NATALEE: Ribociclib With Hormonal Therapy Cuts Recurrence Risk by 25% in Most Common Type of Breast Cancer


The trial included patients with earlier stage disease who are normally considered lower risk than the high-risk population.

Adding the CDK4/6 inhibitor ribociclib (Kisqali, Novartis) to hormonal therapy made cancer 25% less likely to return for those patients with hormone receptor (HR) positive, HER2-negative early-stage breast cancer (EBC), according to results to be presented today at the 2023 Annual Meeting of the American Society of Clinical Oncology.

Interim findings from the NATALEE trial (NCT03701334) could have widespread impact, as HR+/HER- breast cancer accounts for 70% of all new breast cancer cases, according to National Institutes of Health data. NATALEE enrolled patients with stage II and stage III HR+/HER2- early breast cancer (EBC), regardless of nodal involvement. The primary end point, invasive disease-free survival (iDFS), measures whether a patient’s cancer has returned.

“NATALEE is different from some other early breast cancer studies with CKD4/6 [inhibitors] in 3 important ways,” said lead investigator Dennis J. Slamon, MD, PhD, medical oncologist at UCLA Health. In a press briefing, Slamon listed the ways the trial broke new ground:

  • The trial included patients with earlier stage disease, who Slamon said are “normally considered lower risk than the high-risk population.”
  • In an effort to improve safety, the dose was reduced from the usual 600 mg to 400 mg, based on findings from other trials with metastatic breast cancer patients that showed when doses were reduced due to tolerability, efficacy was not lost.
  • The study treated patients for 3 years instead of 2 years.

The trial randomized 5101 men and premenopausal and postmenopausal women with breast cancer who were at risk of recurrence. Patients received either adjuvant ribociclib with hormonal therapy (2549 patients) or hormonal therapy alone (2552 patients). After a median follow-up of 34 months, 20.2% of those in the ribociclib group completed 3 years of therapy and 56.8% completed 2 years of treatment.

The prespecified analysis evaluated data once there were 426 iDFS events. Data being presented at ASCO show 189 people in the ribociclib group (7.4% of patients) had a cancer recurrence, compared with 237 people in the hormonal therapy alone group (9.2% of patients).

Pairing ribociclib with hormonal therapy created significant improvement in survival. Results showed:

  • 3-year iDFS rates were 90.4% in the ribociclib group compared with 87.1% in the hormonal therapy alone group. Adding ribociclib reduced the risk for recurrence by 25%.
  • The addition of ribociclib created survival improvement for a broad population of people with HR+/HER2- EBC.
  • This therapeutic option would support patients whose cancer has not spread to the lymph nodes.
  • Overall, 74.7% of participants remained on treatment at the data cutoff, with 1984 patients on ribociclib and 1826 patients on hormonal therapy alone.

“Based on the numbers of patients that are challenged with this subtype of disease,” Slamon said, the findings “could result in a significant efficacy improvement.”

He noted that findings were consistent across subgroups, disease stage, menopausal status, and even nodal status. “So that means even patients with node negative disease—which are normally thought to be those with lower risk disease—they benefited as well,” he said.

Slamon noted that the reduced dose appeared to improve some safety signals in cardiotoxicity.

“While early, these results are very promising and suggest that there will be a role for adjuvant ribociclib for stage II and higher hormone receptor-positive (HR-positive), HER2- negative breast cancer,” said commentator Rita Nanda, MD, associate professor of medicine, University of Chicago.

The NATALEE study protocol calls for ongoing follow-up to evaluate long-term outcomes, including overall survival.

The January 2023 update to the National Comprehensive Cancer Network (NCCN) clinical guidelines for breast cancer recommends ribociclib as the only Category 1 preferred CDK4/6 inhibitor for first-line treatment of patients with HR+/HER2- metastatic breast cancer when combined with an aromatase inhibitor.

In March, when Novartis officials announced topline results for NATALEE, they said it represented the broadest patient population of any CDK4/6 inhibitor trial to date. Citing data published in the New England Journal of Medicine, officials said 30% to 60% of the patient population represented in the NATALEE trial currently remains at risk of breast cancer recurrence with endocrine therapy only, and that EBC represents more than 90% of patients with breast cancer.


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 17):abstr LBA500

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