Phase 3 Randomized, Double-Blind Study of Tucatinib with Ado-Trastuzumab Emtansine in Unresectable Locally-Advanced or Metastatic HER2-Positive Breast Cancer

The primary objective of this randomized, double-blind, phase 3 study is to compare **progression-free survival (PFS)** by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 between treatment arms in subjects with unresectable locally-advanced or metastatic HER2-positive breast cancer. This objective is clinically relevant as it evaluates the efficacy of the treatment in delaying disease progression, which is crucial for improving patient outcomes in this aggressive cancer type.

Secondary objectives include:

• Comparing overall survival (OS) between treatment arms, which is vital for assessing the long-term benefits of the treatment.
• Comparing PFS by investigator assessment per RECIST v1.1 in subjects with brain metastases at baseline (PFS.BM per investigator) between treatment arms, providing insights into the treatment's effectiveness in a subgroup with a poor prognosis.
• Comparing the objective response rate (ORR) by investigator assessment per RECIST v1.1 between treatment arms, which helps evaluate the proportion of patients achieving a significant reduction in tumor size.
• Comparing overall survival in subjects with brain metastases at baseline (OS.BM) between treatment arms, which is important for understanding the treatment's impact on survival in this high-risk group.

The clinical trial involves a total of **466 participants** diagnosed with **unresectable locally-advanced or metastatic HER2+ breast cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as having a histologically confirmed HER2+ breast carcinoma and a history of prior treatment with a taxane and trastuzumab. The trial also considers the **Eastern Cooperative Oncology Group (ECOG) performance status**, requiring a score of 0 or 1, indicating that participants are fully active or restricted in physically strenuous activity but ambulatory. The trial population includes individuals with varying health statuses, including those with brain metastases under certain conditions. Lifestyle factors such as diet and physical activity are not specified in the available data. The trial does not exclude vulnerable populations, indicating a broad inclusion strategy to assess the treatment's efficacy across diverse demographic groups.

The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the efficacy and safety of **tucatinib** in combination with **ado-trastuzumab emtansine** (T-DM1) compared to placebo in subjects with unresectable locally-advanced or metastatic **HER2-positive breast cancer**. The trial aims to compare progression-free survival (PFS) as the primary endpoint, assessed by investigators using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints include overall survival (OS), PFS in brain metastases (PFS.BM), overall response rate (ORR), and OS in brain metastases (OS.BM). The trial is expected to run from October 2019 to December 2025, with a maximum treatment period of 74 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed HER2-positive breast carcinoma, prior treatment history, and measurable disease status. The trial includes follow-up visits to monitor treatment response and safety, with assessments conducted according to RECIST v1.1 guidelines. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any adverse events. The expected length of participant involvement is up to 74 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

The investigational products include **Kadcyla** (ado-trastuzumab emtansine) administered via intravenous infusion and **TUKYSA** (tucatinib) in film-coated tablet form, taken orally. Placebo tablets are also used to maintain the double-blind design. The trial is conducted under strict regulatory compliance, ensuring the safety and well-being of participants throughout the study duration.

The clinical trial involves the administration of **Kadcyla**, a 160 mg powder for concentrate for solution for infusion, containing the active substance **trastuzumab emtansine**. This medication is an antibody-drug conjugate and is administered via **intravenous infusion**. The maximum daily dose is 3.6 mg/kg, with a total maximum dose of 386.4 mg/kg over a treatment period of up to 74 weeks. The pharmaceutical form is a solution for infusion, and the product is manufactured by Roche Registration GmbH. Participant compliance is monitored through regular assessments and adherence checks.

**TUKYSA** is another experimental medication used in this trial, available in two dosages: 150 mg and 50 mg film-coated tablets. The active substance is **tucatinib**, a chemical compound. The maximum daily dose for TUKYSA is 600 mg, with a total maximum dose of 1,352,400 mg over the same treatment period of 74 weeks. The tablets are administered orally, and the product is manufactured by Seagen B.V. The clinical trial uses a high-density polyethylene (HDPE) bottle for clinical material, differing from the commercial blister pack, with specific storage conditions of 2-8°C and a 36-month shelf-life for clinical use.

The trial also includes the use of placebo tablets, which are designed to match the appearance of the TUKYSA tablets. These placebo tablets are available in 150 mg and 50 mg dosages and are used to maintain the double-blind nature of the study. The placebo tablets do not contain any active substance and are administered orally in the same manner as the active TUKYSA tablets. Compliance with the placebo administration is monitored similarly to the active treatments.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**, as determined by investigator assessment using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. This primary endpoint will compare PFS between treatment arms, specifically evaluating the combination of tucatinib or placebo with ado-trastuzumab emtansine (T-DM1) in subjects with unresectable locally-advanced or metastatic HER2-positive breast cancer.

Secondary endpoints include overall survival (OS), PFS in patients with brain metastases (PFS.BM) per RECIST v1.1, overall response rate (ORR) per RECIST v1.1, and OS in patients with brain metastases (OS.BM). These endpoints will also be assessed by investigator evaluation using the RECIST v1.1 criteria. The trial is designed as a randomized, double-blind, phase 3 study, with the efficacy parameters being measured and collected at specified intervals throughout the trial duration, which is estimated to conclude by December 2025.