A Phase III, Randomized, Double-blind Study to Evaluate Pembrolizumab plus Chemotherapy vs Placebo plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy for Triple Negative Breast Cancer (TNBC)

The primary objective of this study is to evaluate the rate of **pathological complete response (pCR)** using the definition of ypT0/Tis ypN0, which indicates no invasive residual in the breast or nodes, while allowing noninvasive breast residuals. This assessment is conducted by the local pathologist at the time of definitive surgery in subjects with locally advanced **Triple Negative Breast Cancer (TNBC)**. Evaluating pCR is clinically relevant as it serves as a surrogate marker for long-term outcomes in breast cancer treatment, potentially indicating a favorable prognosis.

Secondary objectives include:

• Evaluating overall survival (OS) in subjects with locally advanced TNBC tumors.
• Evaluating the rate of pCR using an alternative definition, ypT0 ypN0, in subjects with locally advanced TNBC and in individuals with programmed death ligand 1 (PD-L1) positive tumors (combined positive score [CPS] ≥1).
• Evaluating the rate of pCR using the definition of (ypT0/Tis ypN0) in individuals with PD-L1 (+) tumors (CPS ≥1).
• Evaluating the event-free survival (EFS) as assessed by the investigator in individuals with PD-L1 (+) tumors (CPS ≥1).
• Evaluating the rate of pCR using an alternative definition, ypT0/Tis, in subjects with locally advanced TNBC and in individuals with PD-L1 (+) tumors (CPS ≥1).
• Evaluating overall survival (OS) in individuals with PD-L1 (+) tumors (CPS ≥1).
• Determining the safety and tolerability of pembrolizumab in combination with neoadjuvant chemotherapy and as adjuvant therapy in locally advanced TNBC subjects, within and across the neoadjuvant and adjuvant phases.
• Evaluating health-related quality-of-life (QoL) assessments in TNBC subjects and in subjects with PD-L1 (+) tumors (CPS ≥1) using the European Organisation for Research and Treatment of Cancer (EORTC) QoL Core 30 (QLQ-C30) and EORTC Breast Cancer–Specific QoL Questionnaire (QLQ-BR23) within and across the neoadjuvant and adjuvant treatment phases.

The clinical trial involves a total of **735 participants** diagnosed with **Triple Negative Breast Cancer (TNBC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically encompass adults and older adults. Participants were selected based on specific criteria, including a newly diagnosed, locally advanced, centrally confirmed TNBC, as defined by the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. The trial includes individuals with previously untreated, locally advanced non-metastatic TNBC, with specific tumor and lymph node staging as per the American Joint Committee of Cancer (AJCC) criteria. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate organ function is a prerequisite, and lifestyle considerations include the use of contraception for participants of childbearing potential. The trial population includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy and safety across diverse demographics.

The clinical trial is a **Phase III**, randomized, double-blind, controlled study designed to evaluate the efficacy and safety of **pembrolizumab** in combination with chemotherapy compared to a placebo with chemotherapy as neoadjuvant therapy, and pembrolizumab versus placebo as adjuvant therapy for patients with **Triple Negative Breast Cancer (TNBC)**. The trial aims to assess the pathological complete response (pCR) rate and event-free survival (EFS) in subjects with locally advanced TNBC. The study is expected to run from May 2017 to September 2025, with participant involvement lasting up to 51 weeks, depending on the treatment arm and response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as newly diagnosed, locally advanced TNBC, and adequate organ function. The screening will include a core needle biopsy and assessment of the Eastern Cooperative Oncology Group (ECOG) performance status. Following the screening, participants will be randomized to receive either pembrolizumab plus chemotherapy or placebo plus chemotherapy. The treatment phase will involve regular follow-up visits to monitor response and adverse events, with the primary endpoint being the pCR rate at the time of definitive surgery. Secondary endpoints include overall survival and quality of life assessments using the EORTC Quality of Life Core 30 Questionnaire (QLQ-C30) and the Breast Cancer-Specific QoL Questionnaire (QLQ-BR23).

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent. Participants are required to use adequate contraception during the study and for a specified period after the last dose of study treatment, depending on the specific chemotherapy agents received. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of several experimental and non-experimental treatments. **PEGFILGRASTIM** is administered as a subcutaneous injection. It is a polymer-based pharmaceutical with a maximum daily dose of 6 mg and a total dose of 24 mg over a 12-week period. The pharmaceutical form is coded as PHF00231MIG.

**KEYTRUDA** (pembrolizumab) is provided as a 25 mg/mL concentrate for solution for infusion. It is a protein-based treatment with a maximum daily dose of 200 mg and a total dose of 3400 mg over a 51-week period. The administration route is via solution for infusion.

**PACLITAXEL** is administered as a solution for infusion. It is a chemical-based treatment with a maximum daily dose of 80 mg/m² and a total dose of 960 mg/m² over a 12-week period. The pharmaceutical form is coded as PHF00016MIG.

**FILGRASTIM** is administered subcutaneously. It is a protein-based treatment with a maximum daily dose of 5 µg/kg and a total dose of 20 µg/kg over a 12-week period. The pharmaceutical form is coded as PHF802.

**CYCLOPHOSPHAMIDE** is administered as a solution for injection or infusion. It is a chemical-based treatment with a maximum daily dose of 600 mg/m² and a total dose of 2400 mg/m² over a 12-week period. The pharmaceutical form is coded as PHF00231MIG.

**CARBOPLATIN** is administered as a solution for infusion. It is a chemical-based treatment with a maximum daily dose of 750 mg and a total dose of 3000 mg over a 12-week period. The pharmaceutical form is coded as PHF00230MIG.

A **placebo** to Keytruda is used in the study, consisting of normal saline or dextrose. It serves as a comparator treatment and does not contain any active pharmaceutical ingredients.

**DOXORUBICIN** is administered as a solution for infusion. It is a chemical-based treatment with a maximum daily dose of 60 mg/m² and a total dose of 240 mg/m² over a 12-week period. The pharmaceutical form is coded as PHF00231MIG.

**EPIRUBICIN** is administered as a solution for injection. It is a chemical-based treatment with a maximum daily dose of 90 mg/m² and a total dose of 360 mg/m² over a 12-week period. The pharmaceutical form is coded as PHF00231MIG.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **pathological complete response (pCR)** rate, defined as ypT0/Tis ypN0, indicating no invasive residual in the breast or nodes, with noninvasive breast residuals allowed, at the time of definitive surgery. Additionally, event-free survival (EFS) will be evaluated as assessed by the investigator. Secondary endpoints encompass various measures, including alternative definitions of pCR, overall survival (OS), and quality of life scores using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) and the EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23).

The efficacy parameters will be measured and collected at specific timepoints, including the time of definitive surgery for pCR assessments. The EFS and OS will be monitored throughout the study duration. The quality of life assessments will be conducted using validated questionnaires. The analysis of these endpoints will involve statistical methods appropriate for the data type and study design, ensuring robust evaluation of the treatment's efficacy in subjects with locally advanced triple-negative breast cancer (TNBC).