Chicago, IL—The addition of the CDK4/6 inhibitor ribociclib (Kisqali) to endocrine therapy significantly improved invasive disease-free survival (DFS) in patients with hormone receptor (HR)-positive, HER2-negative, early breast cancer, according to interim results of the phase 3 NATALEE trial, which were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.1
“NATALEE met its primary end point, and this was true in all subgroups. The study utilized a 3-year regimen of ribociclib at a 400-mg starting dose in the adjuvant setting. These data support ribociclib plus endocrine therapy as a new treatment of choice in a broad population of patients with stage II or III early breast cancer at risk for recurrence, including those with cancer that has not spread to the lymph nodes,” said the study’s lead investigator Dennis J. Slamon, MD, PhD, Director, Clinical/Translational Research, and Director, Revlon/University of California Los Angeles (UCLA) Women’s Cancer Research Program, UCLA Jonsson Comprehensive Cancer Center.
HR-positive, HER2-negative breast cancer is the most common subtype of the disease, comprising approximately 70% of all breast cancer cases in the United States.2 The current standard of care for patients with early-stage breast cancer is surgery with or without chemotherapy or radiation, followed by 5 to 10 years of adjuvant endocrine therapy. However, approximately one-third of patients with stage II disease and 50% of those with stage III disease will experience a recurrence, indicating the need for more effective treatments.
The NATALEE trial differed from other early breast cancer adjuvant studies using CKD4/6 inhibitors in the following 3 ways:
- It enrolled patients with earlier stage disease who are typically considered at lower risk for disease progression.
- The dose of ribociclib was reduced from 600 mg to 400 mg, based on findings from other trials of patients with metastatic breast cancer, which showed that reduced dosing can improve tolerability without sacrificing efficacy.
- Patients were treated for 3 years instead of the standard 2 years.
The NATALEE trial included 5101 men and premenopausal and postmenopausal women with stage IIA, IIB, or III HR-positive, HER2-negative breast cancer who were at risk for disease recurrence. Participants were randomized in a 1:1 ratio to receive either 400 mg of adjuvant ribociclib for 3 years plus endocrine therapy for at least 5 years (n=2549) or endocrine therapy alone for at least 5 years (n=2552).
Invasive DFS was the primary end point of the trial. Secondary end points included recurrence-free survival, distant DFS, and overall survival. At a median follow-up of 34 months, 20.2% of patients treated with ribociclib plus endocrine therapy had completed 3 years of treatment and 56.8% had completed 2 years of treatment. Overall, approximately 75% of participants were still receiving their assigned treatment at the study’s cutoff for data collection, with 1984 patients receiving ribociclib plus endocrine therapy and 1826 patients receiving endocrine therapy alone. The median duration of follow-up for invasive DFS was 27.7 months for both arms of the study.
At the second efficacy analysis, there was a 25% relative risk reduction for invasive breast cancer, and this benefit was observed across all subgroups, including disease stage, menopausal status, or nodal status. The 3-year invasive DFS rates were 90.4% in the ribociclib plus endocrine group versus 87.1% in the endocrine therapy–alone group. The addition of ribociclib also led to more favorable outcomes in recurrence-free survival, overall survival, and distant DFS.
The most common adverse events associated with the use of ribociclib were neutropenia and joint pain. In the endocrine therapy–alone group, joint pain and hot flashes were the most common adverse events.
Use of the lower dose of ribociclib reduced the risk for QT prolongation, which is a concern with CDK4/6 inhibitors. In the metastatic setting, 600-mg ribociclib led to a 74% incidence of QT prolongation compared with 62% in the NATALEE trial.
“While early, these results are very promising and suggest that there will be a role for adjuvant ribociclib for stage II and higher [HR-positive], HER2-negative breast cancer,” said ASCO Expert Rita Nanda, MD, Director, Breast Oncology Program, University of Chicago Medicine, IL, during a press conference where these findings were presented.3
- Slamon DJ, Stroyakovskjy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the phase 3 NATALEE trial. J Clin Oncol. 2023;41(suppl 16):LBA500.
- National Cancer Institute. Cancer stat facts: female breast cancer. https://seer.cancer.gov/statfacts/html/breast.html. Accessed June 19, 2023.
- American Society of Clinical Oncology. Adding ribociclib to hormonal therapy reduces risk of recurrence for people with most common subtype of cancer. June 2, 2023. https://old-prod.asco.org/about-asco/press-center/news-releases/adding-ribociclib-hormonal-therapy-reduces-risk-recurrence. Accessed June 19, 2023.