Phase 3b/4 Study of Trastuzumab Deruxtecan in HER2-Positive Breast Cancer Patients With or Without Brain Metastasis After Prior Treatment

The primary objective of this study is to describe the overall treatment effect of **trastuzumab deruxtecan** (T-DXd) in patients with HER2-positive metastatic breast cancer (MBC) with or without baseline brain metastasis (BM). This is clinically relevant as it aims to evaluate the efficacy of T-DXd in a population with advanced disease, potentially offering insights into improved therapeutic strategies for managing HER2-positive MBC, particularly in the context of brain metastasis, which is a significant complication in this patient group.

Secondary objectives include:

• Describing the treatment effect on the development and progression of BM in patients with or without baseline BM using additional efficacy measurements.
• Describing efficacy in patients with stable or untreated BM.
• Describing the effect of T-DXd on symptoms, functioning, and health-related quality of life (HRQoL) in HER2-positive MBC patients with or without baseline BM.
• Describing the safety profile of T-DXd.

The clinical trial involves a total of **105 participants** diagnosed with **HER2-positive breast cancer**, with or without brain metastasis. The study population includes both male and female subjects, encompassing an age range of **18 to 64 years**. Participants were selected based on specific inclusion criteria, including pathologically documented breast cancer that is unresectable, advanced, or metastatic, with confirmed HER2-positive status. The trial includes individuals with no evidence of brain metastasis, untreated brain metastasis not requiring immediate local therapy, or previously treated stable or progressing brain metastasis. Participants with brain metastases must be neurologically stable, with specific requirements for dexamethasone and anticonvulsant regimens. The trial population may include individuals from vulnerable populations. Previous treatment with HER2-targeted therapies and evidence of disease progression are also considered in the selection process. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **trastuzumab deruxtecan** in patients with previously treated advanced or metastatic **HER2-positive breast cancer**, with or without brain metastasis. This is a Phase 3b/4, open-label, multinational, and multicenter study. The trial employs a randomized, controlled design to ensure robust data collection and analysis. The estimated duration of the trial is from March 2021 to February 2026, with participant involvement expected to last until the end of the study or until early termination criteria are met.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as documented HER2-positive status and the presence or absence of brain metastasis. Following the screening, eligible participants will be randomized into cohorts based on their baseline brain metastasis status. Regular follow-up visits will be conducted to monitor treatment effects, safety, and disease progression. These visits will include assessments such as imaging studies, laboratory tests, and evaluations of symptoms and quality of life. The end-of-study visit will occur at the conclusion of the treatment period or upon early withdrawal from the study.

The expected length of participant involvement is contingent upon individual response to treatment and disease progression. Conditions that may lead to early termination from the study include significant adverse events, disease progression requiring alternative therapy, or withdrawal of consent. The primary endpoints focus on objective response rate (ORR) and progression-free survival (PFS) as assessed by RECIST 1.1 criteria. Secondary endpoints include overall survival (OS), duration of response (DoR), and safety assessments, among others. The trial aims to provide comprehensive data on the treatment's impact on both systemic and central nervous system disease manifestations.

The clinical trial involves the administration of **trastuzumab deruxtecan**, an experimental medication identified by the sponsor product code DS-8201a. This investigational product is provided in the form of a **solution for infusion**. The pharmaceutical formulation is designed for **intravenous use**. The dosing regimen is specified in milligrams per kilogram (mg/kg), although the exact dosage and frequency of administration are not detailed in the provided data. The maximum treatment period is indicated as 999,999 time units, suggesting an extended duration of administration, though the specific time unit is not defined. The active substance, trastuzumab deruxtecan, is of chemical and biological origin, specifically categorized as a protein of other origin. The product is manufactured by Daiichi Sankyo, Inc.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are explicitly mentioned. The trial is designed to evaluate the overall treatment effect of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer, with or without baseline brain metastasis. Participant compliance with the dosing schedule will be monitored, although specific compliance measures are not detailed in the available data. The trial does not involve a pediatric formulation, and the product is not classified as an orphan drug. The study is conducted under the authorization of AstraZeneca, AB, Molndal, Sweden, as indicated by the MIA number provided.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. For participants without baseline brain metastasis (Cohort 1), the primary endpoint is the Objective Response Rate (ORR) evaluated by RECIST 1.1 criteria as per Independent Central Review (ICR). For participants with baseline brain metastasis (Cohort 2), the primary endpoint is Progression-Free Survival (PFS) by RECIST 1.1 per ICR.

Secondary endpoints include overall survival (OS), duration of response (DoR) by RECIST ICR, time to progression by RECIST ICR, duration of treatment on subsequent therapy lines, and PFS2 for both cohorts. Additionally, for Cohort 1, the incidence of new symptomatic CNS metastasis during treatment will be evaluated. In patients with isolated CNS progression who receive local therapy and continue on protocol therapy, time to next progression (CNS or extracranial) or death, and the site of next progression (CNS vs extracranial vs both) will be assessed.

For participants with baseline brain metastasis (Cohort 2), secondary endpoints include ORR by RECIST 1.1 per ICR, CNS PFS by CNS RECIST 1.1 per ICR, time to new CNS lesions, CNS ORR by CNS RECIST 1.1 per ICR, and CNS DoR by CNS RECIST 1.1 per ICR. Changes in symptoms, functioning, and health-related quality of life (HRQoL) will be measured using the EORTC QLQ-C30, NANO scale, cognitive tests for all patients, MDASI brain tumor-specific items for brain metastasis patients, and SGRQ-I for patients with interstitial lung disease (ILD)/pneumonitis.

Safety and tolerability will be evaluated through adverse events (AEs), vital signs, clinical laboratory results, electrocardiograms (ECGs), the rate of investigator-assessed ILD/pneumonitis, and the rate of AEs among patients with baseline brain metastasis treated with concurrent high-dose steroids (total daily dose > 2 mg dexamethasone or equivalent).