Adding the CDK4/6 inhibitor ribociclib to endocrine therapy resulted in a significant improvement in invasive disease–free survival for patients with hormone receptor–positive, HER2-negative early-stage breast cancer. Findings from the phase III NATALEE trial were presented by Dennis J. Slamon, MD, PhD, and colleagues at the 2023 ASCO Annual Meeting (Abstract LBA500).
Hormone receptor–positive, HER2-negative breast cancer is the most common subtype of the disease, making up nearly 70% of all breast cancer cases in the United States. According to the authors, about one-third of people with stage II hormone receptor–positive, HER2-negative disease experience a recurrence following standard-of-care treatment, and more than one-half of people with stage III disease experience a recurrence. If a recurrence occurs, it is often at a more advanced stage.
Dennis J. Slamon, MD, PhD
Ribociclib is currently approved by the U.S. Food and Drug Administration to treat hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor for premenopausal people or in combination with fulvestrant for postmenopausal people. While ribociclib has previously shown survival benefits in people with metastatic disease, in the NATALEE study, researchers showed that it may also improve outcomes for people with earlier-stage disease, including those with cancer that has not yet spread to the lymph nodes.
About the Study
The NATALEE phase III clinical trial included men and premenopausal or postmenopausal women from 20 different countries with stage IIA, IIB, or III hormone receptor–positive, HER2-negative breast cancer who were at risk for disease recurrence. Participants were randomly assigned to receive either 400 mg of adjuvant ribociclib for 3 years with hormonal therapy for at least 5 years (n = 2,549) or hormonal therapy alone for at least 5 years (n = 2,552). Men and premenopausal women also received goserelin. Prior hormonal therapy use was allowed if it was initiated no more than 1 year before the start of the study.
The current recommended starting dose of ribociclib for people with metastatic disease is 600 mg. However, an extended duration of treatment may help to stop cells from duplicating and dividing and destroy any remaining cancer cells. Because of this, study authors chose a 3-year treatment duration of ribociclib at a dose of 400 mg to reduce side effects while maintaining efficacy.
Key Findings
At a median follow-up of 34 months, 20.2% of participants in the ribociclib group had completed 3 years of treatment and 56.8% had completed 2 years of treatment. Overall, 74.7% of participants remained on study treatment at data cutoff, with 1,984 patients on ribociclib and 1,826 patients on hormonal therapy alone.
The study found that adding ribociclib to hormonal therapy led to a significant improvement in invasive disease–free survival compared with hormonal therapy alone. Researchers evaluated invasive disease–free survival after 426 invasive disease–free survival events occurred, a number that was prespecified for the interim analysis. Of those events, 189 occurred in the ribociclib group (7.4% of patients) vs 237 in the hormonal therapy alone group (9.2% of patients). The 3-year invasive disease–free survival rates were 90.4% in the ribociclib group compared with 87.1% in the hormonal therapy alone group.
Overall, the addition of ribociclib reduced the risk of disease recurrence by 25%. The invasive disease–free survival benefit seen in the ribociclib group was generally consistent across clinically relevant patient subgroups. Ribociclib also showed more favorable outcomes in overall survival, recurrence-free survival, and distant disease–free survival.
For patients receiving ribociclib, the most common adverse effects were neutropenia and joint pain. Rates of gastrointestinal adverse effects and fatigue were low in patients receiving ribociclib. For patients receiving hormonal therapy alone, the most common adverse effects were joint pain and hot flash.
“Currently approved targeted treatments can only be used in a small population of patients diagnosed with [hormone receptor]-positive, HER2-negative early breast cancer, leaving many without an effective treatment option for reducing risk of the cancer returning,” said lead study author Dr. Slamon, Director of Clinical/Translational Research and Director of the Revlon/UCLA Women's Cancer Research Program at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center. “Thus, there is a significant unmet need for both reducing the risk of recurrence and providing a tolerable treatment option that keeps patients cancer-free without disrupting their daily life. The NATALEE study investigated the addition of ribociclib to standard-of-care adjuvant endocrine therapy and was specifically designed to address these unmet needs.”
Next Steps
Researchers will continue to evaluate how the addition of ribociclib to hormonal therapy impacts quality of life and will follow patients to observe long-term outcomes.
Disclosure: The study was funded by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit coi.asco.org.
