More than 90% of patients diagnosed with breast cancer have early breast cancer (EBC) . Despite adjuvant endocrine therapy (ET) or being declared on remission, patients with EBC remain at risk for cancer recurrence, peaking within the first three years after initial diagnosis.[1] Patients with negative-node disease face a risk of recurrence up to 11% within the first three years after diagnosis, and 29% expect to recur within 20 years.[1]

Results from a subgroup analysis of the Phase III NATALEE trial in patients with high-risk, node-negative (N0) hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) EBC demonstrated that ribociclib  (Kisqali®; Novartis) plus ET, compared to ET alone, improved invasive disease-free survival (iDFS), distant recurrence-free survival (DRFS), and distant disease-free survival (DDFS) in high-risk EBC patients with N0 disease. [1]

The data confirmed that adding ribociclib to ET demonstrated a 28% risk reduction in iDFS in subgroup of patients with node-negative (N0) disease at high risk of recurrence.[1] However, Patients with N0 disease are currently ineligible to receive CDK4/6 inhibitor (CDK4/6i) treatment to manage risk of recurrence; treatment with ET alone leaves them with significant unmet need. [1]

Ribociclib is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

ASCO 2024
The data will be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. According to trial analysts these latest results are consistent with the significant benefits observed in the broad population of patients with stage II and III HR+/HER2- EBC in the pivotal NATALEE trial, initially presented at ASCO 2023.[1]

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Overall, the efficacy, safety and tolerability profile observed in N0 disease subgroup​ are consistent with the overall NATALEE study population. [1][3][4] These results of the NATALEE data, the number of patients that could potentially benefit from CDK4/6i treatment to reduce their chances of cancer coming back could double; Novartis has submitted these results to Food and Drug Administration (FDA) and the European Medicine Authority (EMA). [1]

 Ribociclib iDFS, DRFS and DDFS rates in key pre-specified subgroup:

Subgroup3-year iDFS rate, %3-year DRFS rate, %3-year DDFS rate, %
High-risk node-negative (N0)Ribociclib + ET: 93.2

ET alone: 90.6

(HR=0.72; 95% CI: 0.41, 1.27)

Ribociclib + ET: 96.3

ET alone: 92.5

(HR=0.58; 95% CI: 0.29, 1.17)

Ribociclib + ET: 94.3

ET alone: 91.5

(HR=0.70; 95% CI: 0.38, 1.29)


“More than 1 in 3 patients diagnosed with early-stage breast cancer, regardless of nodal involvement, are at risk of experiencing recurrent disease despite treatment with standard chemotherapy and/or endocrine therapy,” explained Denise A. Yardley, MD, Associate Director, Breast Cancer Research; Executive Member, Breast Cancer Research Executive Committee, Sarah Cannon Research Institute; and Principal Investigator of the NATALEE clinical trial.

“Notably, the NATALEE trial has shed light on the node-negative patient population, an important at-risk subgroup that could benefit from more options to reduce their risk of their cancer returning. The findings from this trial underscore the efficacy of ribociclib in early-stage node-negative breast cancer, highlighting its role as a viable and well-tolerated treatment intervention that could significantly diminish the recurrence risk for this particular group,” Yardley added.

The safety profile of ribociclib at the 400 mg dose in the high-risk, N0 subgroup remains consistent with the well-tolerated profile previously demonstrated in the intent-to-treat population with generally low-grade adverse events (AEs), other than laboratory findings. In the N0 subgroup, the rate of discontinuation due to all grade AEs was 24% vs 8% with ribociclib plus ET vs ET alone. No new safety signals were identified. [1]

“Currently available targeted therapies are approved only for a small proportion of patients, leaving a large number of people diagnosed with HR+/HER2- early breast cancer at risk of cancer returning, particularly those with high-risk N0 tumors,” said Jeff Legos, Executive Vice President, Global Head of Oncology Development, Novartis.

“Our robust body of data continues to support the potential for ribociclib to benefit many more patients as they seek to reduce the likelihood of their cancer coming back with the addition of a CDK4/6 inhibitor to their endocrine treatment.” Legos added.

