A phase II, open-label, multicenter, randomized controlled trial exploring the efficacy and safety of Trastuzumab Deruxtecan combined with or without Neratinib in HER2-positive breast cancer with brain metastasis
This study is a prospective, multicenter, open-label, Phase II, randomized controlled clinical trial aimed at evaluating the efficacy and safety of T-DXd with or without neratinib in patients with HER2-positive breast cancer with brain metastases. All eligible subjects will be randomly assigned in a 1:1 ratio across multiple centers in China to receive either T-DXd combined with neratinib or T-DXd monotherapy until extracranial progression as defined by RECIST 1.1, unless unacceptable toxicity occurs, consent is withdrawn, or other criteria for discontinuation are met.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
202
Neratinib, as an irreversible pan-HER tyrosine kinase inhibitor (TKI), holds a unique position in the treatment of HER2-positive breast cancer. From a molecular perspective, Neratinib irreversibly binds to the intracellular kinase domains of HER1 (EGFR), HER2, and HER4 through covalent bonds, comprehensively blocking signal transduction of the HER family. This mechanism of action is markedly different from reversible TKIs such as lapatinib. Neratinib's irreversible binding characteristic allows for a more sustained inhibition of target activity, maintaining anti-tumor effects even after drug plasma concentrations have decreased. This feature is particularly important for HER2-positive breast cancer, which requires continuous suppression of proliferative signals.
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) composed of an anti-HER2 monoclonal antibody (trastuzumab), a cleavable linker, and a topoisomerase I inhibitor (an exatecan derivative). It targets and binds to HER2-positive tumor cells, internalizes, and releases cytotoxic drugs to induce DNA damage and apoptosis. It also has a "bystander effect" that can kill neighboring tumor cells with low HER2 expression, enhancing anti-tumor activity. T-DXd has shown significant efficacy in HER2-positive advanced breast cancer, with key clinical trials (such as DESTINY-Breast03) confirming that its progression-free survival (PFS) and overall survival (OS) are superior to traditional second-line treatments, with a median PFS reaching 28.8 months. Additionally, for HER2-low-expressing (IHC 1+ or 2+/ISH-) metastatic breast cancer (in the DESTINY-Breast04 study), T-DXd can extend PFS and OS, becoming the first targeted therapy to alter the survival outcomes of such patients
Progression Free Survival(PFS)
Time to progressive disease (according to RECIST1.1)
Time frame: 24 months
CNS Progression-free survival (CNS-PFS)
Time from enrollment to the first radiographic documented disease progression (PD) of all CNS target lesions (RANO-BM criteria) or death from any cause without progression was recorded.
Time frame: 24 months
Objective response rate (ORR)
Partial response is defined as a decrease by 30% or more in sums of longest diameter of measurable target lesions
Time frame: 24 months
CNS Objective response rate (CNS-ORR)
The proportion of patients with complete response (CR) and partial response (PR) evaluated as the best response observed from enrollment to progression of all CNS target lesions assessed according to RANO-BM criteria among the total number of patients who could be evaluated.
Time frame: 24 months
Overall survival (OS)
Time from the enrollment to death of any cause
Time frame: 48 months
Safety and Tolerability
Safety and Tolerability Will be Assessed According to Standard (CTCAE Version 5.0) Toxicity Reporting Criteria.
Time frame: 24 months
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