RC48 Plus Bevacizumab or Pyrotinib in HER2-Positive Metastatic Breast Cancer After T-DXd Failure: A Phase II Study

Not Applicable

Recruiting

• Conditions: HER2 + Breast Cancer
• Interventions: Drug: Disitamab Vedotin (RC48); Drug: Bevacizumab; Drug: Pyrotinib

• Registration Number: NCT07065435
• Lead Sponsor: The First Affiliated Hospital with Nanjing Medical University

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study Start: 2024-01-01
• Status Verified: 2025-06
• Study First Submitted: 2025-07-02
• Study First Submitted QC: 2025-07-13
• Last Update Submitted: 2025-07-13
• Study First Posted: 2025-07-15
• Last Update Posted: 2025-07-15
• Primary Completion: 2025-12-01
• Study Completion: 2026-01-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 74

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RC48 + Bevacizumab	Disitamab Vedotin (RC48)	Participants receive Disitamab Vedotin (RC48) at 2.0 mg/kg IV every 2 weeks plus Bevacizumab 7.5 mg/kg IV every 2 weeks. Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or initiation of new anticancer therapy.
RC48 + Bevacizumab	Bevacizumab	Participants receive Disitamab Vedotin (RC48) at 2.0 mg/kg IV every 2 weeks plus Bevacizumab 7.5 mg/kg IV every 2 weeks. Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or initiation of new anticancer therapy.
RC48 + Pyrotinib	Disitamab Vedotin (RC48)	Participants receive Disitamab Vedotin (RC48) at 2.0 mg/kg IV every 2 weeks plus Pyrotinib 320 mg orally once daily (post-meal). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or initiation of new anticancer therapy.
RC48 + Pyrotinib	Pyrotinib	Participants receive Disitamab Vedotin (RC48) at 2.0 mg/kg IV every 2 weeks plus Pyrotinib 320 mg orally once daily (post-meal). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or initiation of new anticancer therapy.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months	The Objective Response Rate (ORR) is defined as the proportion of patients who achieve a complete response (CR) or partial response (PR) according to RECIST version 1.1 criteria, as assessed by independent radiological review. Tumor assessments will be performed every 6 weeks. This endpoint evaluates the antitumor activity of RC48 in combination with either bevacizumab or pyrotinib in patients with HER2-positive advanced breast cancer who have failed prior treatment with trastuzumab deruxtecan (T-Dxd).

Secondary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months	Progression-Free Survival is defined as the time from the date of randomization to the date of first documented disease progression (per RECIST v1.1 by independent review) or death from any cause, whichever occurs first. PFS will be used to evaluate the efficacy of the combination regimens in delaying disease progression in patients with HER2-positive advanced breast cancer previously treated with trastuzumab deruxtecan.
Overall Survival (OS)	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months	Overall Survival is defined as the time from randomization to death from any cause. Patients who are still alive at the time of analysis will be censored at the date of last follow-up. OS will provide a measure of the survival benefit of RC48 combined with either bevacizumab or pyrotinib.
Duration of Response (DoR)	From first documented response until disease progression or death, assessed up to 24 months	Duration of Response is defined as the time from the first documentation of objective tumor response (CR or PR per RECIST v1.1) to the time of disease progression or death. Only patients with confirmed objective response will be included in this analysis.
Disease Control Rate (DCR)	Assessed at 6 weeks and every 8 weeks thereafter up to 24 months	Disease Control Rate is defined as the proportion of patients who achieve a complete response (CR), partial response (PR), or stable disease (SD) lasting at least 6 weeks, based on RECIST v1.1 as assessed by independent review.
Incidence of Treatment-Related Adverse Events	From first dose until 30 days after last dose, assessed up to 36 months	The incidence and severity of treatment-related adverse events (TRAEs) will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. This measure aims to evaluate the safety and tolerability of the treatment regimens.

Trial Locations

Locations (1)

The First Affiliated Hospital with Nanjing Medical University; 🇨🇳 Nanjing, Jiangsu, China