Disitamab Vedotin Plus Bevacizumab in HER2-Low Metastatic Breast Cancer After T-DXd Failure: A Phase II Study

Phase 2RecruitingNCT07446452

The First Affiliated Hospital with Nanjing Medical University37 enrolled

Overview

This is a multicenter, single-arm, phase II clinical trial designed to evaluate the efficacy and safety of disitamab vedotin in combination with bevacizumab in patients with HER2-low advanced or metastatic breast cancer who have experienced disease progression following prior T-DXd therapy. Eligible patients must have HER2-low expression (IHC 1+ or 2+/FISH-) and have previously received T-DXd. Participants will receive RC48 (disitamab vedotin) plus bevacizumab according to the study protocol. Treatment-related adverse events will be closely monitored and managed, with severity graded according to CTCAE v5.0 criteria. Supportive care or dose adjustments will be implemented as necessary. The primary endpoint is objective response rate (ORR). Secondary endpoints include progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DOR), all of which will be evaluated by an independent review committee. Safety assessments will include the incidence, severity, management, and outcomes of adverse events. Patient-reported quality of life will be evaluated using the EORTC QLQ-C30 questionnaire at predefined intervals. In addition, this study will conduct exploratory multi-omics translational research to investigate the potential molecular mechanisms underlying treatment response and resistance, and to identify predictive biomarkers associated with clinical outcomes. The ultimate goal is to assess the therapeutic efficacy and safety of this regimen, and to develop predictive models that may help identify HER2-low patients most likely to benefit, thereby supporting precision and individualized treatment strategies.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Interventions

Disitamab Vedotin (RC48)DRUG

A HER2-targeted antibody-drug conjugate comprising a humanized anti-HER2 monoclonal antibody linked via a cathepsin-cleavable MC-VC-PAB linker to the microtubule inhibitor MMAE (drug-to-antibody ratio ≈4). Administered intravenously at 2.0 mg/kg every 2 weeks.

BevacizumabDRUG

A recombinant humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF) to inhibit tumor angiogenesis. Administered intravenously at 5 mg/kg every 2 weeks in combination with RC48.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Signed written informed consent prior to any study-related procedures. 2. Female or male participants aged 18 years or older. 3. Histologically or cytologically confirmed advanced or recurrent/metastatic HER2-low breast cancer (IHC 1+ or IHC 2+/ISH-). 4. Received at least two cycles of trastuzumab deruxtecan (T-DXd) during treatment for recurrent or metastatic disease. 5. At least one measurable lesion according to RECIST version 1.1. A lesion within a previous radiation field may be considered measurable if disease progression is confirmed at that site. 6. ECOG performance status 0-2. 7. Expected survival time \>3 months. 8. Left ventricular ejection fraction (LVEF) ≥50% by ECHO or MUGA within 4 weeks prior to the first dose. 9. Adequate organ function as determined by laboratory assessments per investigator's judgment. Exclusion Criteria: 1. Uncontrolled comorbid conditions. 2. Clinically uncontrolled pleural effusion, ascites, or pericardial effusion requiring drainage within 2 weeks prior to enrollment. 3. History or current evidence of interstitial lung disease (ILD) or non-infectious pneumonitis. 4. Use of systemic immunosuppressive medications within 14 days prior to the first dose. 5. Clinically significant pulmonary comorbidities. 6. Allogeneic organ transplantation or hematopoietic stem cell transplantation (except corneal transplant). 7. Known hypersensitivity to bevacizumab, disitamab vedotin, or any of their components or excipients. 8. Spinal cord compression or clinically active central nervous system (CNS) metastases. 9. Unresolved toxicities or complications from prior therapy that have not recovered to baseline or ≤Grade 1 (per CTCAE v5.0). 10. Known human immunodeficiency virus (HIV) infection (HIV-1/2 antibody positive). 11. Untreated active hepatitis B infection. 12. Active hepatitis C virus (HCV) infection. 13. Receipt of a live vaccine within 30 days before Cycle 1 Day 1. 14. Pregnant or breastfeeding women. 15. Any severe or uncontrolled systemic disease judged by the investigator to interfere with study participation or safety evaluation. 16. Gastrointestinal perforation or fistula, wound dehiscence requiring medical intervention, wound-healing complications, severe hemorrhage, arterial thrombotic events, or life-threatening (Grade 4) venous thromboembolism, including pulmonary embolism.

Outcomes

Primary Outcomes

Objective Response Rate (ORR)

Time frame: From first dose until disease progression or death, whichever occurs first, assessed up to 24 months.

Secondary Outcomes

Progression-Free Survival (PFS)

Time frame: From first dose to the date of radiographically confirmed disease progression or death, whichever occurs first, assessed up to 24 months.

Disease Control Rate (DCR)

Time frame: From first dose until disease progression or death, whichever occurs first, assessed up to 24 months.

Duration of Response (DOR)

Time frame: From first documented tumor response (CR or PR) until disease progression or death, whichever occurs first, assessed up to 24 months.

Overall Survival (OS)

Time frame: From first dose to the date of death from any cause, assessed up to 36 months.

Number of Participants With Treatment-Emergent Adverse Events as Assessed by NCI-CTCAE v5.0

Adverse events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity will be graded on a scale of 1 to 5, where 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Life-threatening, and 5 = Death. The number of participants with treatment-emergent adverse events (TEAEs) of any grade will be reported.

Time frame: From first dose through 90 days after last dose, assessed up to approximately 36 months.

Change from Baseline in Global Health Status/Quality of Life Score Assessed by EORTC QLQ-C30

The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) is a 30-item questionnaire used to assess the quality of life of cancer patients. The Global Health Status/Quality of Life (GHS/QoL) scale is derived from 2 specific items within the questionnaire (questions 29 and 30). Scoring: The raw score is transformed to a linear scale ranging from 0 to 100. Interpretation: A higher score indicates a higher ("better") quality of life, while a lower score indicates a lower quality of life.

Time frame: Assessed at baseline (pre-dose), every 8 weeks during treatment (±7 days), at end of treatment (within 30 days after the last dose), at safety follow-up (Day 90 ±7 days after the last dose).