Evaluation of Therapeutic De-escalation in HER2-Positive Metastatic Breast Cancer Using Trastuzumab and Drug Combination in Patients with Controlled Disease

The primary objective of the study is to evaluate the feasibility of **therapeutic de-escalation** in patients with HER2-positive metastatic breast cancer whose disease is controlled after 2 years of maintenance treatment with anti-HER2 targeted therapy and who have negative circulating tumor DNA (ctDNA) testing. This objective is clinically relevant as it aims to determine whether reducing treatment intensity can maintain disease control, potentially minimizing treatment-related side effects and improving patient quality of life.

Secondary objectives focus on assessing various efficacy and quality of life parameters:

• In the ctDNA negative cohort at baseline, the study will assess investigator-assessed progression-free survival (PFS), ctDNA dynamics and positivity rate, overall survival (OS), molecular response, and in patients with radiological progression where anti-HER2 treatment is reintroduced, the overall response rate (ORR) and duration of response (DoR).
• The prognostic effect of ctDNA values on PFS and OS at specific landmark times (3, 6, 9, 12, 15, and 18 months) will be investigated.
• In the ctDNA positive cohort at baseline, the study will assess PFS, patterns of progression and treatment in subsequent lines, and OS.
• The quality of life (QoL) and other patient-reported outcomes (PROs), such as anxiety and decision regret, will be evaluated in the ctDNA negative cohort.

The clinical trial involves participants diagnosed with **HER2-positive** locally advanced inoperable or metastatic breast cancer, whose disease has been controlled after two years of maintenance treatment with anti-HER2 targeted therapy. The study population includes both male and female subjects aged 18 years and older. Participants are required to have adequate cardiac, renal, hematological, and hepatic functions, and must have received continuous anti-HER2 targeted therapy for at least two years. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Both men and women of childbearing potential must adhere to specific contraception guidelines during the study. The trial population selection criteria ensure that participants have a documented diagnosis of HER2-positive breast cancer, with an adequate archival tumor tissue sample available for next-generation sequencing analysis. The sponsor has not provided the total number of participants involved in the study.

The clinical trial is designed to evaluate the feasibility of therapeutic de-escalation in patients with **HER2-positive metastatic breast cancer** whose disease is controlled after two years of maintenance treatment with anti-HER2 targeted therapy and negative circulating tumor DNA (ctDNA) testing. This is a Phase IV, randomized, double-blind, controlled study. The trial is expected to commence on November 15, 2024, and conclude by November 14, 2029, with a maximum treatment period of 36 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate cardiac, renal, hematological, and hepatic functions, and a documented diagnosis of HER2-positive breast cancer. The inclusion visit will also involve obtaining informed consent and conducting necessary baseline assessments. Following the inclusion visit, participants will be randomized to receive either continued anti-HER2 therapy or a de-escalated treatment regimen. Regular follow-up visits will be scheduled to monitor disease progression, ctDNA levels, and overall health status. These visits will include radiological assessments and molecular testing to evaluate progression-free rate (PFR) and other secondary endpoints such as progression-free survival (PFS) and overall survival (OS).

The end-of-study visit will occur at the conclusion of the participant's involvement in the trial, which may last up to 36 months unless early termination criteria are met. Conditions that may lead to early termination from the study include documented disease progression, unacceptable toxicity, or withdrawal of consent. Participants will be closely monitored throughout the study to ensure safety and adherence to the protocol. The trial aims to provide valuable insights into the potential for reducing treatment intensity in patients with controlled HER2-positive metastatic breast cancer, thereby improving quality of life while maintaining disease control.

The clinical trial involves the administration of several **experimental medications** for the treatment of HER2-positive metastatic breast cancer. The primary experimental medication is **trastuzumab**, which is provided in the form of a solution for injection. The active substance, trastuzumab, is administered as a solution for infusion. The dosing schedule is determined by the study protocol, with a maximum treatment period of 36 months. The dosage is measured in milligrams, although specific daily and total dose amounts are not predefined, allowing for flexibility based on individual patient needs and response to treatment.

Another experimental medication used in the trial is **pertuzumab**, also provided as a solution for injection. Pertuzumab is administered via infusion, similar to trastuzumab, and follows the same maximum treatment period of 36 months. The dosing is also measured in milligrams, with no fixed daily or total dose amounts specified, ensuring adaptability to patient-specific therapeutic requirements.

**Trastuzumab emtansine** is included in the study as a solution for infusion. This medication combines trastuzumab with a cytotoxic agent, emtansine, to enhance its therapeutic efficacy. The administration route is infusion, and the treatment duration is capped at 36 months. The dosing is flexible, with no set daily or total dose amounts, allowing for personalized treatment adjustments.

Additionally, the trial incorporates **trastuzumab deruxtecan**, which is administered as a solution for injection. This medication is a conjugate of trastuzumab and a topoisomerase inhibitor, designed to target and destroy cancer cells more effectively. The administration is via infusion, with a treatment period of up to 36 months. The dosing is measured in milligrams, with no predetermined daily or total dose limits, facilitating tailored dosing regimens based on patient response and tolerance.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocol. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus remains on evaluating the feasibility of therapeutic de-escalation in patients with controlled disease after two years of maintenance treatment with anti-HER2 targeted therapy and negative circulating tumor DNA testing.

Efficacy in the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the **progression-free rate (PFR)**, which is defined by radiological and/or molecular progression. This includes the time from the date of registration to the first documented event among radiological progressions (as per RECIST 1.1), molecular progressions indicated by ctDNA positivity, or death due to any cause. Patients who are alive without any of these events will be censored.

Secondary endpoints include several measures of efficacy and quality of life. Efficacy will be evaluated through progression-free survival (PFS), overall survival (OS), ctDNA dynamics, molecular response, objective response rate (ORR), and duration of response (DoR). PFS is defined as the time from registration to the first documented cancer progression or death. OS is the time from registration to death due to any cause. ctDNA dynamics will be assessed by changes in ctDNA levels during the surveillance phase, with positivity rate defined as the proportion of patients with positive ctDNA. Molecular response is the percentage of patients achieving ctDNA clearance three months after reintroduction of anti-HER2 treatment. ORR is the number of patients with a confirmed complete or partial response to reintroduction of anti-HER2 treatment. DoR is the time from the onset of response after reintroduction of treatment to progression or death.

Quality of life will be assessed using the EORTC QLQ-C30 and QLQ-BR45 questionnaires, with additional evaluations of anxiety using the STAI-state questionnaire and decision regret using the decision regret scale. These assessments will provide a comprehensive evaluation of the impact of the treatment on patients' quality of life.