Radiation with anlotinib for HER2-negative breast cancer brain metastases

A Prospective, Single-Arm, Phase II Clinical Study of Radiotherapy Combined With Anlotinib and a Tubulin Inhibitor for the Treatment of HER2-Negative Breast Cancer With Brain Metastases

This trial tests whether adding the drug anlotinib to stereotactic or whole-brain radiotherapy (with a microtubule inhibitor) helps people with HER2-negative breast cancer that has spread to the brain.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 39 (estimated)
• Ages: 18 Years to 70 Years
• Sex: Female
• Sponsor: The First Affiliated Hospital with Nanjing Medical University (Academic / other)
• Drugs / interventions: bevacizumab, anlotinib
• Locations: 1 site (Nanjing)
• Trial ID: NCT07396454 on ClinicalTrials.gov

What this trial studies

Angiogenesis inhibition is a promising target in breast cancer but prospective data combining tyrosine kinase inhibitors with local brain radiotherapy are limited. This Phase II trial gives patients stereotactic radiotherapy (SRT) or whole-brain radiotherapy (WBRT) together with the oral TKI anlotinib and a microtubule inhibitor to measure intracranial response and safety. Eligible participants are women 18–70 years old with HER2-negative disease and at least one measurable brain metastasis on contrast MRI. The study primarily monitors intracranial tumor control and treatment-related adverse events over a defined follow-up period.

Who should consider this trial

Good fit: Women aged 18–70 with pathologically confirmed HER2-negative breast cancer, a measurable brain metastasis on contrast MRI, and a Karnofsky Performance Status ≥70 (or 60 if due to neurologic symptoms) are the intended candidates.

Not a fit: Patients who are HER2-positive, have very poor functional status, uncontrolled extracranial disease, or cannot access the single study site in Nanjing are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, the combination could improve control of brain metastases, delay neurologic progression, and reduce symptoms compared with radiotherapy alone.

How similar studies have performed: Previous work with angiogenesis inhibitors and TKIs in advanced breast cancer has produced limited and mixed results, so combining a TKI with local brain radiotherapy remains relatively novel and not yet proven.

Eligibility criteria

Inclusion Criteria:

* Female patients aged 18 to 70 years (calculated on the date of informed consent signing).
* Karnofsky Performance Status (KPS) score ≥ 70, or KPS = 60 primarily attributable to neurological symptoms.
* HER2-negative status confirmed by pathology from Jiangsu Provincial Hospital's Pathology Department. HER2 immunohistochemistry (IHC) must be (-) or (1+). Patients with HER2 IHC (2+) must have a negative result on confirmatory fluorescence in situ hybridization (FISH) testing.
* Presence of brain metastases confirmed by contrast-enhanced cranial MRI prior to enrollment. At least one measurable intracranial lesion is required according to RANO-BM criteria.
* If prior anti-tumor therapy (excluding treatments specifically targeting intracranial metastases) has been administered, a washout period of at least 2 weeks is required. Any prior treatment-related toxicities must have resolved to ≤ Grade 2 (CTCAE v3.0; excluding alopecia and hematological toxicities). Concurrent use of bisphosphonates, mannitol, corticosteroids, etc., is permitted during the study. Corticosteroid dosage must have been stable for at least one week prior to enrollment (e.g., dexamethasone ≤ 16 mg/day or equivalent).
* Life expectancy of at least 3 months.
* Adequate organ and hematological function, meeting the following criteria:

  1. Hematology (without transfusion or growth factor support within 14 days):

     * Hemoglobin (Hb) ≥ 80 g/L.
     * Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L.
     * Platelet count (PLT) ≥ 50 × 10⁹/L.
  2. Biochemistry:

     * Total bilirubin (TBIL) \< 1.5 × upper limit of normal (ULN), or ≤ 3 × ULN in patients with liver metastases.
     * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN, or ≤ 5 × ULN in patients with liver metastases.
     * Serum creatinine (Cr) ≤ 1.5 × ULN or calculated creatinine clearance ≥ 60 mL/min (Cockcroft-Gault formula).
     * Magnesium ≥ lower limit of normal (LLN).
* Women of childbearing potential must be surgically sterile, postmenopausal, or agree to use highly effective contraception (e.g., oral contraceptives, intrauterine device, sexual abstinence, or barrier methods with spermicide) during the study and for 6 months after the final dose. A negative serum pregnancy test within 7 days prior to enrollment is required for all non-sterile, premenopausal women (positive results must be ruled out as false-positive by ultrasound). Patients must not be breastfeeding.
* Voluntary participation with written informed consent.

Exclusion Criteria:

* Patients with extensive leptomeningeal metastasis or hemorrhagic brain metastases.
* Patients with uncontrolled seizures.
* Patients with any other severe and/or poorly controlled concurrent medical condition that, in the investigator's judgment, prohibits their participation in this clinical study, including but not limited to:

  1. Factors significantly affecting oral drug intake (e.g., inability to swallow, chronic diarrhea, intestinal obstruction).
  2. Known hypersensitivity to anlotinib or any component of the investigational product.
  3. History of immunodeficiency, including HIV positivity, other acquired or congenital immunodeficiency diseases, or history of organ transplantation.
  4. Clinically significant cardiovascular disease (defined as: unstable angina, symptomatic congestive heart failure of New York Heart Association \[NYHA\] Class ≥ II, uncontrolled severe arrhythmia), or myocardial infarction within 6 months prior to enrollment.
  5. Active or uncontrolled infection requiring systemic treatment within 2 weeks prior to enrollment (excluding simple urinary tract infections or upper respiratory tract infections).
  6. History of concurrent other malignancies, except for cured basal cell carcinoma of the skin or carcinoma in situ of the cervix.
* Patients who are pregnant, breastfeeding, or planning to become pregnant during the treatment period or within 6 months after treatment completion.
* Patients (including female patients and/or their male partners) unwilling to use effective contraception during the treatment period and for 6 months after treatment completion.
* Patients ineligible for contrast-enhanced MRI examinations.
* Patients who have previously received anti-angiogenic TKI therapy and experienced intracranial progression (Note: Patients who received prior anti-angiogenic TKI therapy without subsequent disease progression are eligible. Patients previously treated with anti-angiogenic macromolecular agents, such as bevacizumab, are eligible).
* Patients with a history of other malignancies within the past 5 years or concurrent other malignancies, except for cured basal cell carcinoma of the skin or carcinoma in situ of the cervix. (Note: This appears to be a duplicate of criterion 3f. In standard protocols, it is typically listed once.).
* Patients unwilling or unable to comply with scheduled follow-up as required by the study protocol.
* Any other condition assessed by the investigator that may affect the patient's compliance with the protocol or the evaluation of study endpoints, rendering the patient unsuitable for study participation.

Where this trial is running

Nanjing

• The First Affiliated Hospital of Nanjing Medical University — Nanjing, China (Recruiting)

Study contacts

• Study coordinator: Chi Zhang

Conditions HER2-Negative Breast Cancer