Evaluation of ERBB2 mRNA Cut-Point for Predicting Trastuzumab Deruxtecan Efficacy in Advanced or Metastatic Cancer Patients

The primary objective of this study is to identify the optimal **ERBB2 mRNA** cut-point predictive of response to **Trastuzumab Deruxtecan** in breast cancer. This is clinically relevant as it aims to enhance the precision of treatment by determining the most effective threshold for predicting therapeutic response, potentially improving patient outcomes in breast cancer management.

Secondary objectives include:

• Identifying the optimal ERBB2 mRNA cut-point predictive of Trastuzumab Deruxtecan response in all tumors.
• Evaluating the correlation of mRNA ERBB2 levels in baseline FFPE tumor samples with overall response in Trastuzumab Deruxtecan-treated cohorts.
• Assessing the association of mRNA ERBB2 levels with progression-free survival and overall survival.
• Evaluating the association of PAM50 intrinsic subtypes with overall response, progression-free survival, and overall survival.
• Investigating the association of immune-related genes with overall response, progression-free survival, and overall survival.
• Designing a new gene expression signature predictive of Trastuzumab Deruxtecan benefit.
• Evaluating the benefit of Trastuzumab Deruxtecan across somatic mutations.
• Correlating early changes in ctDNA with Trastuzumab Deruxtecan benefit.
• Identifying acquired somatic mutations of resistance to Trastuzumab Deruxtecan upon progression in plasma samples.

The clinical trial involves **patients diagnosed with advanced or metastatic cancer** who are treated with Trastuzumab Deruxtecan, regardless of the histologic type. The study population comprises women aged 18 years and older, as the trial does not include male participants. The sponsor has not provided the total number of participants. Participants were selected based on their treatment status with Trastuzumab Deruxtecan, either starting, currently receiving, or having received the treatment. The trial does not focus on a vulnerable population. Participants are required to provide a formalin-fixed, paraffin-embedded tumor tissue block for central molecular analysis. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The trial aims to identify the optimal ERBB2 mRNA cut-point predictive of Trastuzumab Deruxtecan response in breast cancer.

The clinical trial is designed to evaluate the efficacy of **trastuzumab deruxtecan** in patients diagnosed with advanced or metastatic cancer. This study is a Phase IV, randomized, double-blind, controlled trial, aiming to identify the optimal ERBB2 mRNA cut-point predictive of response to the treatment. The trial commenced on December 13, 2019, and is expected to conclude by September 30, 2027. Participants will be involved in the study for a maximum treatment period of 100 days, with the treatment administered via intravenous infusion.

Study visits are structured to ensure comprehensive data collection and participant safety. The inclusion visit, or screening, will confirm eligibility based on criteria such as age (≥18 years), cancer diagnosis, and prior or current treatment with trastuzumab deruxtecan. Participants must provide a formalin-fixed, paraffin-embedded tumor tissue block for central molecular analysis. Follow-up visits will occur at regular intervals to monitor treatment response and collect additional data, including blood samples and tumor biopsies if necessary. The end-of-study visit will assess the overall response and gather final data for analysis.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include adverse reactions to the treatment, withdrawal of consent, or any medical circumstances that compromise participant safety. The trial's primary endpoint is to correlate mRNA ERBB2 levels with overall response, while secondary endpoints include evaluating associations with progression-free survival, overall survival, and the benefit of trastuzumab deruxtecan across various genetic markers. The study aims to enhance understanding of the treatment's biological effects and optimize therapeutic strategies for patients with advanced or metastatic cancer.

The clinical trial involves the administration of **trastuzumab deruxtecan**, marketed under the name Enhertu. This experimental medication is provided in the form of a powder for concentrate, which is then prepared as a solution for infusion. The pharmaceutical form is specifically designed for **intravenous use**. Each vial contains 100 mg of the active substance, trastuzumab deruxtecan, which is a protein-based compound. The maximum daily and total dose is set at 100 mg, with a treatment period extending up to 100 days. The administration schedule is determined by the study protocol, ensuring that the dosing is consistent with the trial's objectives. Participant compliance is monitored through regular assessments and documentation of infusion sessions.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on evaluating the efficacy and safety of trastuzumab deruxtecan in the context of the trial's objectives. The trial aims to identify the optimal ERBB2 mRNA cut-point predictive of trastuzumab deruxtecan response in breast cancer. The study is conducted under the authorization of relevant regulatory bodies, ensuring adherence to clinical trial standards and protocols.

Efficacy in the clinical trial titled "HER2-PREDICT: Translational study of tumor samples from patients treated with Trastuzumab Deruxtecan (T-DXd; DS-8201a)" will be assessed using several primary and secondary endpoints. The primary endpoint focuses on identifying the optimal **ERBB2 mRNA** cut-point predictive of Trastuzumab Deruxtecan response in breast cancer. This involves correlating mRNA ERBB2 levels, measured as a continuous variable in baseline formalin-fixed, paraffin-embedded (FFPE) tumor samples, with the overall response in cohorts treated with DS-8201a.

Secondary endpoints include evaluating the association of mRNA ERBB2 levels with progression-free survival and overall survival. Additionally, the study will assess the association of PAM50 intrinsic subtypes (Luminal A, Luminal B, HER2-enriched, and Basal-like) with overall response rate, progression-free survival, and overall survival. The trial will also explore the association of immune-related genes with these outcomes, design a new gene expression signature predictive of DS8201a benefit, evaluate the benefit of DS8201a across somatic mutations, correlate early changes in circulating tumor DNA (ctDNA) with DS8201a benefit, and identify acquired somatic mutations of resistance to DS8201a upon progression in plasma samples.