Adjuvant Ribociclib Plus AI Therapy Shows More Pronounced iDFS Benefit After 5 Years in HR+, HER2-Negative Early Breast Cancer

Adjuvant ribociclib (Kisqali) plus endocrine therapy showed a sustained reduction in recurrence risk beyond its initial 3-year treatment window, according to Sara A. Hurvitz, MD, FACP, who added that the ongoing separation of the Kaplan-Meier curves for invasive disease–free survival (iDFS) reinforces the drug’s efficacy for patients with hormone receptor–positive, HER2-negative early breast cancer who are at a high risk of recurrence.1

Earlier findings from the phase 3 NATALEE trial (NCT03701334) demonstrated a statistically significant and clinically meaningful improvement in iDFS with ribociclib plus endocrine therapy vs endocrine therapy alone, supporting the regimen’s 2024 FDA approval for patients with hormone receptor–positive, HER2-negative early breast cancer.

​​Data from the 5-year prespecified analysis of NATALEE were presented during the 2025 ESMO Congress. At a median follow-up of 55.4 months, adjuvant ribociclib (Kisqali) plus an aromatase inhibitor (AI) continued to show superior iDFS vs an AI alone, (HR, 0.716; 95% CI, 0.618-0.829; 1-sided P < .0001). The 36-month iDFS rates were 90.8% in the ribociclib arm (n = 2594) vs 88.0% in the AI-alone arm (n = 2552); at 60 months, respective rates were 85.5% and 81.0%.

“These data are exciting because when we initially saw the presentation of data [from NATALEE] after just a few years, that difference [in iDFS] between the 2 arms was a bit less striking,” Hurvitz shared with OncLive®.

In the interview, Hurvitz provided a brief overview of the NATALEE trial, shared updated efficacy data presented during the meeting, and emphasized the importance of continuing to follow the data and evaluate the positive trend in overall survival (OS) with adjuvant ribociclib plus an AI.

Hurvitz is a medical oncologist, senior vice president, professor in, and director of the Clinical Research Division at Fred Hutchinson Cancer Center in Seattle, Washington. She also serves as the Smith Family Endowed Chair in Women’s Health.

OncLive: How was the NATALEE trial designed, and what findings have been previously reported from the primary analysis?

Hurvitz: The NATALEE trial was a phase 3 randomized study [evaluating] whether adding ribociclib to standard endocrine therapy for early-stage breast cancer improves outcomes. It was done in patients with hormone receptor–positive, HER2-negative breast cancer who had stage 2 or higher curable breast cancer.

Patients in the study were randomly assigned to receive an AI with or without ribociclib. Ribociclib was administered at a dose of 400 mg every day for 3 weeks on and one week off. That dose is a little bit lower than we use in the metastatic setting and was aimed to demonstrate an improvement in iDFS.

What updated data were presented at the 2025 ESMO Congress? How might these results influence clinical decision-making?

Ribociclib was the second CDK4/6 inhibitor to demonstrate a significant improvement in invasive disease-free survival in breast cancer patients with hormone receptor–positive, HER2-negative, early-stage disease. It is the only CDK4/6 inhibitor that has demonstrated benefit in patients with node-negative stage 2 disease.

At this meeting, the 5-year outcome data from this study [were presented], and demonstrated that iDFS was actually improved by 4.5%, which translates to an approximately 30% relative risk reduction in iDFS. As patients with hormone receptor–positive early breast cancer experience recurrence years after they have been diagnosed, you can begin to see with an effective drug that a separation of the Kaplan-Meier curves [occurs] over time

What should be known about the safety profile of ribociclib in this trial?

Overall, we did not see any new safety signals [from this analysis]. Ribociclib is associated with neutropenia, as are all 3 approved CDK4/6 inhibitors, so patients need to be monitored [for these toxicities]. They also have to be monitored for liver enzyme abnormalities. A couple of EKGs also have to be done at baseline and in the first month of therapy, because QTc prolongation can occur. For this reason, we do not combine ribociclib with tamoxifen.

What next steps are planned for this research?

We are excited to see a positive trend in OS [with ribociclib plus an AI]. It will take time to see a difference in OS because patients can experience recurrence so late in their disease. We also saw a reduction in distant recurrences with ribociclib, which is also particularly exciting.

The next step are to continue to follow the data and see how OS actually turns out. A number of studies in the metastatic setting are evaluating the use of ribociclib in combination with other targeted therapies, so it is an exciting time.

References

1. FDA approves Novartis Kisqali to reduce risk of recurrence in people with HR+/HER2- early breast cancer. News release. Novartis. September 17, 2024. Accessed October 19, 2025.https://www.novartis.com/news/media-releases/fda-approves-novartis-kisqali-reduce-risk-recurrence-people-hrher2-early-breast-cancer
2. Crown J, Stroyakovskii D, Yardley D, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor therapy in patients with HR+/HER2– early breast cancer: NATALEE 5-year outcomes. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA14.