Novartis submitted NATALEE data to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2023, and further submissions to global authorities are ongoing.

A global trial
NATALEE is a global Phase III multi-center, randomized, open-label trial to evaluate the efficacy and safety of ribociclib with ET as an investigational adjuvant treatment versus ET alone in patients with stage II and III HR+/HER2- EBC, being conducted in collaboration with TRIO. [4]

The adjuvant ET in both treatment arms was a non-steroidal aromatase inhibitor (NSAI; anastrozole or letrozole) and goserelin if applicable.[4]

The primary endpoint of NATALEE is iDFS as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria.[5]  A total of 5,101 adult patients with HR+/HER2- EBC across 20 countries were randomized in the trial. [4]

Results previously announced at the San Antonio Breast Cancer Symposium (SABCS) in December 2023 showed ribociclib plus ET, compared to ET alone, lowered the risk of cancer recurrence by 25.1% (HR=0.749; 95% CI: 0.628, 0.892; p=0.0006), along with consistent clinically meaningful iDFS benefit across key pre-specified subgroups. [4]

NATALEE explored a lower starting dose (400 mg) of ribociclib than the dose approved for treatment in metastatic breast cancer (MBC) (600 mg) with the goal to minimize disruptions to patient quality of life without compromising efficacy. Compared to the 600 mg dose, the safety profile of ribociclib at 400 mg was observed to have lower rates of symptomatic AEs and less need for dose modifications when administered up to three years. [5] AEs of special interest (grade 3 or higher) are neutropenia (44.3%), liver-related AEs (e.g., elevated transaminases) (8.6%), and QT interval prolongation (1.0%). [4][5][6][7]

Clinical trial
A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/​HER2- Early Breast Cancer (NATALEE) – ID NCT03701334

Highlights of Prescribing information
Ribociclib (Kisqali®; Novartis) [Prescribing Information]

[1] Yardley D, Untch M, et al. Baseline (BL) characteristics and efficacy endpoints for patients (pts) with node-negative (N0) HR+/HER2− early breast cancer (EBC) in NATALEE. Presented at the American Society of Clinical Oncology Annual Meeting, May 31, 2024. Chicago, USA.
[2] Howlader N, Altekruse S, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5):dju055. doi: 10.1093/jnci/dju055.[br][3] Fasching P, Slamon D et al. Health-related quality of life in the phase 3 NATALEE study of adjuvant ribociclib plus a NSAI vs NSAI alone in patients with HR+/HER2− early breast cancer). Presentation at European Society for Medical Oncology (ESMO) Virtual Plenary on 14 September 2023.[4] Slamon D, Stroyakovskiy D, Yardley D, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer: primary results from the Phase III NATALEE trial. Presented at the American Society of Clinical Oncology Annual Meeting, June 2, 2023. Chicago, USA.
[5] Hortobagyi G, Stroyakovskiy D, Yardley DA, et al. Ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) as adjuvant treatment in patients with HR+/HER2- early breast cancer: final invasive disease-free survival (iDFS) analysis from the NATALEE trial. Presented at San Antonio Breast Cancer Symposium (SABCS). December 8, 2023. San Antonio, USA.
[6] Iqbal J, Ginsburg O, Rochon PA, Sun P, Narod SA. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States [published correction appears in JAMA. 2015 Jun 9;313(22):2287]. JAMA. 2015;313(2):165-173. doi:10.1001/jama.2014.17322
[7] Yardley DA, Yap YS, et al. Pooled exploratory analysis of survival in patients (pts) with HR+/HER2- advanced breast cancer (ABC) and visceral metastases (mets) treated with ribociclib (RIB) + endocrine therapy (ET) in the MONALEESA (ML) trials. Poster presented at the European Society of Medical Oncology Congress. September 9-13, 2022. Paris, France.

Featured image: ASCO Annual Meeting – Photo Courtesy © 2022 ASCO/Zach Boyden-Holmes. Used with permission.

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