Metastatic Breast Cancer (MBC), HER2-Positive Breast Cancer, Hormone Receptor-Positive Breast Cancer
Conditions
Keywords
HR+/HER2+, trastuzumab-resistant, pyrotinib, fulvestrant, HER2-ADC, CDK4/6 inhibitor
Brief summary
The purpose of this clinical trial is to evaluate whether, in patients with hormone receptor-positive (HR-positive) and HER2-positive advanced breast cancer whose disease has progressed after trastuzumab-based therapy, switching to pyrotinib, fulvestrant, and dalpiciclib after induction with trastuzumab rezetecan-among those without disease progression-is superior to continued treatment with trastuzumab rezetecan. The three medicines are pyrotinib (a medicine that blocks HER2 and similar signals), fulvestrant (a hormone therapy), and dalpiciclib (a medicine that slows cancer cell division). The primary question this study aims to answer is: Does switching to pyrotinib, fulvestrant, and dalpiciclib prolong the time participants live without their cancer worsening compared with continued treatment with trastuzumab rezetecan? The study will also assess overall survival, tumor response to treatment, and adverse events. Researchers will compare the three-medicine combination with continued trastuzumab rezetecan. Participants will: Receive trastuzumab rezetecan once every 3 weeks for 6 cycles. If the cancer has not worsened after these 6 cycles, be randomly assigned to receive either the three-medicine combination or continued trastuzumab rezetecan. Undergo imaging scans every 6 weeks during the first 24 weeks and every 9 weeks thereafter to assess the cancer. Undergo blood tests, cardiac assessments, and other safety evaluations during treatment and follow-up.
Detailed description
Hormone receptor-positive/HER2-positive breast cancer has biologic features distinct from other HER2-positive subtypes, including cross-talk between estrogen receptor and HER2 signaling pathways. After trastuzumab failure, HER2-directed antibody-drug conjugates are commonly used, but treatment-related toxicity may limit long-term continuous use. Combining endocrine therapy, HER2 inhibition, and CDK4/6 inhibition may provide a biologically rational and lower-toxicity treatment strategy for this population. This multicenter, open-label, randomized, controlled, superiority phase 3 trial will enroll women with HR-positive/HER2-positive metastatic breast cancer whose disease has progressed after trastuzumab-based therapy. All participants will first receive six cycles of trastuzumab rezetecan induction. Those without disease progression will then be randomized 1:1 to receive fulvestrant plus pyrotinib plus dalpiciclib or continued trastuzumab rezetecan. Randomization will be stratified by the presence or absence of visceral metastases and by whether the disease was stage IV at initial diagnosis. Tumor assessments will be performed at baseline, every 6 weeks for the first 24 weeks, and every 9 weeks thereafter; survival follow-up will continue every 90 days after treatment discontinuation. The primary endpoint is progression-free survival, defined as the time from randomization to radiologically confirmed disease progression or death from any cause, whichever occurs first. Progression-free survival will be assessed by blinded independent central review according to RECIST 1.1. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, safety, and quality of life measured with FACT-B and QLQ-BR23. Exploratory biomarker analyses using tumor tissue and peripheral blood samples are planned.
Interventions
DRUGFulvestrant
Selective estrogen receptor downregulator (SERD) with no agonist activity. Binds to and degrades the estrogen receptor, inhibiting estrogen signaling in HR-positive breast cancer cells. Supplied as a 250 mg/5 mL injection and administered intramuscularly. In this trial, a loading dose of 500 mg (two 250 mg/5 mL injections) is given on Days 0, 14, and 28, followed by 500 mg once monthly thereafter. Given in combination with pyrotinib and dalpiciclib in the experimental arm.
DRUGPyrotinib
Oral, irreversible pan-HER tyrosine kinase inhibitor that covalently binds the intracellular kinase domains of EGFR (HER1), HER2, and HER4, blocking downstream signaling and inhibiting tumor cell growth. Supplied as 80 mg tablets and administered orally at 400 mg (five 80 mg tablets) once daily, continuously. Given in combination with fulvestrant and dalpiciclib in the experimental arm.
DRUGDalpiciclib
Oral, highly selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor that blocks CDK4/6-mediated phosphorylation of retinoblastoma protein, arresting cell-cycle progression and inhibiting tumor cell proliferation. Supplied as 125 mg tablets and administered orally at 125 mg (one 125 mg tablet) once daily for 21 consecutive days followed by 7 days of. Given in combination with pyrotinib and fulvestrant in the experimental arm.
