Currently, no phase III RCT has directly compared SG and T-DXd sequencing strategies, and the predictive role of biomarkers remains unclear. Additionally, there is no standard scoring system for Trop-2 expression. The ASCENT trial utilized an H-score method (H-score = 3×%IHC3+ + 2×%IHC2+ + 1×%IHC1+), with scores \<100, 100-200, and \>200 defining low, medium, and high Trop-2 expression, respectively.This prospective study aims to: 1) Evaluate the efficacy of SG vs. T-DXd in HER2-low/Trop-2-high metastatic breast cancer, prioritizing SG for Trop-2-high patients and T-DXd for others. 2) Compare sequential treatment outcomes-T-DXd after SG failure versus SG after T-DXd failure-to inform ADC sequencing in HER2-low disease. Up to one intervening therapy is allowed before sequencing. 3) Identify biomarkers of ADC efficacy and resistance through quantitative protein analysis to optimize patient selection.
This investigator-initiated study aims to evaluate the efficacy of sequential treatment with sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) in patients with HER2 IHC 1+ /Trop-2-high metastatic breast cancer. It will also explore the correlation between changes in tumor-associated protein expression levels and ADC efficacy, and investigate mechanisms of ADC resistance. The study will establish a multicenter cohort of patients treated with SG/T-DXd: Cohort A (Triple-Negative Breast Cancer, TNBC): Includes patients with unresectable locally advanced or metastatic triple-negative breast cancer (HER2 IHC 1+) who have received ≥1 prior line of systemic therapy for metastatic disease. Prior to enrollment, all patients will undergo Trop-2 expression testing. Patients identified as Trop-2-high will be randomized 1:1 to either:SG Treatment (Trop-2 Group), orT-DXd Treatment (HER2 Group). The initially administered ADC is designated as ADC1. Upon disease progression, patients may cross over to receive the other ADC as sequential therapy (designated as ADC2). One intervening non-ADC therapy (e.g., targeted therapy, chemotherapy) is permitted prior to cross-over. Randomization will maintain a 1:1 allocation between the Trop-2 and HER2 groups. Cohort B (HR+/HER2-ultralow or HER2 IHC 1+ Breast Cancer): Includes patients with unresectable locally advanced or metastatic HR+/HER2-ultralow or HER2 IHC 1+ breast cancer who have progressed on prior endocrine therapy. Prior to enrollment, all patients will undergo Trop-2 expression testing. Patients identified as Trop-2-high will be randomized 1:1 to either:SG Treatment (Trop-2 Group), orT-DXd Treatment (HER2 Group). Upon progression, patients may cross over to receive the other ADC as sequential therapy. One intervening non-ADC therapy (e.g., targeted therapy, chemotherapy) is permitted prior to cross-over. Randomization will maintain a 1:1 allocation between the Trop-2 and HER2 groups.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
216
Recommended Dose: 10 mg/kg administered by intravenous infusion on Days 1 and 8 of each 21-day treatment cycle. Continue treatment until disease progression or unacceptable toxicity.
Dosage and Administration: The recommended dose is 5.4 mg/kg administered by intravenous infusion once every 3 weeks (21-day cycles). Continue treatment until disease progression or unacceptable toxicity.
Progression-Free Survival 1 (PFS1)
Progression-Free Survival 1 (PFS1):Time from the initiation of the first ADC (ADC1) therapy to the first occurrence of disease progression (PD) or death from any cause, whichever occurs earlier.
Time frame: Until progression, assessed up to approximately 24 months
Progression-Free Survival 2 (PFS2)
Progression-Free Survival 2 (PFS2): Time from initiation of the second ADC (ADC2) therapy to the first occurrence of disease progression (PD) or death from any cause, whichever occurs earlier.
Time frame: Until progression, assessed up to approximately 24 months
Objective Response Rate (ORR1, ORR2)
Objective Response Rate (ORR1, ORR2): Proportion of patients with best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 criteria.
Time frame: Until progression, assessed up to approximately 24 months
Disease Control Rate (DCR
Disease Control Rate (DCR): Proportion of patients with best overall response of CR, PR, or stable disease (SD) according to RECIST 1.1 criteria.
Time frame: Baseline through end of study, assessed up to 24 months]
Overall Survival (OS)
Overall Survival (OS): Time from treatment initiation to death from any cause.
Time frame: Until death, assessed up to approximately 24 months
Safety Endpoints
Safety Endpoints: Include adverse event profiles, incidence rates, dose reductions, treatment delays, and discontinuations due to adverse events.
Time frame: Up to follow-up period, approximately 24 months]
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