Fulvestaciclib Combined With Anti-HER2 and Endocrine Therapy for HR+/HER2+ Advanced Breast Cancer (FACET)

Efficacy and Safety of Fulvestaciclib Combined With Anti-HER2 and Endocrine Therapy for First-line Maintenance or Upfront Chemo-Free Treatment in HR+/HER2+ Advanced Breast Cancer: A Multicenter, Open-label, Randomized Controlled Phase II Study

This phase II, multicenter, open-label, randomized controlled trial (FACET study) evaluates the efficacy and safety of fulvestaciclib, a novel oral CDK4/6 inhibitor, combined with anti-HER2 dual blockade (trastuzumab and pertuzumab, HP) and endocrine therapy (ET) in hormone receptor-positive (HR+) and HER2-positive advanced breast cancer (ABC).

Patients with HR+/HER2+ ABC without prior systemic therapy for advanced disease are randomized in a 1:1:1 ratio into three arms, stratified by visceral metastasis status (yes vs. no) and metastatic type (de novo vs. recurrent).

Arm A: After 4-8 cycles of induction chemotherapy (taxane) plus HP, patients receive fulvestaciclib + HP + ET as maintenance therapy.

Arm B: After 4-8 cycles of induction chemotherapy (taxane) plus HP, patients receive HP + ET alone (without fulvestaciclib) as maintenance therapy.

Arm C (exploratory): Patients receive upfront fulvestaciclib + HP + ET as first-line therapy without induction chemotherapy (chemo-free).

For premenopausal/perimenopausal patients, ovarian function suppression (OFS) is added in all arms. Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or death.

The primary endpoint is investigator-assessed progression-free survival (PFS) comparing Arm A versus Arm B. Secondary endpoints include PFS (Arm A vs. Arm C), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), cumulative incidence of central nervous system (CNS) metastases, safety, and patient-reported outcomes (PROs).

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer; HER2-positive Breast Cancer; Hormone Receptor-positive Breast Cancer; HR+/HER2+ Breast Cancer
• Intervention / Treatment: Drug: Fulvestrant; Drug: Fulvestaciclib; Biological: Trastuzumab; Biological: Pertuzumab; Drug: Letrozole; Drug: Anastrozole; Drug: Taxane

• Study Type: Interventional
• Enrollment (Estimated): 240
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jian Zhang, MD; Phone Number: +86 18017312991; Email: syner2000@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years, with inoperable locally advanced or recurrent/metastatic breast cancer not amenable to curative-intent therapy.
• Histologically or cytologically confirmed hormone receptor-positive (HR+) and HER2-positive (HER2+) breast cancer. HR+ is defined as estrogen receptor (ER) and/or progesterone receptor (PR) positivity with ≥1% of invasive tumor cells positive by immunohistochemistry (IHC). HER2+ is defined as IHC 3+ or IHC 2+ with in situ hybridization (ISH) positivity.
• No prior systemic therapy for advanced breast cancer, including endocrine therapy, chemotherapy, anti-HER2 therapy, or any CDK4/6 inhibitor.
• Patients may have received neoadjuvant or adjuvant therapy. If prior endocrine therapy was received in the neoadjuvant/adjuvant setting, the disease-free interval from completion of endocrine therapy to randomization must be ≥12 months. If prior anti-HER2 therapy was received, the disease-free interval from completion of anti-HER2 therapy to randomization must be ≥6 months.
• Patients with stable central nervous system (CNS) metastases (meeting all the following criteria: no disease progression on screening imaging after local therapy; at least 3 weeks from completion of local CNS therapy to Cycle 1 Day 1; no requirement for medication to control symptoms) or asymptomatic CNS metastases are eligible.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Any menopausal status. Postmenopausal status is defined as: a. bilateral oophorectomy; b. age ≥60 years; c. age <60 years with amenorrhea for >1 year in the absence of chemotherapy, tamoxifen, toremifene, or ovarian function suppression, and with serum FSH and estradiol levels within the postmenopausal range. For patients <60 years on tamoxifen or toremifene with amenorrhea, serum FSH and estradiol levels must be within the postmenopausal range on consecutive measurements.
• At least one evaluable lesion per RECIST 1.1 (measurable and/or non-measurable lesion).
• For women of childbearing potential: negative serum or urine pregnancy test within 7 days prior to randomization, and agreement to use adequate contraception during study treatment and for 6 months after the last dose of fulvestaciclib.
• Voluntarily sign the informed consent form (ICF), understand the study, and be willing to comply with all study procedures and follow-up.
• Adequate bone marrow and organ function defined as:

Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L; Hemoglobin ≥90 g/L (no red blood cell transfusion within 14 days prior to randomization); Platelet count ≥75 × 10⁹/L; Serum total bilirubin ≤1.5 × upper limit of normal (ULN); AST and ALT ≤3 × ULN (or ≤5 × ULN in the presence of liver metastases); Serum creatinine ≤1 × ULN or calculated creatinine clearance >50 mL/min (Cockcroft-Gault formula); Baseline left ventricular ejection fraction (LVEF) ≥50%.

