This multicenter, Phase II study (RADIANT-BC01) evaluates the efficacy and safety of Disitamab Vedotin (RC48) in combination with either bevacizumab or pyrotinib in adult patients with HER2-positive metastatic breast cancer whose disease has progressed on prior trastuzumab deruxtecan (T-Dxd) therapy.

Eligible participants will be randomized 1:1 to receive RC48 plus bevacizumab (7.5 mg/kg IV every 2 weeks) or RC48 plus pyrotinib (320 mg orally once daily). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or initiation of new anticancer therapy.

The primary endpoint is objective response rate (ORR); key secondary endpoints include progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety.

This study aims to identify new post-T-Dxd treatment options and improve outcomes for patients with advanced HER2-positive breast cancer.

Despite the remarkable benefits of trastuzumab deruxtecan (T-Dxd) as second-line therapy, resistance inevitably develops in HER2-positive metastatic breast cancer, and no standard treatment exists after T-Dxd failure. Disitamab Vedotin (RC48) is a novel antibody-drug conjugate (ADC) targeting HER2, with a cathepsin-cleavable linker and MMAE payload that has demonstrated encouraging antitumor activity and tolerability in earlier studies. Preclinical and real-world data suggest that combining RC48 with anti-angiogenic agents (bevacizumab) or a pan-HER tyrosine kinase inhibitor (pyrotinib) may enhance tumor penetration, overcome resistance mechanisms, and provide synergistic effects without overlapping toxicity.

RADIANT-BC01 is designed as two parallel Simon two-stage cohorts: one evaluating RC48 + bevacizumab and the other RC48 + pyrotinib. In each arm, 14 patients will be enrolled in the first stage, with progression to a total of 37 patients if at least five responses are observed. Patients must have received at least two cycles of prior T-Dxd, possess measurable disease per RECIST 1.1, an ECOG performance status of 0-2, and adequate organ function. Key exclusion criteria include uncontrolled comorbidities, active interstitial lung disease, and prior adverse reactions to study agents.

The study's primary objective is to determine the ORR of each combination regimen. Secondary objectives encompass PFS, DCR, DOR, OS, and safety assessments. Exploratory biomarker analyses will be conducted on serial blood and stool samples to identify predictors of response and resistance. Tumor assessments occur every 6 weeks, with safety evaluations at each treatment visit and a follow-up period of 90 days post-treatment, then every 3 months for survival status. By exploring these combination strategies, RADIANT-BC01 seeks to establish new therapeutic options for patients who have exhausted current HER2-targeted treatments.

Inclusion Criteria:

1. Age ≥18 years.
2. Histologically or cytologically confirmed HER2-positive (IHC 3+ or IHC 2+ with ISH amplification) advanced or metastatic breast cancer.
3. Prior treatment with trastuzumab deruxtecan (T-DXd) and documented disease progression during or after therapy.
4. At least one measurable lesion at baseline as defined by RECIST v1.1.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Adequate organ and marrow function, including:

Absolute neutrophil count ≥1.5 × 10⁹/L Platelet count ≥100 × 10⁹/L Hemoglobin ≥9 g/dL ALT and AST ≤2.5 × ULN Total bilirubin ≤1.5 × ULN Creatinine clearance ≥50 mL/min Estimated life expectancy of ≥12 weeks. Ability to understand and willingness to sign a written informed consent form.

Exclusion Criteria:

1. Prior treatment with disitamab vedotin (RC48).
2. Active infections requiring systemic therapy (bacterial, viral, or fungal).
3. History of interstitial lung disease or non-infectious pneumonitis requiring corticosteroid therapy.
4. Uncontrolled cardiovascular disease, including but not limited to: uncontrolled hypertension, recent myocardial infarction (within 6 months), unstable angina, or congestive heart failure.
5. Pregnant or breastfeeding women.
6. Concurrent malignancy other than adequately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix, unless disease-free for ≥5 years.
7. Participation in another interventional clinical trial with investigational agents not yet completed.
8. Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements or jeopardize their safety.