Overview

The DIAMOND study (DIAMOND-01) is a multicenter, randomized, open-label, non-inferiority Phase III clinical trial conducted by Fudan University Shanghai Cancer Center. The study aims to evaluate the efficacy and safety of an oral, "non-intravenous" regimen (pyrotinib + trastuzumab \[subcutaneous\] + dalpiciclib) compared to a standard intravenous chemotherapy-containing regimen (pyrotinib + trastuzumab \[subcutaneous\] + docetaxel) in patients with advanced HER2-positive breast cancer.

Approximately 502 patients with histologically confirmed advanced HER2-positive breast cancer who have received at most one prior line of systemic therapy (including anti-HER2 treatment) in the advanced setting will be randomized 1:1 to either the experimental or control arm. Stratification factors include ER status and presence of visceral metastases. The primary endpoint is Progression-Free Survival (PFS). Key secondary endpoints include Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR), Clinical Benefit Rate (CBR), safety, and patient-reported quality of life. Exploratory endpoints involve correlating circulating tumor cells (CTCs) and PAM50 molecular subtyping with survival outcomes.

This study seeks to determine if the all-oral, chemotherapy-free combination is non-inferior to the standard chemo-containing regimen, potentially offering a less toxic and more convenient treatment option for patients with advanced HER2-positive breast cancer.

Eligibility

Inclusion Criteria:

1. Age ≥ 18 years.
2. Patients with histopathologically confirmed recurrent/metastatic breast cancer that is HER2-positive (HER2 positivity is defined as IHC 3+, or IHC 2+/FISH amplified), based on the most recent pathological report.
3. Hormone receptor status is known, based on the most recent pathological report.
4. At least one measurable lesion meeting RECIST 1.1 criteria.
5. Have received no more than one prior line of systemic anti-tumor therapy for the advanced stage, which may include anti-HER2 therapy, chemotherapy, targeted therapy, immunotherapy, etc.
6. ECOG performance status of 0 to 1.
7. Adequate organ function meeting the following requirements:
   • Blood Routine: ANC ≥ 1.5 × 10⁹/L; PLT ≥ 75 × 10⁹/L; Hb ≥ 90 g/L (transfusion or medication to maintain hemoglobin level is permitted).
   • Blood Biochemistry: TBIL ≤ 1.5 × ULN; ALT and AST ≤ 3 × ULN (≤ 5.0 × ULN in patients with liver metastases); BUN or Cr ≤ 1.5 × ULN OR Creatinine Clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula).
   • 12-Lead ECG: QTcF \< 470 ms for females, \< 450 ms for males.
   • Cardiac Ultrasound: LVEF ≥ 50%.
8. Prior use of TKI drugs (including but not limited to pyrotinib or neratinib) in the neoadjuvant/adjuvant setting is permitted, provided the following conditions are both met:
   • The patient did not experience disease progression or recurrence/metastasis during the prior TKI therapy.
   • There was a period of ≥ 6 months between the discontinuation of the prior TKI and the occurrence of disease progression or recurrence/metastasis.
9. Recovery from any adverse events related to prior anti-tumor therapies to Grade ≤1 (according to NCI-CTCAE v5.0) before the first dose of study drug, with the exception of: a. Alopecia; b. Pigmentation.
10. The subject voluntarily participates in the study, has signed the Informed Consent Form (ICF), demonstrates good compliance, and is willing to cooperate with follow-up

Exclusion Criteria:

1. Presence of symptomatic brain metastases or leptomeningeal metastases.
2. Active brain metastases, except for asymptomatic brain metastases or those that have been stable for at least 4 weeks after local treatment.
3. Inability to swallow, presence of intestinal obstruction, or other factors affecting drug administration and absorption.
4. Presence of uncontrolled third-space fluid accumulation (e.g., massive pleural effusion or ascites) that cannot be managed by drainage or other methods.
5. Received radiotherapy, chemotherapy, or targeted therapy within 4 weeks prior to enrollment, or endocrine therapy within 2 weeks prior to enrollment. (Bisphosphonates used for treating bone metastases or preventing osteoporosis are excluded from this restriction). Or, current participation in any interventional drug clinical trial.
6. Pregnant or lactating female subjects, or subjects of childbearing potential with a positive baseline pregnancy test, or unwilling to use effective contraception.
7. History of other active malignancies within the past 5 years (excluding cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, and cutaneous squamous cell carcinoma).
8. Major surgical procedure or significant trauma within 4 weeks prior to randomization, or anticipation of the need for major surgery during the study.
9. Known history of allergy to any component of the study drug regimen.
10. Subjects with cardiac insufficiency, including but not limited to: congestive heart failure, transmural myocardial infarction, angina pectoris requiring medication, clinically significant valvular heart disease, and high-risk arrhythmias.
11. Active hepatitis (For hepatitis B: HBsAg positive AND HBV DNA ≥ 1000 IU/mL; For hepatitis C: HCV antibody positive AND HCV RNA above the upper limit of normal).
12. Uncontrolled hypertension (resting blood pressure: systolic \> 160 mmHg or diastolic \> 100 mmHg).
13. History of definite neurological or psychiatric disorders, including epilepsy or dementia.
14. Any other condition that, in the investigator's judgment, renders the patient unsuitable for participation in this study. This includes any concomitant illness or condition that could interfere with study participation, or any serious medical disorder that might affect subject safety (e.g., active or uncontrolled infection, severe diabetes, immunodeficiency disease, etc.).