Evaluation of Adjuvant Pembrolizumab Versus Observation in Early Triple-Negative Breast Cancer with Pathologic Complete Response Post-Neoadjuvant Therapy

Trial ID: 2024-515787-31-00
Protocol: UC-BCG-2401
Sponsor: Unicancer

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Diseases & Conditions

Triple negative breast cancer

Objectives

The primary objective of this study is to determine the non-inferiority of **observation** compared to 6 months of adjuvant **pembrolizumab** after surgery in terms of recurrence-free survival (RFS) in patients with early-stage triple-negative breast cancer (TNBC) who have achieved a pathologic complete response (pCR) following neoadjuvant chemotherapy and pembrolizumab. This is clinically relevant as it may allow for a reduction in treatment burden without compromising patient outcomes.

Secondary objectives include:

Evaluating the incidence of Grade ≥ 2 adverse events (AEs), particularly immune-related AEs (irAEs), and changes in PRO-CTCAE composite scores for selected events in patients undergoing observation versus those treated with pembrolizumab.
Assessing the impact of pembrolizumab on overall quality of life (QoL), including specific domains such as fatigue, emotional distress, pain, and sleep quality, as well as fear of cancer recurrence (FCR).
Comparing fertility outcomes, such as menstruation recovery and pregnancy rates, and describing patterns of LHRH agonist prescription.
Assessing efficacy outcomes, including invasive breast cancer-free survival (IBCFS), distant relapse-free survival (DRFS), second cancer rates, and overall survival (OS).
Conducting a hierarchical composite evaluation of observation versus standard care on events such as deaths, recurrences, and irAEs, and comparing cost-effectiveness and budget impact.

Participants

The clinical trial involves participants diagnosed with **early triple-negative breast cancer** (TNBC) who have achieved a pathologic complete response (pCR) following neoadjuvant systemic chemotherapy and pembrolizumab. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are ambulatory and capable of self-care. Participants are required to have adequate organ and bone marrow function, and they must not be pregnant or nursing. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include having undergone breast surgery with histologically negative margins for invasive tumors and having received adequate locoregional radiation therapy. Participants are expected to comply with study visits and procedures and must be affiliated with a Social Security System or equivalent. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the **non-inferiority** of observation compared to six months of adjuvant **pembrolizumab** treatment in patients with early-stage triple-negative breast cancer (TNBC) who have achieved a pathologic complete response (pCR) following neoadjuvant chemotherapy and pembrolizumab. This is a Phase III, randomized, double-blind, controlled trial. The trial aims to assess recurrence-free survival (RFS) as the primary endpoint, with secondary endpoints including safety, tolerability, health-related quality of life, and efficacy measures such as invasive breast cancer-free survival and overall survival. The trial is expected to conclude by January 31, 2035, with recruitment starting on January 1, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically documented TNBC, completion of neoadjuvant chemotherapy, and adequate organ function. Randomization must occur within 12 weeks post-surgery. Follow-up visits will be scheduled to monitor treatment effects, adverse events, and disease status. The end-of-study visit will evaluate the final outcomes and collect data on any long-term effects. The expected duration of participant involvement is up to 27 months, with conditions for early termination including withdrawal of consent, significant adverse events, or disease progression.

Participants will receive pembrolizumab intravenously, with a maximum daily dose of 400 mg and a total dose not exceeding 1800 mg. The trial will ensure compliance with ethical standards, requiring informed consent and adherence to protocol-specified procedures. The study will exclude individuals who are pregnant, nursing, or unable to comply with study requirements. The trial will also monitor for safety and tolerability, focusing on Grade ≥2 immune-related adverse events and other potential side effects. The trial's comprehensive design aims to provide robust data on the efficacy and safety of pembrolizumab as an adjuvant therapy in this patient population.

Treatment

The clinical trial involves the administration of **pembrolizumab**, an experimental medication, to evaluate its efficacy in patients with early-stage triple-negative breast cancer who have achieved a pathologic complete response after standard neoadjuvant chemotherapy and pembrolizumab. **Pembrolizumab** is provided in the form of a **solution for infusion** and is administered **intravenously**. The maximum daily dose is set at **400 mg**, with a total maximum dose of **1800 mg** over the course of the treatment. The treatment period is limited to a maximum of **27 weeks**. The active substance, **pembrolizumab**, is a protein of other origin, and the formulation used in this trial is not a pediatric formulation.

In addition to the experimental treatment, the study includes a non-experimental treatment arm where participants undergo observation without additional medication. This arm serves as a comparator to assess the non-inferiority of observation compared to six months of adjuvant pembrolizumab in terms of recurrence-free survival. The trial aims to determine the optimal adjuvant prescription of pembrolizumab in the specified patient population. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

Efficacy

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **recurrence-free survival (RFS)**, defined as the time from randomization to invasive loco-regional or distant recurrence or death from any cause. Patients who are alive at the time of analysis without documented breast cancer recurrence will be censored at the time of their last disease evaluation.