HER2-directed antibody-drug conjugate (ADC) composed of a humanized anti-HER2 IgG1 monoclonal antibody (trastuzumab) conjugated via a cleavable tetrapeptide-based linker to a topoisomerase I inhibitor payload (rezetecan, an exatecan derivative; also known as SHR169265), with a drug-to-antibody ratio of approximately 6. After binding to HER2 on tumor cells, the conjugate is internalized and the linker is cleaved in lysosomes, releasing the payload, which stabilizes topoisomerase I-DNA complexes and induces DNA double-strand breaks and apoptosis. Administered intravenously at 4.8 mg/kg once every 3 weeks (21-day cycle). In this trial, given as 6 cycles of induction before randomization, and continued as the control regimen after randomization for participants not switched to the experimental triplet.
Sponsors
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Adult female patients aged 18 to 80 years with metastatic breast cancer confirmed by pathology or imaging, not amenable to curative surgery or radiotherapy. 2. Pathologically confirmed estrogen receptor (ER) and/or progesterone receptor (PR) positive (≥10% tumor cells by immunohistochemistry) and HER2-positive (IHC 3+ or FISH-positive). 3. Disease progression during or within 1 year after neoadjuvant/adjuvant trastuzumab, or prior trastuzumab-based therapy for metastatic disease. 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and estimated life expectancy ≥3 months. 5. Prior treatment-related toxicity resolved to Grade ≤1 per NCI CTCAE v4.03 (except alopecia or other toxicity deemed by the investigator not to pose a safety risk). 6. Adequate bone marrow function within 1 week before enrollment: white blood cell count ≥3.0×10⁹/L, absolute neutrophil count ≥1.5×10⁹/L, platelet count ≥100×10⁹/L. 7. Adequate hepatic, renal, and cardiac function within 1 week before enrollment: total bilirubin ≤1.5×ULN; ALT/AST ≤2.5×ULN (≤5×ULN in patients with liver metastases); serum creatinine ≤1.5×ULN or creatinine clearance ≥60 mL/min; left ventricular ejection fraction ≥55%; QTcF ≤470 ms. 8. Patient understands the study procedures, voluntarily agrees to participate, and provides written informed consent.
Exclusion criteria
1. No prior trastuzumab, chemotherapy, or endocrine therapy. 2. Central nervous system metastases. 3. Visceral crisis. 4. Considered by the investigator to be a candidate for chemotherapy. 5. Inability to swallow, chronic diarrhea, or bowel obstruction that may affect drug administration or absorption. 6. More than one prior line of endocrine therapy, chemotherapy, or targeted therapy for metastatic disease. 7. Other malignancy within the past 5 years, except curatively treated cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin. 8. Concurrent other anticancer therapy. 9. Known allergy to any component of the study drugs; history of immunodeficiency, including HIV positivity, HCV, active hepatitis B, or other acquired/congenital immunodeficiency; history of organ transplantation. 10. Severe cardiac disease or condition, including but not limited to: heart failure or systolic dysfunction (LVEF ≤50%), uncontrolled hypertension, significant ventricular arrhythmia, high-grade atrioventricular block, angina requiring anti-anginal therapy, clinically significant valvular disease, or ECG evidence of acute myocardial infarction. 11. Pregnancy or lactation, or a positive pregnancy test at baseline in women of childbearing potential. 12. Any severe concomitant disease that, in the investigator's judgment, would compromise patient safety or study completion. 13. History of neurological or psychiatric disorders, including epilepsy or dementia. 14. Any other condition that, in the investigator's judgment, makes the patient unsuitable for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | 24 months | Time from randomization to first radiologically confirmed disease progression, treatment discontinuation due to intolerable toxicity without recorded progression, or death from any cause, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 36 months | Time from randomization to death from any cause. |
| Objective response rate (ORR) | 24 months | According to recist1.1 standard, the proportion of patients whose best remission was CR or PR accounted for the total number of evaluable patients. |
| Clinical Benefit Rate (CBR) | 24 months | According to recist1.1 standard, the proportion of patients whose best remission was CR or PR or SD ≥ 24 weeks accounted for the total number of evaluable patients. |
| FACT-B | 24 months | It includes physical well-being, social/family well-being, emotional well-being, functional well-being, and additional concerns, comprehensively assessing patients' physical, psychological, and social functioning, as well as treatment-related symptoms such as hair loss and nausea. |
| QLQ-BR23 | 24 months | It comprises 23 items assessing quality of life, symptoms, functional status, and psychological experiences in patients with breast cancer. |
| Incidence of adverse events(AE) | from the date of enrollment to one year | Incidence of adverse events(AE) |
| Biomarkers and treatment sensitivity analysis | 12 months | Cox univariate and multivariate analysis will be used to explore the correlation between endocrine and HER2 pathway related biomarkers and treatment sensitivity（The biomarkers to be analyzed included 324 tumor related genes included in the FoundationOne CDx, and ER/PR/HER2/ki67 in IHC） |
Countries
China
Contacts
CONTACTYing Wang
CONTACTJianli Zhao
PRINCIPAL_INVESTIGATORYing Wang
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Outcome results
None listed