ≤10 mg/day of prednisone equivalent, or physiological dose replacement therapy are allowed for inclusion).
16. Need for use of any immunosuppressants within 14 days prior to the administration of study drugs or planned use during the study period.
17. Pregnant or lactating women, or women of childbearing potential who refuse to accept contraceptive measures.
18. Patients who are difficult or impossible to follow up.
19. Subjects judged by the investigator to have conditions that may affect compliance or other circumstances making them unsuitable for inclusion.