Phase III Randomized Double-Blind Placebo-Controlled Trial of Atezolizumab and Trastuzumab Emtansine in High-Risk HER2-Positive Breast Cancer Post-Preoperative Therapy

The primary objective of this study is to evaluate the **efficacy** of atezolizumab when administered in combination with trastuzumab emtansine, compared to placebo and trastuzumab emtansine, in patients with early human epidermal growth factor receptor 2 (HER2) positive breast cancer. This is clinically relevant as it aims to determine the potential benefit of adding atezolizumab to the standard treatment regimen, which could improve outcomes for patients at high risk of recurrence following preoperative therapy.

Secondary objectives include:

• Evaluating the efficacy of atezolizumab in combination with trastuzumab emtansine based on invasive disease-free survival (IDFS), including second primary non-breast invasive cancer, disease-free survival, overall survival, distant recurrence-free interval, and the proportion of patients with clinically meaningful deterioration in global health status/quality of life (GHS/QoL).
• Assessing the safety of atezolizumab when combined with trastuzumab emtansine compared to placebo and trastuzumab emtansine.
• Characterizing the pharmacokinetic profiles of atezolizumab and trastuzumab emtansine.
• Evaluating the immune response to atezolizumab and trastuzumab emtansine.

The clinical trial involves a total of **773 participants** diagnosed with **early human epidermal growth factor receptor 2 (HER2) positive 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 criteria, including a histologically confirmed diagnosis of invasive breast carcinoma and pathologic evidence of residual invasive carcinoma post-surgery. The trial does not include a vulnerable population. Participants have completed preoperative systemic chemotherapy and HER2-directed treatment, with adequate surgical excision of all clinically evident disease. The interval between primary surgery and randomization does not exceed 12 weeks. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of adjuvant **atezolizumab** in combination with **trastuzumab emtansine** compared to placebo and trastuzumab emtansine in patients with early **HER2-positive breast cancer** at high risk of recurrence following preoperative therapy. The trial aims to assess the primary endpoint of invasive disease-free survival, with secondary endpoints including overall survival, disease-free survival, and the incidence of adverse events. The trial is expected to run from May 2021 to June 2035, with a maximum treatment period of 42 weeks 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 histologically confirmed invasive breast carcinoma and completion of preoperative systemic chemotherapy. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any adverse events. The expected length of participant involvement is up to 42 weeks, with conditions for early termination including significant adverse events or withdrawal of consent.

The trial methodology involves administering **Tecentriq 1,200 mg** concentrate for solution for infusion and **Herceptin 600 mg** solution for injection, with the placebo group receiving **Tecentriq placebo**. The study will utilize intravenous infusion and subcutaneous routes for drug administration. Participants will be monitored for serum concentrations of atezolizumab and trastuzumab emtansine, as well as the incidence of antidrug antibodies. The trial's rigorous design ensures the collection of robust data to evaluate the therapeutic potential of the investigational treatments in improving outcomes for patients with HER2-positive breast cancer.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Tecentriq 1,200 mg** is an experimental medication used in this study. It is provided as a **concentrate for solution for infusion** and contains the active substance **atezolizumab**. The medication is administered via **intravenous infusion**. The maximum daily dose is 1,200 mg, with a total maximum dose of 16.8 g over a treatment period of 42 days. The product is manufactured by Roche Registration GmbH and is packaged and labeled specifically for clinical trial use.

Another experimental treatment in the trial is **Herceptin 600 mg**, which is a **solution for injection in a vial**. The active substance in Herceptin is **trastuzumab**. This medication is administered **subcutaneously**. The maximum daily dose is 600 mg, with a total maximum dose of 8.4 g over a 42-day treatment period. Like Tecentriq, Herceptin is also produced by Roche Registration GmbH and is prepared with secondary packaging and labeling suitable for clinical trial use.

**Kadcyla 160 mg** is also part of the experimental treatments and is provided as a **powder for concentrate for solution for infusion**. The active substance is **trastuzumab emtansine**. This medication is administered via **intravenous infusion**. The dosing is based on body weight, with a maximum daily dose of 3.6 mg/kg and a total maximum dose of 50.4 mg/kg over the course of 42 days. The product is manufactured by Roche Registration GmbH and is packaged and labeled for clinical trial purposes.

The non-experimental treatment in this trial is a **placebo** for Tecentriq, referred to as **Tecentriq placebo**. The pharmaceutical form, dosage, and route of administration for the placebo are not specified in the provided data. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know who is receiving the active treatment or the placebo.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is **invasive disease-free survival**. Secondary endpoints include invasive disease-free survival including second primary non-breast invasive cancer, disease-free survival, overall survival, and distant recurrence-free interval. Additionally, the trial will evaluate the proportion of patients experiencing clinically meaningful deterioration in global health status/quality of life (GHS/QoL) physical, role, and cognitive function, as measured by the European Organisation for Research and Treatment of Cancer quality of life questionnaire for cancer (EORTC QLQ C30). Mean absolute scores and mean change from baseline scores in GHS/QoL, physical, role, and cognitive function will also be assessed using the EORTC QLQ C30.

The trial will further monitor the incidence and severity of adverse events, as well as the maximum and minimum serum concentrations for atezolizumab and trastuzumab emtansine. The incidence of antidrug antibodies (ADAs) to atezolizumab and trastuzumab emtansine will be measured at specified timepoints. These efficacy parameters will be collected and analyzed to determine the effectiveness of atezolizumab in combination with trastuzumab emtansine compared to placebo and trastuzumab emtansine in patients with HER2-positive breast cancer at high risk of recurrence following preoperative therapy.