Exclusion Criteria:

• Inflammatory breast cancer.
• Leptomeningeal disease.
• Active brain metastases (patients with asymptomatic brain metastases, or clinically stable and not requiring steroids or other CNS-directed therapy for ≥4 weeks are eligible).
• Diagnosis of any other malignancy, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix that has been definitively treated.
• Known severe hypersensitivity to any component of the study drugs.
• Myocardial infarction within 6 months prior to first dose; uncontrolled cardiac arrhythmias (QTc interval ≥470 ms by Fridericia's formula); New York Heart Association (NYHA) Class III-IV cardiac insufficiency; LVEF <50% on echocardiography; or clinically significant pleural effusion, pericardial effusion, or ascites requiring intervention.
• Dysphagia, active gastrointestinal disease, major gastrointestinal surgery, malabsorption syndrome, or any other condition that may interfere with the absorption of study drugs.
• Known active infection, including hepatitis B (HBsAg positive with HBV DNA ≥1×10⁴ copies/mL or ≥2000 IU/mL), hepatitis C, syphilis, or human immunodeficiency virus (HIV) infection.
• Major surgery, radiotherapy, tumor immunotherapy, monoclonal antibody therapy, or other systemic antitumor therapy within 30 days prior to the first dose, or any therapy that the investigator considers may interfere with the efficacy of study drugs.
• Concurrent use of other investigational drugs or therapies.
• Planned or prior organ or bone marrow transplantation.
• Known history of substance abuse or drug addiction.
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for participation in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fulvestaciclib + HP + ET Maintenance; After 4-8 cycles of induction chemotherapy (taxane) plus trastuzumab and pertuzumab (HP), participants receive maintenance therapy with oral fulvestaciclib 200 mg daily (21 days on, 7 days off, 28-day cycle), HP (trastuzumab 8 mg/kg loading then 6 mg/kg IV Q3W; pertuzumab 840 mg loading then 420 mg IV Q3W), and endocrine therapy (ET: fulvestrant 500 mg IM on Days 1,15,29 then monthly, or letrozole 2.5 mg or anastrozole 1 mg PO daily). Premenopausal/perimenopausal patients also receive ovarian function suppression (OFS). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Drug: Fulvestrant; Fulvestrant; Drug: Fulvestaciclib; Oral CDK4/6 inhibitor, 200 mg once daily, 21 days on/7 days off per 28-day cycle.; Other Names: HLX902; Biological: Trastuzumab; Anti-HER2 monoclonal antibody, 8 mg/kg loading dose then 6 mg/kg IV every 21 days.; Biological: Pertuzumab; Anti-HER2 monoclonal antibody, 840 mg loading dose then 420 mg IV every 21 days.; Drug: Letrozole; Aromatase inhibitor, 2.5 mg orally once daily.; Drug: Anastrozole; Aromatase inhibitor, 1 mg orally once daily.; Drug: Taxane; Induction chemotherapy (paclitaxel, docetaxel, or nab-paclitaxel) plus HP for 4-8 cycles prior to maintenance therapy.
Active Comparator: HP + ET Maintenance (Control); After 4-8 cycles of induction chemotherapy (taxane) plus trastuzumab and pertuzumab (HP), participants receive maintenance therapy with HP (trastuzumab 8 mg/kg loading then 6 mg/kg IV Q3W; pertuzumab 840 mg loading then 420 mg IV Q3W) and endocrine therapy (ET: fulvestrant 500 mg IM on Days 1,15,29 then monthly, or letrozole 2.5 mg or anastrozole 1 mg PO daily) without fulvestaciclib. Premenopausal/perimenopausal patients also receive ovarian function suppression (OFS). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Drug: Fulvestrant; Fulvestrant; Biological: Trastuzumab; Anti-HER2 monoclonal antibody, 8 mg/kg loading dose then 6 mg/kg IV every 21 days.; Biological: Pertuzumab; Anti-HER2 monoclonal antibody, 840 mg loading dose then 420 mg IV every 21 days.; Drug: Letrozole; Aromatase inhibitor, 2.5 mg orally once daily.; Drug: Anastrozole; Aromatase inhibitor, 1 mg orally once daily.; Drug: Taxane; Induction chemotherapy (paclitaxel, docetaxel, or nab-paclitaxel) plus HP for 4-8 cycles prior to maintenance therapy.
