Metastatic Breast Cancer (MBC)Phase 3NCT07892274
Trastuzumab Rezetecan Followed by Pyrotinib, Fulvestrant, and Dalpiciclib in HR-Positive, HER2-Positive Advanced Breast Cancer
A Phase 3 study testing Fulvestrant, Pyrotinib and Dalpiciclib in people with Metastatic Breast Cancer (MBC) and HER2-Positive Breast Cancer, run by Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University at 1 site in China.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 80 years, women only
- Conditions the study is for
- Metastatic Breast Cancer (MBC), HER2-Positive Breast Cancer, Hormone Receptor-Positive Breast Cancer
- What is being tested?
- Fulvestrant, Pyrotinib and Dalpiciclib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 226 participants
- Where
- 1 siteChina
- Study dates
- 1 Nov 2026to 31 Dec 2031
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult female patients aged 18 to 80 years with metastatic breast cancer confirmed by pathology or imaging, not amenable to curative surgery or radiotherapy.
- Pathologically confirmed estrogen receptor (ER) and/or progesterone receptor (PR) positive (≥10% tumor cells by immunohistochemistry) and HER2-positive (IHC 3+ or FISH-positive).
- Disease progression during or within 1 year after neoadjuvant/adjuvant trastuzumab, or prior trastuzumab-based therapy for metastatic disease.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and estimated life expectancy ≥3 months.
- 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).
- 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.
- 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.
- Patient understands the study procedures, voluntarily agrees to participate, and provides written informed consent.
Who cannot join
- No prior trastuzumab, chemotherapy, or endocrine therapy.
- Central nervous system metastases.
- Visceral crisis.
- Considered by the investigator to be a candidate for chemotherapy.
- Inability to swallow, chronic diarrhea, or bowel obstruction that may affect drug administration or absorption.
- More than one prior line of endocrine therapy, chemotherapy, or targeted therapy for metastatic disease.
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- Other malignancy within the past 5 years, except curatively treated cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin.
- Concurrent other anticancer therapy.
- 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.
- 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.
- Pregnancy or lactation, or a positive pregnancy test at baseline in women of childbearing potential.
- Any severe concomitant disease that, in the investigator's judgment, would compromise patient safety or study completion.
- History of neurological or psychiatric disorders, including epilepsy or dementia.
- Any other condition that, in the investigator's judgment, makes the patient unsuitable for the study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
China1 site
Sun Yat-sen Memorial Hospital, Sun Yat-sen University
Guangzhou, Guangdong, 510000
Jianli Zhao, 020-34070499, zhaojli5@mail.sysu.edu.cn
About this study
Official title: An Open-Label, Multicenter Clinical Study of Trastuzumab Rezetecan Followed by Pyrotinib in Combination With Fulvestrant and Dalpiciclib in Patients With HR-Positive, HER2-Positive Advanced Breast Cancer
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:
Read more
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.
Read the 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.
- Conditions
- Metastatic Breast Cancer (MBC), HER2-Positive Breast Cancer, Hormone Receptor-Positive Breast Cancer
- Being tested
- Fulvestrant, Pyrotinib, Dalpiciclib, Trastuzumab Rezetecan
- Keywords
- HR+/HER2+, trastuzumab-resistant, pyrotinib, fulvestrant, HER2-ADC, CDK4/6 inhibitor
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FulvestrantDrug
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.
PyrotinibDrug
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.
DalpiciclibDrug
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.
Trastuzumab RezetecanDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Fulvestrant + Pyrotinib + Dalpiciclib | Experimental | Not described Receives: Drug: Fulvestrant; Drug: Pyrotinib; Drug: Dalpiciclib |
| Trastuzumab Rezetecan | Active comparator | Not described Receives: Drug: Trastuzumab Rezetecan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression-Free Survival (PFS)
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.
Measured: 24 months
Secondary outcomes (7)
Overall Survival (OS)
Time from randomization to death from any cause.
Measured: 36 months
Objective response rate (ORR)
According to recist1.1 standard, the proportion of patients whose best remission was CR or PR accounted for the total number of evaluable patients.
Measured: 24 months
Clinical Benefit Rate (CBR)
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.
Measured: 24 months
FACT-B
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.
