Neratinib Combined With Fulvestrant and Eribulin in the Treatment ofHR+/HER2+ Advanced Breast Cancer (NETHER)

Neratinib Combined With Fulvestrant and Eribulin in the Treatment ofHR+/HER2+ Advanced Breast Cancer After Trastuzumab Deruxtecan Resistance:A Single-Arm, Multicenter, Exploratory Clinical Study

This study aims to explore the efficacy and safety of neratinib combined with fulvestrant and eribulin in the treatment of HR+/HER2+ advanced breast cancer after trastuzumab deruxtecan resistance. The treatment regimen of neratinib + fulvestrant + eribulin in this study is expected to provide a new and effective therapeutic strategy for patients with triple-positive breast cancer who develop resistance to trastuzumab deruxtecan, and offer novel therapeutic insights for advanced triple-positive breast cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Brest Cancer
• Intervention / Treatment: Drug: Neratinib Combined with Fulvestrant and Eribulin

Detailed Description

This study is a single-arm, exploratory clinical trial. Eligible patients with recurrent or metastatic breast cancer will be screened and enrolled after signing the informed consent form, and will receive neratinib combined with fulvestrant and eribulin until disease progression or intolerable toxicity occurs. During the treatment period, clinical tumor imaging assessments will be performed every 6 weeks (2 cycles) in accordance with RECIST v1.1; safety assessments will be conducted using NCI-CTCAE 5.0, and adverse events will be recorded throughout the study and within 30 days after the end of treatment (the recording period for serious adverse events or adverse events related to the drugs involved in this trial will be extended to 90 days after the end of treatment).

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ethics Committee of the First Affiliated Hospital of Air Force; Phone Number: 029-84771794; Email: EC84771794@163.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Female patients aged ≥18 years and ≤75 years;
• ECOG performance status of 0-2;
• Histologically confirmed HR-positive/HER2-positive advanced breast cancer:
• Definition of HER2 positivity: IHC 3+ or IHC 2+/ISH positive prior to T-DXd treatment;
• Definition of HR positivity: ER or PR ≥1%;
• Refractory to prior treatment containing T-DXd (definition of resistance: a. Definite disease progression per RECIST v1.1 criteria; b. Intolerance to T-DXd treatment);
• Prior exposure to anthracyclines and taxanes (including use in the adjuvant/neoadjuvant setting);
• Presence of at least one measurable lesion (per RECIST v1.1 criteria);
• Estimated survival time ≥3 months;
• Adequate function of major organs, meeting the following requirements (no blood transfusion, no use of leukocyte- or platelet-stimulating agents within 2 weeks prior to screening);
• For premenopausal or non-surgically sterilized female patients: Agreement to abstain from sexual activity or use effective contraceptive methods during treatment and for at least 7 months after the last dose of study treatment;
• Voluntary participation in the study, signing of the informed consent form, good compliance, and willingness to cooperate with follow-up.

Exclusion Criteria:

• Severe allergic reactions to neratinib, eribulin, fulvestrant, or any of their excipients;
• Prior treatment with neratinib, other small-molecule anti-HER2 TKIs, or eribulin;
• Patients with inflammatory breast cancer;
• A history of other malignant tumors within the past 5 years or concurrent malignant tumors (including cured malignant tumors such as carcinoma in situ of the cervix, basal cell carcinoma, or squamous cell carcinoma);
• Concurrent receipt of anti-tumor therapies in other clinical trials, including endocrine therapy, bisphosphonate therapy, or immunotherapy;
• Receipt of major surgical procedures unrelated to breast cancer within 4 weeks prior to enrollment, or failure to fully recover from such surgical procedures;
• Severe cardiac diseases or disorders, including but not limited to: --Documented history of heart failure or systolic dysfunction (LVEF < 50%); --High-risk uncontrolled arrhythmias, such as atrial tachycardia, resting heart rate > 100 bpm, significant ventricular arrhythmias (e.g., ventricular tachycardia), or high-grade atrioventricular block (i.e., Mobitz II second-degree atrioventricular block or third-degree atrioventricular block);
• Poorly controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg);
• Inability to swallow, intestinal obstruction, or other factors affecting drug administration and absorption;
• Known history of allergies to any components of the study drugs; history of immunodeficiency (including positive HIV test results), other acquired or congenital immunodeficiency diseases, or history of organ transplantation;
• Pregnant or lactating female patients; female patients of childbearing potential with a positive baseline pregnancy test; or fertile patients unwilling to use effective contraceptive methods throughout the trial and for 7 months after the last dose of study treatment;
• Severe comorbid diseases or other concurrent conditions that may interfere with the planned treatment, or any other circumstances deemed by the investigator to make the patient unsuitable for participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neratinib Combined with Fulvestrant and Eribulin; Neratinib Combined with Fulvestrant and Eribulin after Trastuzumab Deruxtecan Resistance	Drug: Neratinib Combined with Fulvestrant and Eribulin; neratinib combined with fulvestrant and eribulin in the treatment of HR+/HER2+ advanced breast cancer after trastuzumab deruxtecan resistance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate(ORR)	The proportion of patients whose tumor lesions achieve "Partial Response (PR)" or "Complete Response (CR)" after treatment	From treatment initiation to disease progression, intolerable toxicity, or study completion, whichever occurs first，assessed up to 10 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression free survival	the length of time from a patient's enrollment to the first occurrence of either "disease progression (PD)" or "death from any cause".	From first treatment initiation to the first occurrence of disease progression (per RECIST v1.1) or death from any cause, or study completion (whichever occurs first)，assessed up to 60 months
overall survival	the length of time from a patient's enrollment to death from any cause	From first treatment initiation to death from any cause or study completion, whichever occurs first, with a minimum follow-up of 12 months for surviving patients，assessed up to 100 months
Disease control rate		From first treatment initiation to disease progression, intolerable toxicity, or study completion (whichever occurs first), with disease control status confirmed for ≥4 weeks per RECIST v1.1
duration of response		From the first confirmed Complete Response (CR) or Partial Response (PR) (per RECIST v1.1, maintained for ≥4 weeks) to the first documented disease progression (PD) or death from any cause, or study completion，assessed up to 10 months
adverse effects		From the first dose of study treatment (neratinib + fulvestrant + eribulin) to 30 days after the last dose of study treatment. For serious adverse events (SAEs), the follow-up and recording period is extended to 90 days after the last dose.

Collaborators and Investigators

• Sponsor: Xijing Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): December 20, 2025
• Primary Completion (Estimated): November 20, 2027
• Study Completion (Estimated): November 20, 2028

Study Registration Dates

• First Submitted: December 14, 2025
• First Submitted That Met QC Criteria: December 31, 2025
• First Posted (Estimated): January 12, 2026

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: December 31, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Eribulin; Neratinib; Fulvestrant; HR+/HER2+ Advanced Breast Cancer
• Additional Relevant MeSH Terms: Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Fulvestrant; eribulin
• Other Study ID Numbers: XJYY-KY-20252554

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
• product manufactured in and exported from the U.S.: No