Trastuzumab Rezetecan Followed by Pyrotinib, Fulvestrant, and Dalpiciclib in HR-Positive, HER2-Positive Advanced Breast Cancer

NCT07892274 | Not Yet Recruiting Phase 3

• 1 other identifier: SYSKY-2025-874-01
• Study Type: interventional
• Target: 226
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Breast Cancer (MBC); HER2-Positive Breast Cancer; Hormone Receptor-Positive Breast Cancer

Keywords

HR+/HER2+; trastuzumab-resistant; pyrotinib; fulvestrant; HER2-ADC; CDK4/6 inhibitor

Outcome Measures

Primary Outcomes (1)

• 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.

  24 months

Secondary Outcomes (7)

• Overall Survival (OS)

  36 months

• Objective response rate (ORR)

  24 months

• Clinical Benefit Rate (CBR)

  24 months

• FACT-B

  24 months

• QLQ-BR23

  24 months

Study Arms (2)

Fulvestrant + Pyrotinib + Dalpiciclib

EXPERIMENTAL

Drug: Fulvestrant; Drug: Pyrotinib; Drug: Dalpiciclib

Trastuzumab Rezetecan

ACTIVE COMPARATOR

Drug: Trastuzumab Rezetecan

Interventions

Fulvestrant DRUG

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.

Fulvestrant + Pyrotinib + Dalpiciclib

Pyrotinib DRUG

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.

Fulvestrant + Pyrotinib + Dalpiciclib

Dalpiciclib DRUG

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.

Fulvestrant + Pyrotinib + Dalpiciclib

Trastuzumab Rezetecan DRUG

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.

Trastuzumab Rezetecan

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University: lead

Study Sites (1)

Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Guangzhou, Guangdong, 510000, China

Location

Related Publications (8)

• 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.

  PMID: 31430226 BACKGROUND

• Ma 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.

  PMID: 28498781 BACKGROUND

• Zhao 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.

  PMID: 39712455 BACKGROUND

• Hurvitz 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.

  PMID: 36495879 BACKGROUND

• Andre 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.

  PMID: 37086745 BACKGROUND

• Modi 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.

  PMID: 31825192 BACKGROUND

• Kaufman 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.

  PMID: 19786670 BACKGROUND

• Siegel 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.

  PMID: 35020204 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Fulvestrant; pyrotinib; dalpiciclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Ying Wang

  Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ying Wang

CONTACT

86-20-34070870; wangy556@mail.sysu.edu.cn

Jianli Zhao

CONTACT

86-20-34070499; zhaojli5@mail.sysu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: October 17, 2026
• First Posted: October 23, 2026
• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2031
• Last Updated: October 23, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)