A phase II, open-label, multicenter, randomized controlled trial exploring the efficacy and safety of Trastuzumab Deruxtecan combined with or without Neratinib in HER2-positive breast cancer with brain metastasis

This study is a prospective, multicenter, open-label, Phase II, randomized controlled clinical trial aimed at evaluating the efficacy and safety of T-DXd with or without neratinib in patients with HER2-positive breast cancer with brain metastases. All eligible subjects will be randomly assigned in a 1:1 ratio across multiple centers in China to receive either T-DXd combined with neratinib or T-DXd monotherapy until extracranial progression as defined by RECIST 1.1, unless unacceptable toxicity occurs, consent is withdrawn, or other criteria for discontinuation are met.

Inclusion Criteria:

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Participants must meet all of the following inclusion criteria in order to be enrolled in this study:

1. Female, aged 18-70 years old.

2. ECOG score ranges from 0 to 1.

3. Expected survival period is greater than 12 weeks.

4. Histologically confirmed invasive HER2 positive breast cancer (HER2 IHC+++or FISH/CISH positive, all samples need to be verified by the pathology department of the research center).

5. Tumor staging: recurrent or metastatic breast cancer; Patients with local recurrence need to be confirmed by the researcher that radical surgical resection cannot be performed.

6. The subject has at least one lesion (measurable and/or unmeasurable) that has not received radiation therapy in the past.

7. MRI or CT shows brain metastasis and meets one of the following conditions:

   i) Untreated brain parenchymal metastases detected through imaging screening;

   Ii) Stable or progressive brain parenchymal metastases that have undergone previous local treatment and meet one of the following conditions:

   1. Stable imaging for ≥ 4 weeks;
   2. New brain parenchymal metastases detected by MR or CT.

8. Transfer treatment ≤ 2 lines, and did not receive T-DXd or nalatinib.

9. The main organ functions are basically normal, meeting the following conditions:

   1. The standard for blood routine examination should meet: HB ≥ 90g/L (no blood transfusion within 14 days); ANC≥1.5×109/L；PLT≥75×109/L；
   2. Biochemical tests must meet the following standards: TBIL ≤ 1.5 × ULN (upper limit of normal value); ALT and AST ≤ 3 × ULN; If there is liver metastasis, ALT and AST should be ≤ 5 × ULN; Serum Cr ≤ 1.5 × ULN, endogenous creatinine clearance rate ≥ 30mL/min (Cockcroft Gault formula).

10. Prior to enrollment, the use of mannitol and hormone therapy is allowed, but the medication dosage should be stable for at least one week without the need for an increase.

11. Female participants with fertility agreed to take effective contraceptive measures until 3 months after the last use of medication.

12. The subjects voluntarily joined this study, signed informed consent forms, had good compliance, and cooperated with follow-up.

Exclusion Criteria:

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Subjects with any of the following conditions are not eligible for inclusion in this study:

1. Transfer treatment exceeding 2 lines, or previous use of T-DXd or nalatinib.

2. Meningeal metastasis.

3. Brain metastases that require emergency intervention treatment, or brain metastases that require treatment with more than 3mg/d dexamethasone or equivalent drugs.

4. A history of clinically significant or uncontrolled heart disease, including congestive heart failure, angina, myocardial infarction within the past 6 months, or ventricular arrhythmia.

5. Due to ongoing grade ≥ 2 adverse reactions caused by previous treatments (excluding hair loss).

6. Pregnancy period.

7. Other malignant tumors within the past 5 years, excluding cured cervical carcinoma in situ, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin.

8. Unable to swallow, chronic diarrhea, and intestinal obstruction, there are multiple factors that affect medication intake and absorption.

9. There is a third interstitial fluid accumulation that cannot be controlled by drainage or other methods (such as a large amount of pleural fluid and ascites).

10. Participated in clinical trials of other anti-tumor drugs within 4 weeks prior to the first use of the investigational drug.

11. Long term unhealed wounds or fractures with incomplete healing.

12. Known subjects with active HBV or HCV infection.

13. Active primary immunodeficiency, known to be HIV positive.

14. Uncontrolled infections requiring intravenous injection of antibiotics, antiviral drugs, or antifungal drugs.

15. A history of non communicable ILD/pneumonia requiring steroids, currently suffering from ILD/pneumonia, or unable to rule out suspected ILD/pneumonia through imaging during screening.

16. Lung standard:

    1. Pulmonary specific comorbidities with clinically significant diseases, including but not limited to any potential pulmonary diseases (such as pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease, restrictive pulmonary disease, pleural effusion, etc. within 3 months of recruitment).
    2. Any autoimmune disease, connective tissue disease, or inflammatory disease (such as rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.). There are records or suspicions of lung involvement during screening. For participants participating in the study, all detailed information about the disease should be recorded in the CRF.
    3. Previous complete lung resection surgery.

17. Individuals with allergies, or those with a known history of allergies to the components of this medication regimen, or subjects who are allergic to other monoclonal antibodies.

Researchers believe that substance abuse or medical conditions may interfere with participants' participation in clinical studies or the evaluation of clinical study results.