Experimental: Upfront Fulvestaciclib + HP + ET (Chemo-free); Participants receive first-line therapy with oral fulvestaciclib 200 mg daily (21 days on, 7 days off, 28-day cycle), HP (trastuzumab 8 mg/kg loading then 6 mg/kg IV Q3W; pertuzumab 840 mg loading then 420 mg IV Q3W), and endocrine therapy (ET: fulvestrant 500 mg IM on Days 1,15,29 then monthly, or letrozole 2.5 mg or anastrozole 1 mg PO daily) without induction chemotherapy. Premenopausal/perimenopausal patients also receive ovarian function suppression (OFS). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Drug: Fulvestrant; Fulvestrant; Drug: Fulvestaciclib; Oral CDK4/6 inhibitor, 200 mg once daily, 21 days on/7 days off per 28-day cycle.; Other Names: HLX902; Biological: Trastuzumab; Anti-HER2 monoclonal antibody, 8 mg/kg loading dose then 6 mg/kg IV every 21 days.; Biological: Pertuzumab; Anti-HER2 monoclonal antibody, 840 mg loading dose then 420 mg IV every 21 days.; Drug: Letrozole; Aromatase inhibitor, 2.5 mg orally once daily.; Drug: Anastrozole; Aromatase inhibitor, 1 mg orally once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) Assessed by Investigator	PFS is defined as the time from randomization to the first documented disease progression according to RECIST 1.1 criteria as assessed by the investigator, or death from any cause, whichever occurs first.	From randomization to first documented progression per RECIST 1.1 or death, assessed every 6 weeks for 12 weeks then every 12 weeks until progression, up to 6 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) Assessed by Investigator (Arm A vs Arm C)	PFS is defined as the time from randomization to the first documented disease progression according to RECIST 1.1 criteria as assessed by the investigator, or death from any cause, whichever occurs first. Comparison between Arm A (fulvestaciclib + HP + ET maintenance) and Arm C (upfront fulvestaciclib + HP + ET chemo-free).	From randomization to first documented progression per RECIST 1.1 or death, assessed every 6 weeks for 12 weeks then every 12 weeks until progression, up to 6 years.
Overall Survival (OS)	OS is defined as the time from randomization to death from any cause.	From date of randomization to date of death from any cause, assessed up to approximately 6 years.
Objective Response Rate (ORR)	ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) per RECIST 1.1 criteria as assessed by the investigator.	From randomization to progression or start of subsequent therapy, assessed every 6 weeks for 12 weeks then every 12 weeks, up to 6 years.
Clinical Benefit Rate (CBR)	CBR is defined as the proportion of patients with a best overall response of CR, PR, or stable disease lasting at least 24 weeks per RECIST 1.1 criteria as assessed by the investigator.	From randomization to progression or start of subsequent therapy, assessed every 6 weeks for 12 weeks then every 12 weeks, up to 6 years.
Duration of Response (DoR)	DoR is defined as the time from the first documented response (CR or PR) to the first documented disease progression per RECIST 1.1 criteria as assessed by the investigator, or death from any cause, whichever occurs first.	From first documented CR or PR to first progression per RECIST 1.1 or death, assessed up to 6 years.
Cumulative Incidence of Central Nervous System (CNS) Metastases	Cumulative incidence of CNS metastases will be estimated using the competing risk model (Gray's method), with death as a competing risk event.	From date of randomization to date of first documented CNS metastasis, assessed up to approximately 6 years.
Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) as Assessed by NCI-CTCAE v5.0	Safety and tolerability will be assessed by the incidence, severity, and causality of AEs and SAEs graded according to NCI-CTCAE v5.0, as well as changes in vital signs, 12-lead ECGs, echocardiograms, and clinical laboratory parameters.	From informed consent through 28 days after last dose; labs/ECGs every 3 weeks, echocardiograms every 12 weeks, up to 6 years.
Patient-Reported Outcomes (PROs) Assessed by the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire	Health-related quality of life assessed using FACT-B, a 36-item scale across 5 domains: physical, social/family, emotional, functional well-being, and breast cancer-specific concerns. Total scores range from 0 to 148, with higher scores indicating better quality of life.	Measured at Cycle 1 Day 1 (each cycle is 28 days), every 12 weeks thereafter, and at treatment discontinuation and safety follow-up, up to 6 years.

Collaborators and Investigators

• Sponsor: Fudan University
• Collaborators: Shanghai Henlius Biotech Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): August 31, 2030
• Study Completion (Estimated): December 31, 2032

Study Registration Dates

• First Submitted: July 15, 2026
• First Submitted That Met QC Criteria: July 20, 2026
• First Posted (Actual): July 21, 2026

Study Record Updates

• Last Update Posted (Actual): July 21, 2026
• Last Update Submitted That Met QC Criteria: July 20, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Polycyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Steroids; Fused-Ring Compounds; Nitriles; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Triazoles; Trastuzumab; Letrozole; Fulvestrant; Anastrozole; pertuzumab; taxane
• Other Study ID Numbers: HLX902-IIT-MA-BC02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No