No Chemotherapy in Intermediate-risk HR+ HER2- Early Breast Cancer Treated With Ribociclib (LEE-011) in the Adjuvant Setting, a Non-inferiority Phase III Trial
The advent of CDK4/6 inhibitors (drugs designed to block the action of CDK4/6 proteins, which play a key role in cell proliferation) has improved treatment prospects for patients with metastatic breast cancer whose tumour cells express hormone receptors but not the HER2 protein (HR+/HER2-). The NATALEE study showed that the addition of ribociclib for three years to conventional adjuvant hormone therapy (i.e. after surgery) prolonged survival free of invasive disease (i.e. extending to surrounding tissues) in patients with early HR breast cancer+ /HER2-. Unlike other studies, NATALEE included a group of patients at intermediate risk of recurrence, usually treated with adjuvant chemotherapy before receiving hormone therapy. However, the benefit of adjuvant chemotherapy in these patients is uncertain. The hypothesis of the NoLEEta study is that by using the CDK 4/6 inhibitor, patients could avoid adjuvant chemotherapy and therefore be spared the side-effects associated with this chemotherapy, without reducing the efficacy of the treatment.
• Patient must have signed a written informed consent prior to any trial-specific screening procedure.
• Note: When the patient is physically unable to give their written consent, an impartial witness of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent.
• Patient is ≥ 18 years old.
• Patient is female with known menopausal status at the time of randomization.
• Post-menopausal status is defined as:
‣ Patient underwent bilateral oophorectomy, or
‣ Age ≥ 60 years, or
‣ Age \< 60 years and either amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) or Follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges.
‣ If taking tamoxifen or toremifene and age \<60 years, then FSH and plasma estradiol level in postmenopausal ranges.
• The following criteria must be met for histologically confirmed invasive breast carcinoma, as determined by the local pathologist:
∙ Pathological stage (8th edition of the AJCC), including pT2 pN0 Grade 3 or pT2 pN0 Grade 2 with Ki67≥20% or pT0-2 pN1 or pT3-4 pN0
‣ ER-positive (with tumor cells showing ≥10% ER staining) and HER2-negative according to the most recent ASCO/CAP guidelines.
• Note: Multifocal and multicentric tumors are allowed if they meet the clinical stage II criteria of the 8th Edition of the AJCC. All tumors must be ER-positive and HER2-negative. Patients with bilateral invasive breast cancer (diagnosed simultaneously or within 6 months of each other) are eligible if all lesions tested on both sides are ER+ (ie, ≥10% positive stained cells) and HER2- AND adequate surgery has been performed in both breasts.
• Chemotherapy eligible per investigator decision, based on clinicopathological findings or the results of any genomic signature.
• Patient has no contraindication for the adjuvant endocrine therapy (ET) or chemotherapy in the trial and is planned to be treated with ET for 5 years (after randomization date) or more.
• Curative surgery for the invasive disease must have been performed with negative surgical margins within 12 weeks before randomization. If positive surgical margins, patients are eligible if revision surgery or other adequate local treatment (i.e local radiotherapy) is planned.
• Women of childbearing potential (CBP) must have a confirmed negative serum pregnancy test (β-hCG) before starting study treatment.
• Women of childbearing potential must agree to use one effective form of contraception during trial treatment and up to 21 days after the last dose of study drugs or longer, if required per standard of care;
⁃ Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 28 days prior to randomization.
⁃ Adequate hematological, renal, and hepatic function, as outlined below:
• Absolute neutrophil count (ANC) ≥1.5 x 10⁹/L
∙ Platelet count ≥100 x 10⁹/L
∙ Hemoglobin ≥9 g/dL
∙ Total bilirubin \< ULN. Patients with known Gilbert syndrome may be enrolled with total bilirubin ≤3 x ULN or direct bilirubin ≤1.5 x ULN
∙ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<2.5 x ULN
∙ Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥60 mL/min/1.73m² (CKD-EPI equation (2021))
∙ Potassium, total calcium (corrected for serum albumin), and magnesium should be within institutional normal limits or corrected to within normal limits using supplements before the first dose of study medication.
⁃ Standard 12-lead ECG values assessed, as:
• QTcF interval (QT interval using Fridericia's correction) at screening \< 450 milliseconds (msec)
∙ Resting heart rate 50-100 beats per minute (determined from the ECG)
⁃ Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
⁃ Absence of any psychological, familial or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
⁃ Patients must be affiliated to a Social Security System (or equivalent) based on local regulations.