Evaluation of Image-Guided De-Escalation of Neoadjuvant Chemotherapy with Trastuzumab, Pertuzumab, and Drug Combination in HER2-Positive Breast Cancer

The primary objective of the study is to evaluate the **efficacy** of image-guided de-escalating chemotherapy in the presence of dual HER2-blockade with Herceptin® and pertuzumab in HER2-positive breast cancer, as measured by three-year event-free survival. This is clinically relevant as it aims to optimize treatment regimens, potentially reducing treatment burden while maintaining efficacy in managing HER2-positive breast cancer.

Secondary objectives include:

• To evaluate 3-year overall survival.
• To evaluate the pathological complete response (pCR) rate in breast and axilla.
• To evaluate 5-year and 10-year overall and event-free survival rates.
• To evaluate the association between pCR and long-term outcomes.
• To evaluate the association between radiologic complete response (rCR) and pCR.
• To evaluate the association between on-treatment vacuum-assisted core biopsies (VACBs) and pCR.
• To compare short-term and long-term efficacy by the number of chemotherapy cycles received.
• To compare non-radical resection percentages between rCR and no rCR.
• To compare quality of life after receiving 3, 6, or 9 cycles of chemotherapy using the EORTC QLQ-30 and QLQ-BR45 questionnaires.
• To assess the incidence and severity of adverse events grade ≥3 (CTCAE v5.0).
• To assess the incidence and severity of cardiotoxicity and neuropathy grade ≥2.
• To assess the incidence of symptomatic left ventricular systolic dysfunction (LVSD) and asymptomatic decrease in left ventricular ejection fraction (LVEF), defined as an asymptomatic decline in LVEF requiring treatment or leading to discontinuation of pertuzumab and Herceptin® or T-DM1, or a decrease ≥10 percentage points from baseline to an LVEF <50%.

The clinical trial focuses on evaluating the efficacy of image-guided de-escalating chemotherapy in the presence of dual **HER2**-blockade with Herceptin® and pertuzumab in patients with **HER2-positive breast cancer**. The study population includes both male and female participants, aged 18 years and older, with a confirmed diagnosis of primary infiltrating breast cancer. Participants must have Stage II or III disease according to TNM-staging and meet specific laboratory and health criteria, such as adequate bone marrow, hepatic, and renal function, as well as a WHO performance status of 0 or 1. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on specific inclusion criteria, including the overexpression and/or amplification of HER2, known estrogen and progesterone receptor expression, and visible breast tumors on contrast-enhanced MRI or the presence of malignant lymph nodes. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use adequate contraceptive methods during treatment and for a specified period afterward. The trial does not include individuals who do not meet these stringent health and diagnostic criteria.

The clinical trial is designed to evaluate the efficacy of image-guided de-escalation of **chemotherapy** in the presence of dual HER2-blockade with Herceptin and **pertuzumab** in HER2-positive **breast cancer**. This is a randomized, double-blind, controlled trial with an estimated duration from October 2018 to October 2032. The trial involves multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed primary infiltrating breast cancer, stage II or III disease, and overexpression of HER2. Participants must also meet specific laboratory requirements and have a WHO performance status of ≤1.

Following the screening, participants will be randomized to receive either the investigational treatment or a comparator. The investigational treatment includes Herceptin, Kadcyla, and Perjeta, administered via intravenous infusion or subcutaneous injection, with a maximum treatment period of 12 to 56 weeks depending on the specific product. The comparator involves standard chemotherapy agents such as **paclitaxel** and **carboplatin**, also administered intravenously, with a maximum treatment period of 36 weeks. The trial will assess primary and secondary endpoints, including three-year event-free survival, overall survival, and pathologic complete response.

Study visits will occur at regular intervals to monitor treatment response and safety, with follow-up visits scheduled to assess long-term outcomes. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 56 weeks, depending on the treatment arm. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide valuable insights into the potential benefits of de-escalated chemotherapy regimens in improving outcomes for patients with HER2-positive breast cancer.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Herceptin** (trastuzumab) is utilized in two forms: a 150 mg powder for concentrate for solution for infusion and a 600 mg solution for injection in a vial. The powder form is reconstituted and administered as an **intravenous infusion** with a maximum daily dose of 8 mg/kg, over a treatment period of 12 weeks. The solution for injection is administered via **subcutaneous injection** with a maximum daily dose of 600 mg, also over a 12-week period. Both forms are produced by Roche Registration GmbH and are not pediatric formulations.

**Kadcyla** (trastuzumab emtansine) is provided as a 160 mg and 100 mg powder for concentrate for solution for infusion. This medication is administered as an **intravenous infusion** with a maximum daily dose of 3.6 mg/kg, over a treatment period of 56 weeks. Kadcyla is also manufactured by Roche Registration GmbH and is not intended for pediatric use.

**Perjeta** (pertuzumab) is available as a 420 mg concentrate for solution for infusion. It is administered via **intravenous infusion** with a maximum daily dose of 840 mg, over a 12-week treatment period. This product is also developed by Roche Registration GmbH and is not a pediatric formulation.

In addition to the experimental treatments, the trial includes non-experimental chemotherapy agents. **Paclitaxel** is administered as an **intravenous infusion** with a maximum daily dose of 80 mg/m², over a 36-week period. **Carboplatin** is also administered intravenously with a maximum daily dose of 400 mg/m², over the same 36-week period. Both agents are classified as chemical substances and are part of the standard chemotherapy regimen.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to evaluate the efficacy of image-guided de-escalation of neoadjuvant chemotherapy in HER2-positive breast cancer, with a focus on three-year event-free survival.

The efficacy of the clinical trial will be assessed primarily through the measurement of three-year event-free survival in patients with HER2-positive breast cancer undergoing image-guided de-escalation of neoadjuvant chemotherapy. This trial involves dual HER2-blockade with **Herceptin** and pertuzumab. Secondary endpoints include overall survival, pathologic complete response in breast and axilla, radiologic complete response, concordance between radiologic and pathologic responses, differences in event-free survival and overall survival between patients with pathologic complete response after 3, 6, and 9 cycles, differences in radical resections in radiologic complete response and no radiologic complete response, and health-related quality of life.

Measurements will be collected at specified intervals, including assessments after 3, 6, and 9 cycles of treatment. Radiologic complete response will be evaluated through MRI and ultrasound with fine-needle aspiration examination, while pathologic complete response will be determined by the absence of invasive tumor cells. The trial will utilize validated imaging and laboratory techniques to ensure accurate and reliable data collection. The analysis will focus on comparing the efficacy outcomes between different treatment cycles and correlating radiologic and pathologic responses with survival outcomes.