Adjuvant Pembrolizumab and Chemotherapy or Surveillance in Early Triple Negative breAst Cancer With High Stromal Tumor-infiltrating Lymphocytes (TILs) Score
Triple-negative breast cancer (TNBC) is a group of tumors that occurs mainly in young, premenopausal women and accounts for 10-20% of breast cancers. Over the past decade, the incidence of women diagnosed with early-stage TNBC has significantly increased due to the widespread use of screening mammography. Treatment of patients with localized TNBC mainly involves surgery and (neo)adjuvant chemotherapy with or without radiotherapy. However, the benefit of chemotherapy may be controversial in patients with early-stage TNBC defined by small size and absence of lymph node involvement, and with significant tumor lymphocyte infiltration. The ETNA study is a phase II trial designed to evaluate a chemotherapy de-escalation strategy in patients with TNBC T1b/c N0M0 and stromal TILs (sTILs) ≥ 30%. ETNA comprises two cohorts defined according to the level of TILs and the age of patients. Patients aged \> 40 years with 30% ≤ sTILs \< 50% and those aged ≤ 40 years with 30% ≤ sTILs \< 75% will be included in the cohort 1 and will receive adjuvant pembrolizumab 200 mg every three weeks for 9 cycles and Paclitaxel 80 mg/m² weekly for 12 cycles. Patients aged \> 40 years with sTILs ≥ 50% and those aged ≤ 40 years with sTILs ≥ 75% will be included in cohort 2 and will not receive adjuvant treatment, they will undergo standard surveillance every six months.
• Understand, sign, and date the written informed consent form prior to any protocol- specific procedures performed,
• Men and women aged ≥ 18 years,
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1,
• Histologically confirmed and radically removed pT1b/c N0M0 TNBC as defined according to AJCC TNM stage-8th version,
‣ Histologically documented TNBC (negative HER2, ER, and PgR status). HER2 negativity is defined by local laboratory assessment using in situ hybridization and immunohistochemistry assays as per ASCO/CAP criteria and ER/PgR negativity is defined by local laboratory assessment \< 10% using immunohistochemistry assays,
⁃ Bilateral and/or multifocal primary tumor is allowed and the tumor with the most advanced T stage should be used to asses for eligibility. If multifocal tumor, a pathologic confirmation of TNBC is required for each focus,
• Adequately excised breast cancer: subjects must have undergone either breast- conserving surgery or mastectomy/nipple- or skin-sparing mastectomy.
‣ For subjects who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist. Reresections to ensure no ink on tumor margins are allowed. Subjects with margins positive for lobular carcinoma in situ (LCIS) are eligible without additional resection.
⁃ For subjects who undergo mastectomy/nipple- or skin-sparing mastectomy, margins must be free of gross residual tumor. It is recommended that subjects should have a negative microscopic margin in accordance with local pathology protocol,
• Have had sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) for evaluation of pathologic nodal status.
• Axillary nodal dissection(s) should yield a total of at least six nodes (including the axillary lymph nodes resected at the SLNB plus the lymph nodes collected at the axillary nodal dissection),
• At least 4 weeks but no more than 12 weeks between definitive breast surgery (or the last surgery with curative intent if additional resection is required for breast cancer) and treatment initiation for cohort 1 and no more than 12 weeks for cohort 2,
• Centrally assessed TILs score from surgical formalin-fixed paraffin embedded (FFPE) tumor sample, using an H\&E stained diagnostic digital slide, according to the most recent International TILs Working Group guidelines,
‣ Cohort 1 will include patients aged \> 40 years with 30% ≤ sTILs \< 50% and those aged
• 40 years with 30% ≤ sTILs \< 75%
⁃ Cohort 2 will include patients aged \> 40 years with sTILs ≥ 50% and those aged ≤ 40 years with sTILs ≥ 75%
• Women of childbearing potential have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication for cohort 1 and within 7 days of inclusion for cohort 2,
⁃ Women of childbearing potential must agree to use protocol-specified method(s) of contraception for 3 years after patient inclusion. Men subjects who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception during trial treatments and for at least 6 months after the last dose of trial treatments.
⁃ Females of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year,
⁃ Patients affiliated to the social security system (or equivalent)- France only,
⁃ Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.
⁃ Additional inclusion criteria for subjects of cohort 1:
⁃ Left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by echocardiogram or cardiac scintigraphy,
⁃ Demonstrate adequate organ function within 7 days of inclusion
∙ Absolute Neutrophil Count (ANC) ≥ 1,500 /µL
‣ Platelets ≥ 100,000 /µL
‣ Hemoglobin ≥ 9 g/dL
‣ Creatinine clearance ≥ 30 mL/min for subject with creatinine levels \> 1.5 x institutional upper limit of normal (ULN)
‣ Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN
‣ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
‣ Albumin ≥ 3.0 g/dL
‣ Lactate dehydrogenase (LDH) \< 2.5 X ULN
‣ International normalized ratio/partial thromboplastin time (INR/PTT) ≤ 1.5 x ULN (unless subject is receiving anticoagulant therapy as long as prothrombin time (PT) or PTT is within therapeutic range of intended use of anticoagulants)
‣ Thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) within normal ranges
‣ Cortisol at 8 AM within normal ranges
‣ Lipase and amylase \< 3 ULN
‣ Fasting plasma glucose ≤ 120 mg/dl or 6.7 mmol/L
‣ Troponin within normal range