Efficacy and Safety Evaluation of Trastuzumab Deruxtecan in Patients with Unresectable or Metastatic Solid Tumors Harboring HER2 Activating Mutations

The primary objective of this Phase II, multicenter, open-label study is to assess the **efficacy** of Trastuzumab Deruxtecan (T-DXd) in patients with metastatic or unresectable solid tumors harboring specific HER2 activating mutations across various tumor types. This is clinically relevant as it aims to determine the potential of T-DXd as a targeted therapy for tumors with these specific genetic alterations, which could lead to more personalized and effective treatment options for patients with such tumors.

Secondary objectives include:

• To further assess the efficacy of T-DXd in patients with metastatic or unresectable tumors harboring pre-specified HER2 activating mutations across tumor types.
• To assess the safety and tolerability of T-DXd.
• To assess the pharmacokinetics (PK) of T-DXd, total anti-HER2 antibody, and MAAA-1181a in serum.
• To investigate the immunogenicity of T-DXd.

The clinical trial involves a total of **62 participants** diagnosed with **unresectable and/or metastatic solid tumors** harboring specific HER2 activating mutations, irrespective of tumor histology. The study population includes both male and female adults aged 18 years and older, with the age range extending to include older adults as per local regulations. Participants were selected based on the presence of pre-specified HER2 mutations, determined locally by next-generation sequencing (NGS) on tumor tissue, and have either progressed following prior treatment or lack satisfactory alternative treatment options. The trial includes individuals who have previously received HER2 targeted therapy. All participants are required to provide a formalin-fixed paraffin-embedded (FFPE) tumor sample for retrospective central HER2 testing. The general health status of participants is assessed with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and a left ventricular ejection fraction (LVEF) of 50% or higher. The trial also considers vulnerable populations, ensuring comprehensive representation within the study cohort.

The clinical trial is a **Phase II, multicenter, open-label study** designed to evaluate the efficacy and safety of **trastuzumab deruxtecan** for the treatment of unresectable and/or metastatic solid tumors harboring specific HER2 activating mutations, regardless of tumor histology. The trial aims to assess the efficacy of the investigational product in patients with metastatic or unresectable tumors with these mutations. The primary endpoint is the confirmed objective response rate by RECIST v1.1 based on independent central review. Secondary endpoints include duration of response, disease control rate, progression-free survival, overall survival, occurrence of adverse events, and pharmacokinetics, among others.

The trial is expected to run from March 15, 2021, to July 14, 2026. Participants will be involved in the study for the duration necessary to achieve the endpoints, with the possibility of early termination if specific conditions arise, such as adverse events or lack of efficacy. The study involves several visits, starting with an inclusion (screening) visit to determine eligibility based on criteria such as age, tumor characteristics, and prior treatments. Follow-up visits will be conducted to monitor the participants' response to the treatment and any adverse effects. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and collecting data for analysis.

Participants must be adults aged 18 years or older with unresectable and/or metastatic solid tumors with pre-specified HER2 mutations, as determined by next-generation sequencing on tumor tissue. Prior HER2 targeted therapy is permitted, and all patients must provide a formalin-fixed paraffin-embedded tumor sample for retrospective central HER2 testing. Key inclusion criteria include a left ventricular ejection fraction of at least 50% and an Eastern Cooperative Oncology Group performance status of 0-1. The investigational product, DS-8201a, is administered as a **solution for infusion** via **intravenous use**. The study is not classified as a low-intervention trial, and it does not involve a pediatric formulation.

The clinical trial involves the administration of **trastuzumab deruxtecan**, commercially known as DS-8201a, which is an investigational medication. This medication is provided in the form of a **solution for infusion** and is intended for **intravenous use**. The active substance, trastuzumab deruxtecan, is a protein-based compound categorized under "Protein - Other". The pharmaceutical formulation is designed for the treatment of patients with unresectable and/or metastatic solid tumors harboring HER2 activating mutations, regardless of tumor histology. The dosing regimen is specified in milligrams per kilogram (mg/kg), although the exact dosage and frequency are not detailed in the provided data. The maximum treatment period is set at an extensive duration, indicating long-term administration potential.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on evaluating the efficacy and safety of trastuzumab deruxtecan. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol. The investigational product is not a pediatric formulation and is not classified as an orphan drug. The trial is conducted under the sponsorship of Daiichi Sankyo, Inc., which is responsible for the development and provision of the investigational product.

The efficacy of **Trastuzumab Deruxtecan (T-DXd)** in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the confirmed objective response rate (ORR) evaluated by RECIST v1.1 criteria based on independent central review (ICR). Secondary endpoints include the duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), all assessed by ICR. Additionally, the trial will evaluate the confirmed ORR based on investigator assessment, the occurrence of adverse events (AEs) and serious adverse events (SAEs), pharmacokinetics (PK) through serum concentration measurements of T-DXd, total anti-HER2 antibody, and MAAA-1181, as well as the immunogenicity of T-DXd by detecting anti-drug antibodies (ADAs).