Ribociclib Plus NSAI Maintains Manageable Safety Profile in HR+/HER2– Early Breast Cancer

Dose reductions of ribociclib plus an NSAI did not decrease the regimen’s efficacy in patients with HR-positive, HER2-negative early breast cancer.

 Carlos Barrios, MD

Carlos Barrios, MD

Updated findings from the phase 3 NATALEE trial (NCT03701334) demonstrated that 3-year treatment with ribociclib (Kisqali) in combination with a nonsteroidal aromatase inhibitor (NSAI) remained well tolerated, and dose reductions did not appear to affect efficacy in patients with hormone receptor–positive, HER2-negative, early-stage breast cancer, with most treatment-related toxicities deemed identifiable and manageable, according to a presentation during the 2024 ESMO Breast Cancer Congress.1

A landmark analysis of invasive disease-free survival (iDFS) showed that reducing the dose of ribociclib due to adverse effects (AEs) did not negatively impact the treatment’s efficacy. At the 25th percentile (1.87 months) following randomization, 13 of 123 patients who required dose reductions of ribociclib experienced iDFS events compared with 208 of 2315 patients who did not need dose reductions. At the 50th percentile (3.17 months), 19 of 276 patients who required dose reductions had iDFS events vs 193 of 2117 patients who did not need dose reductions. At the 75th percentile (7.28 months) following randomization, 35 of 406 patients requiring dose reductions and 158 of 1933 patients not requiring dose reductions experienced iDFS events.

No new safety signals were observed with the ribociclib combination in the updated analysis. AEs were reported in 98.0% of patients treated with ribociclib plus an NSAI and 87.8% of patients treated with an NSAI alone.

“Neutropenia and arthralgia are the main 2 AEs related to the experimental arm,” lead study author Carlos Barrios, MD, explained in a presentation of the data. “[In general] ...most grade 3 or higher AEs [were] asymptomatic laboratory findings that were easily identifiable, mostly manageable, and reversible.”

Barrios is an assistant professor of the William Harrington Latin American Program of the University of Miami School of Medicine; director of the Oncology Research Unit at Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul, and director of Clinical Research and oncologist in the Oncoclínicas Group in Porto Alegre, Brazil.

Previously reported data from a prespecified interim analysis of NATALEE showed that the addition of adjuvant ribociclib to an NSAI significantly improved iDFS vs NSAI monotherapy in this patient population.2

“This benefit has been demonstrated as very consistent across different subgroups, including [patients with] stage II and III [disease], and [those with] both node-negative and node-positive disease,” Barrios noted during the presentation.1

At a data cutoff of January 11, 2023, and a median follow-up of 27.7 months, the 3-year iDFS rate was 90.4% in patients who received the combination (n = 2549) vs 87.1% among those treated with an NSAI alone (n = 2552; HR, 0.75; 95% CI, 0.62-0.91; 2-sided P = .003). The 3-year distant disease–free survival (DDFS) rates were 90.8% vs 88.6%, respectively (HR, 0.74; 95% CI, 0.60-0.91).2

Barrios explained that the 400 mg starting dose of ribociclib was chosen to potentially improve tolerability and treatment adherence without compromising clinical efficacy, based on data from the phase 2 AMALEE trial (NCT03822468) and a pooled analysis of the phase 3 MONALEESA trials (NCT01958021, NCT02422615, NCT02278120). Similarly, the 3-year duration of ribociclib treatment was selected to minimize disease recurrence through prolongation of cell cycle arrest.1

The updated analysis was conducted to obtain further safety and tolerability data from ribociclib plus an NSAI that could inform management approaches during treatment.

The international, open-label NATALEE study enrolled adult patients with hormone receptor–positive, HER2-negative, stage IIA, IIB, or IIIA breast cancer. For patients with stage IIA/B disease, no nodal involvement or 1 involved lymph node was required. Patients with stage IIA disease who had no nodal involvement were required to have grade 2 disease and have a Ki-67 proliferation index of at least 20% or be of a high genomic risk group. Those with stage III disease had N0, N1, N2, or N3 tumors. Notably, all patients were allowed to have received adjuvant or neoadjuvant endocrine therapy for up to 12 months prior to randomization.

Upon enrollment, patients were stratified by anatomical stage (II vs III), menopausal status (premenopausal women and men vs postmenopausal women), previous adjuvant or neoadjuvant chemotherapy (yes vs no), and geographic location (North America, Western Europe, and Oceania vs rest of the world). Eligible patients were randomly assigned 1:1 to the ribociclib combination vs NSAI alone. In the combination arm, patients received 400 mg of oral ribociclib once daily for 3 weeks on and 1 week off in 28-day cycles for 3 years, plus either 2.5 mg of oral letrozole or 1 mg of oral anastrozole once daily for at least 5 years; men and premenopausal women in this arm also received goserelin. Patients in the control arm received the NSAI regimen alone.

The primary end point of the study was investigator-assessed iDFS per the Standardized Definitions for Efficacy End Points criteria. Key secondary end points included DDFS, recurrence-free survival, overall survival (OS), safety and tolerability, patient-reported outcomes, and pharmacokinetics. Locoregional recurrence–free survival was a key exploratory end point, along with assessment of gene expression and alterations in circulating tumor DNA or RNA.

