Sac-TMT Sequential Capecitabine Versus Capecitabine in Early-Stage High-Risk Triple-Negative Breast Cancer Without BRCA Mutations

Sacituzumab Tirumotecan (Sac-TMT) Sequential Capecitabine Versus Capecitabine as Adjuvant Regimen for Triple-Negative Breast Cancer With Early-Stage, High-Risk, Non-BRCA Mutated Status: A Phase III, Randomized, Controlled, Open-Label, Multicenter Clinical Trial

The goal of this clinical trial is to evaluate the efficacy and safety of sacituzumab tirumotecan (sac-TMT) sequential capecitabine versus single-agent capecitabine as adjuvant intensified therapy in patients with high-risk early-stage triple-negative breast cancer (TNBC) without BRCA mutations.

The main questions it aims to answer are:

1. Does sacituzumab tirumotecan (sac-TMT) sequential capecitabine improve survival outcomes compared with capecitabine monotherapy in this patient population?
2. What is the safety profile of sacituzumab tirumotecan (sac-TMT)-containing adjuvant therapy versus capecitabine monotherapy? Researchers will compare the sacituzumab tirumotecan (sac-TMT)-sequential-capecitabine experimental arm with the capecitabine-alone control arm to see if the experimental regimen provides superior adjuvant anti-tumor efficacy with acceptable safety.

Participants will be randomized in a 1:1 to Receive assigned study treatment as follows:

Experimental arm: Sacituzumab tirumotecan (sac-TMT) 4 mg/kg intravenously on Day 1 of each 3-week cycle for 8 cycles, followed by sequential capecitabine at stratified doses; patients with prior PD-1/L1 inhibitor exposure will continue PD-1/L1 inhibitor therapy for up to 1 year Control arm: Capecitabine monotherapy at stratified doses; patients with prior PD-1/L1 inhibitor exposure will continue PD-1/L1 inhibitor therapy for up to 1 year

Inclusion Criteria:

1. Female aged ≥ 18 years old.

2. Diagnosis of operable primary invasive breast cancer.

3. Negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), defined as follows: ER-negative is defined as <10 % positive tumor cells by immunohistochemistry (IHC); PR-negative is defined as <10 % positive tumor cells by IHC; HER2-negative is defined as IHC score of 0 or 1+, or IHC score of 2+ with negative (non-amplified) results confirmed by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH).

4. Non-mutated for BRCA1/2 genes.

5. Patients must satisfy any one of the following conditions:

   1. Baseline clinical lymph node-positive (cLN+) or pathological lymph node-positive (pN+) status with non-pathological complete response (non-pCR), who have completed adequate neoadjuvant therapy (at least 6 cycles of chemotherapy containing anthracycline and/or taxane, with or without PD-1 inhibitor immunotherapy).
   2. Pathological lymph node-positive (pN+) status without prior neoadjuvant therapy, who have undergone adequate surgery, adjuvant chemotherapy (at least 6 cycles of taxane- and/or anthracycline-containing regimen with or without carboplatin), and adjuvant radiotherapy (if applicable).

6. No evidence of distant metastasis shown by imaging examinations performed within 3 months prior to randomization.

7. Adequate organ and bone marrow function.

8. Acute toxicities from any prior therapy have recovered to baseline levels or resolved to Grade ≤ 1 per NCI CTCAE Version 5.0 (excluding adverse events deemed non-safety risks at the investigator's discretion).

9. Post-menopausal status or documented non-childbearing potential. For women of childbearing potential, urine pregnancy tests must be negative at post-surgery screening and baseline visits. All participants and their male partners of childbearing potential must use effective medical contraception from the date of informed consent signature until 6 months after the last dose of study treatment.

10. Voluntarily participate in the study, provide written informed consent, and be able to comply with protocol-specified visits and procedures.

Exclusion Criteria:

1. Patients with Stage T4 disease, including those with inflammatory breast cancer;
2. Patients with Stage N3 disease;
3. Patients with positive supraclavicular or internal mammary lymph nodes;
4. Previous history of breast cancer;
5. Significant cardiovascular diseases such as baseline left ventricular ejection fraction (LVEF) < 50% assessed by echocardiography (ECHO) or multigated acquisition (MUGA) scan at screening, or New York Heart Association (NYHA) Class III or IV cardiomyopathy;
6. Prior treatment with TROP2-targeted therapy and/or topoisomerase I inhibitors;
7. History of other malignant neoplasms within the past 5 years, excluding cured carcinoma in situ of the cervix, cutaneous basal cell carcinoma, or cutaneous squamous cell carcinoma;
8. Known hypersensitivity to study drugs and their components, history of immunodeficiency, or history of organ transplantation;
9. History of non-infectious interstitial lung disease (ILD) or non-infectious pneumonia requiring steroid therapy, current ILD or non-infectious pneumonia, or suspected ILD/non-infectious pneumonia that cannot be ruled out by imaging at screening; clinically significant severe pulmonary impairment secondary to concomitant pulmonary diseases, including but not limited to any underlying pulmonary disorders (e.g., pulmonary embolism within 3 months prior to first dose, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion) or any autoimmune, connective tissue, or inflammatory diseases potentially involving the lungs (i.e., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis), or prior pneumonectomy;
10. Documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or history of corneal disorders that hinder delayed corneal healing;
11. Active autoimmune diseases requiring systemic therapy within the past 2 years (hormone replacement therapy is not considered systemic therapy, e.g., type 1 diabetes mellitus, hypothyroidism managed with thyroid hormone replacement only, adrenal or pituitary insufficiency managed with physiological-dose glucocorticoid replacement only);
12. Active infections requiring systemic therapy within 2 weeks prior to the first dose;
13. Patients with malabsorption syndromes affecting glucuronosyltransferase (Gl) function, history of gastric or small bowel resection, or inability to swallow capecitabine tablets;
14. Concomitant severe diseases that jeopardize patient safety or interfere with study completion as judged by the investigator, including but not limited to uncontrolled hypertension, severe diabetes mellitus, and active infections;
15. Any other conditions rendering the patient ineligible for study participation in the investigator's opinion.