Secondary efficacy endpoints include **invasive breast cancer-free survival (IBCFS)**, which measures the time from randomization to invasive ipsilateral or contralateral breast tumor recurrence, loco-regional invasive recurrence, distant recurrence, and death from breast cancer, non-breast cancer, or unknown causes. **Distant relapse-free survival (DRFS)** is another secondary endpoint, defined as the time from randomization to distant recurrence, death from non-breast cancer, or unknown causes. Additionally, the incidence of second primary cancer will be evaluated in a competing risk model with deaths, and **overall survival** will be assessed as the time from randomization to death, with patients known to be still alive or lost to follow-up being censored.

These efficacy parameters will be measured and collected at specified timepoints throughout the trial, with patients being censored at the time of their last examination if they are alive with no evidence of an event. The analysis will be conducted using appropriate statistical methods to determine the non-inferiority of observation compared to 6 months of adjuvant pembrolizumab in terms of recurrence-free survival in patients who achieved a pathologic complete response after neoadjuvant chemotherapy and pembrolizumab.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient must have signed a written informed consent prior to any trial-related procedures. When the patient is physically unable to give his written consent, a trusted person of his choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent;
Adequate organ and bone marrow functions. All screening lab tests should be performed within 28 days before random d. Creatinine clearance ≥ 30 mL/min for subject with creatinine levels > 1.5 x institutional upper limit of normal (ULN) e. Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN (Patients with Gilbert’s disease with a total bilirubin ≤ 2.5 x ULN and direct bilirubin within normal limits are permitted) f. Aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤ 2.5 x ULNisation; a. Absolute Neutrophil Count (ANC) ≥ 1,000 /μL b. Platelets ≥ 100,000 /μL c. Hemoglobin ≥ 9 g/dL
Randomisation must take place no more than 12 weeks after breast surgery. Adjuvant radiotherapy is authorized. If given, as per investigator discretion it can be given concurrently with pembrolizumab;
Patients must not be pregnant or nursing (for women of childbearing potential only, a negative serum pregnancy test must be obtained within 7 days of Cycle 1 Day 1);
Women of childbearing potential and male patients must agree to use 1 effective form of contraception and up to 4 months after the last dose of study drugs;
Patients should be able and willing to comply with study visits and procedures as per protocol;
Patients must be affiliated to a Social Security System (or equivalent).
Age ≥ 18 years;
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
Histologically documented stage T1cN1-2 or T2-4N0-2 triple negative or ER/PR low breast cancer (Estrogen receptor (ER) and Progesterone receptor (PR) ≤10%; HER2-negative as per ASCO/CAP guidelines). Staging according to the primary tumourregional lymph node anatomic staging criteria of the American Joint Committee on Cancer (AJCC), 8th edition as determined by the investigator during radiologic assessment, clinical assessment or both.
Patients previously treated with neoadjuvant chemotherapy in combination with pembrolizumab for a minimum of 6 cycles (All systemic chemotherapy must have been completed preoperatively);
Absence of residual invasive disease in the breast or lymph nodes after the completion of neoadjuvant therapy (i.e., ypT0 ypN0 in the current AJCC staging system) (Residual ductal carcinoma in situ [DCIS] is allowed);
Have had an adequately excised breast cancer (surgical removal of all clinically evident disease in the breast and lymph nodes) : a. Breast surgery: patients must have undergone either breast-conserving surgery or total mastectomy with histologically negative margins for invasive tumour and DCIS. Patients with margins positive for lobular carcinoma in situ (LCIS) are eligible without additional resection. b. Lymph node surgery: patients must have had sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) to evaluate the pathologic nodal status;
Patients that have received adequate locoregional radiation therapy or with planned adequate locoregional radiation therapy;

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Exclusion Criteria

Radiological or clinical evidence of metastatic disease (stage IV) documented by imaging or clinical examination;
Evidence of recurrent disease following preoperative therapy and surgery;
Any prior history of (ipsi- or contralateral) invasive breast cancer;
Patients with a history of another malignancy without complete remission for more than 5 years, except for properly treated cervical carcinoma in situ and non-melanoma cancer of the skin
Patients for whom pembrolizumab has been permanently discontinued during the neoadjuvant phase of treatment due to pembrolizumab-related AE;
History of intolerance, including Grade 3 or 4 infusion reaction or hypersensitivity to pembrolizumab or murine proteins or any component of the product;
Medical conditions that require chronic systemic steroids (>10 mg prednisone or equivalent) or any other form of immunosuppressive medication in the past 2 years. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment;
Known active liver disease, e.g. due to HBV, HCV, autoimmune hepatic disorders, or sclerosing cholangitis;
HIV-infected patients on effective anti-retroviral therapy with detectable viral load within 6 months prior to enrollment;
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better;
Patients unwilling or unable to comply with the medical follow-up required by the trial due to geographic, familial, social, or psychological reasons;
Persons deprived of their liberty or under protective custody or guardianship;
Participation in another therapeutic trial within the 30 days prior to randomisation