The trial was initiated in January 2019; the data cutoff for the current analysis was July 21, 2023. In the safety set, a total of 2549 and 2552 patients were assigned to the combination vs NSAI monotherapy arms, respectively; of these, 2525 and 2442 patients received the study drug. At the time of data cutoff, treatment with an NSAI was ongoing for the majority of patients across both arms (75.8% with the combination; 71.5% with NSAI alone). Among patients who discontinued treatment (24.2%; 28.5%), 5.2% and 4.6%, respectively, did so due to AEs. In the combination arm, 69.4% of patients completed at least 2 years of treatment with ribociclib.Of the 79.1% of patients who stopped treatment with ribociclib, 43.2% completed 3 years of the regimen. Ribociclib was discontinued in 35.9% of patients.

“Importantly, 20.9% of patients up to this point were still ongoing with ribociclib [treatment],” Barrios emphasized.

Any-grade AEs reported in more than 10% of patients included neutropenia (ribociclib regimen, 41.5%; NSAI alone, 3.0%), arthralgia (37.3%; 43.3%), neutrophil count decrease (24.1%; 1.7%), nausea (23.3%; 7.8%), headache (22.8%; 17.0%), fatigue (22.3%; 13.2%), COVID-19 (21.3%; 14.1%), positive SARS-CoV-2 test (21.2%; 13.6%), alanine aminotransaminase increase (ALT; 19.5%; 5.6%), hot flush (19.2%; 20.0%), asthenia (17.0%; 11.9%), aspartate aminotransaminase increase (AST; 16.9%; 5.7%), alopecia (15.0%; 4.5%), diarrhea (14.5%; 5.5%), leukopenia (13.3%; 2.0%), constipation (13.3%; 5.0%), cough (13.1%; 8.2%), insomnia (11.6%; 11.5%), pyrexia (11.1%; 6.0%), back pain (10.8%; 10.1%), and pain in extremities (10.3%; 9.0%).

AE-related dose reductions of ribociclib were observed in 22.8% of patients; these were primarily attributed to neutropenia (8.5%) and decreased neutrophil count (5.6%). The median time to AE-related dose reduction was 3.15 months (range, 0.26-34.17), and the median relative disease intensity during ribociclib treatment was 94%. A total of 19.7% of patients discontinued ribociclib treatment due to AEs, the most common of which were increased ALT (7.1%) and AST (2.8%). Among these patients, 14.0% patients discontinued without prior dose reduction, and 5.7% had their dose reduced prior to discontinuation. The median time to AE-related discontinuation was 4.17 months (range, 0.10-35.75).

“AEs generally occurred early in treatment, allowing for prompt ribociclib dose adjustments,” Barrios summarized.

Grouped AEs of special interest (AESIs) included neutropenia, liver-related AEs, and QT interval prolongation. Overall, any-grade AESIs were more frequent in the combination arm (62.5% for neutropenia; 26.4% for liver-related AEs; 5.3% for QT interval prolongation) vs NSAI arm (4.6%; 26.4%; 1.4%). The incidence of grade 3 or higher AESIs was also higher with the combination (44.3%; 8.6%; 1.0%) vs a NSAI alone (0.9%; 1.7%; 0.6%).

In the combination arm, dose reductions were required for 14.2%, 2.6% and 0.1% of patients experiencing neutropenia, liver-related AEs, and QT interval prolongation, respectively; discontinuation of any treatment component was observed in 1.1%, 8.9%, and 0.4% of patients with each respective AESI. In the NSAI monotherapy arm, no patients required dose reductions due to AESIs, and 0.1% of patients discontinued treatment due to liver-related AEs.

Disclosures: Dr Barrios reports institutional research grants from Pfizer, PharmaMar, Polyhor, Shanghai Henlius Biotech, Merck KGaA, LEO Pharma, ImClone Systems, Exelixis, Medivation, Asana Biosciences, AB Sciences, Abraxis Biosciences, Daiichi Sankyo, Bristol Myers Sqiubb, BioMarin, Astellas Pharma, AbbVie, Merck (MSD), Merrimack, Mylan, Taiho Pharmaceutical, Sanofi, GSK, Roche/Genentech, Lilly, Boehringer Ingelheim, Novartis, AstraZeneca, Amgen, Pfizer; he reports personal fees from Boehringer Ingelheim, Sanofi, Lilly, Zodiac, AstraZeneca, Bayer, Eisai, Roche/Genentech, Pfizer, Novartis, Daiichi Sankyo; he has stock from MEDSIR.


  1. C Barrios, Harbeck N, Hortobagyi G, et al. NATALEE update: safety and treatment (tx) duration of ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAID) in patients (pts) with HR+/HER2- early breast cancer (EBC). Presented at: 2024 ESMO Breast Cancer Congress; May 15-17, 2024; Berlin, Germany. Abstract 113MO.
  2. Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med. 2024;390:1080-1091. doi:10.1056/NEJMoa2305488
Related Videos
4 KOLs are featured in this series.
4 KOLs are featured in this series.
2 KOLs are featured in this program.
2 KOLs are featured in this program.
A panel of 5 experts on breast cancer
A panel of 5 experts on breast cancer
Mina Lobbous, MD, MPH
Peter Forsyth, MD
A panel of 3 experts on breast cancer
Paolo Tarantino, MD