Measured: 24 months
QLQ-BR23
It comprises 23 items assessing quality of life, symptoms, functional status, and psychological experiences in patients with breast cancer.
Measured: 24 months
Incidence of adverse events(AE)
Incidence of adverse events(AE)
Measured: from the date of enrollment to one year
Biomarkers and treatment sensitivity analysis
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）
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Oct 2026
- Study start1 Nov 2026 (estimated)
- Primary completion31 Dec 2030 (estimated)
- Study completion31 Dec 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Metastatic Breast Cancer (MBC)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 226 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ying Wang, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
- Investigators
- Ying Wang, Principal investigator, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07892274
- Sponsor's protocol ID
- SYSKY-2025-874-01
- Status last verified
- Apr 2026
- First submitted
- 17 Oct 2026
- Last updated
- 23 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Because the data involves the patient's personal information, it is temporarily decided that we will not disclose the individual participant data.
Publications
Ma F, Ouyang Q, Li W, Jiang Z, Tong Z, Liu Y, Li H, Yu S, Feng J, Wang S, Hu X, Zou J, Zhu X, Xu B. Pyrotinib or Lapatinib Combined With Capecitabine in HER2-Positive Metastatic Breast Cancer With Prior Taxanes, Anthracyclines, and/or Trastuzumab: A Randomized, Phase II Study. J Clin Oncol. 2019 Oct 10;37(29):2610-2619. doi: 10.1200/JCO.19.00108. Epub 2019 Aug 20.
PubMed 31430226Ma F, Li Q, Chen S, Zhu W, Fan Y, Wang J, Luo Y, Xing P, Lan B, Li M, Yi Z, Cai R, Yuan P, Zhang P, Li Q, Xu B. Phase I Study and Biomarker Analysis of Pyrotinib, a Novel Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. J Clin Oncol. 2017 Sep 20;35(27):3105-3112. doi: 10.1200/JCO.2016.69.6179. Epub 2017 May 12.
PubMed 28498781Zhao J, Yu Y, Ren W, Ding L, Chen Y, Yuan P, Yue J, Yang Y, Zou G, Chen T, Chai J, Zhang L, Wu W, Zeng Y, Gui X, Cai Y, Luo S, Yuan Z, Zhang K, Yao H, Wang Y. Combined pyrotinib and fulvestrant for hormone receptor-positive and HER2-positive metastatic breast cancer: A multicenter, single-arm, phase II trial. MedComm (2020). 2024 Dec 20;6(1):e70031. doi: 10.1002/mco2.70031. eCollection 2025 Jan.
PubMed 39712455Hurvitz SA, Hegg R, Chung WP, Im SA, Jacot W, Ganju V, Chiu JWY, Xu B, Hamilton E, Madhusudan S, Iwata H, Altintas S, Henning JW, Curigliano G, Perez-Garcia JM, Kim SB, Petry V, Huang CS, Li W, Frenel JS, Antolin S, Yeo W, Bianchini G, Loi S, Tsurutani J, Egorov A, Liu Y, Cathcart J, Ashfaque S, Cortes J. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023 Jan 14;401(10371):105-117. doi: 10.1016/S0140-6736(22)02420-5. Epub 2022 Dec 7.
PubMed 36495879Andre F, Hee Park Y, Kim SB, Takano T, Im SA, Borges G, Lima JP, Aksoy S, Gavila Gregori J, De Laurentiis M, Bianchini G, Roylance R, Miyoshi Y, Armstrong A, Sinha R, Ruiz Borrego M, Lim E, Ettl J, Yerushalmi R, Zagouri F, Duhoux FP, Fehm T, Gambhire D, Cathcart J, Wu C, Chu C, Egorov A, Krop I. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 May 27;401(10390):1773-1785. doi: 10.1016/S0140-6736(23)00725-0. Epub 2023 Apr 20.
PubMed 37086745Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I; DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):610-621. doi: 10.1056/NEJMoa1914510. Epub 2019 Dec 11.
PubMed 31825192Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Revil C, Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009 Nov 20;27(33):5529-37. doi: 10.1200/JCO.2008.20.6847. Epub 2009 Sep 28.
PubMed 19786670Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan;72(1):7-33. doi: 10.3322/caac.21708. Epub 2022 Jan 12.
PubMed 35020204