ribociclib 2025-10-22 10:10:13

ribociclib

Ribociclib: Mechanism, Clinical Efficacy, and Safety in Breast Cancer

Introduction and Mechanism of Action

Ribociclib is a selective, orally bioavailable inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), a crucial pathway involved in the regulation of cell cycle transition from G1 to S phase. Dysregulation of the cyclin D–CDK4/6–p16–retinoblastoma (Rb) pathway is a hallmark of many cancers, especially hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer (Tripathy et al., 2017). By inhibiting CDK4/6, ribociclib prevents phosphorylation of Rb protein, thereby inducing cell cycle arrest and inhibiting cancer cell proliferation.

Indications and Clinical Use

FDA-Approved Indications

Ribociclib is approved for use in combination with endocrine therapy (aromatase inhibitors or fulvestrant) for the treatment of HR+/HER2– advanced or metastatic breast cancer. It can be used as first-line endocrine-based therapy or following progression after prior endocrine therapy. Ribociclib is also approved as adjuvant therapy in early-stage, high-risk HR+/HER2– breast cancer in combination with an aromatase inhibitor (Spring et al., 2017); (Ribociclib - Mayo Clinic).

Clinical Efficacy

Advanced and Metastatic Breast Cancer

MONALEESA-2 (Letrozole Combination, Postmenopausal Women)

Design: Phase III, randomized, placebo-controlled trial (N=668).
Results:
Median progression-free survival (PFS) was significantly longer for ribociclib plus letrozole:
- Initial analysis: PFS not reached vs 14.7 months with placebo (hazard ratio [HR] 0.56; 95% CI, 0.43–0.72; P=3.29×10⁻⁶).
- Updated analysis: Median follow-up 26.4 months, median PFS 25.3 months (95% CI, 23.0–30.3) for ribociclib+letrozole vs 16.0 months (95% CI, 13.4–18.2) for placebo+letrozole (HR 0.568; 95% CI 0.457–0.704; P<1×10⁻⁷) (Hortobagyi et al., 2018).
Overall response rate (ORR):
- 54.5% (ribociclib+letrozole) vs 38.8% (placebo+letrozole) in patients with measurable disease.
Overall Survival (OS):
- Final analysis: Median OS was 63.9 months (95% CI, 52.4–71.0) with ribociclib+letrozole, 51.4 months (95% CI, 47.2–59.7) with placebo+letrozole (HR for death, 0.76; 95% CI, 0.63–0.93; P=0.008) (Hortobagyi et al., 2022).

MONALEESA-3 (Fulvestrant Combination, Postmenopausal Women)

Design: Phase III, randomized, placebo-controlled trial (N=726).
Results:
Median PFS: 20.5 months (95% CI, 18.5–23.5) for ribociclib+fulvestrant vs 12.8 months (95% CI, 10.9–16.3) for placebo+fulvestrant (HR 0.593; 95% CI, 0.480–0.732; P<0.001).
ORR among those with measurable disease: 40.9% (ribociclib) vs 28.7% (placebo).
Clear benefit regardless of prior endocrine therapy exposure (Slamon et al., 2018).

MONALEESA-7 (Premenopausal Women)

Design: Phase III, randomized, double-blind, placebo-controlled trial (N=672).
Results:
Median PFS: 23.8 months (ribociclib group; 95% CI, 19.2–NR) vs 13.0 months (placebo; 95% CI, 11.0–16.4).
Hazard ratio for progression or death: 0.55 (95% CI, 0.44–0.69).
The addition of ribociclib to endocrine therapy significantly improved survival and quality of life (Tripathy et al., 2018).

RIGHT Choice Trial: Ribociclib Plus Endocrine Therapy vs. Combination Chemotherapy

Population: Pre/perimenopausal women with clinically aggressive HR+/HER2– advanced breast cancer.
Results:
Median PFS: 21.8 months (ribociclib + ET; 95% CI, 17.4–26.7) vs 12.8 months (chemotherapy; 95% CI, 10.1–18.4); HR 0.61 (95% CI, 0.43–0.87; P=0.003).
ORR: 66.1% (ribociclib) vs 61.8% (chemotherapy).
Ribociclib yielded fewer symptomatic adverse events (Lu et al., 2024).

Early (Adjuvant) Breast Cancer: NATALEE Trial

Design: Phase III, randomized, adjuvant trial (N>5,000).
Results:
Ribociclib (400mg, 3 weeks on/1 week off for 36 months) plus NSAI vs NSAI alone.
Median follow-up: 33.3 months.
Invasive disease-free survival (iDFS):
- 3-year iDFS: 90.7% (ribociclib+NSAI) vs 87.6% (NSAI alone).
- HR 0.749 (95% CI, 0.628–0.892; P=0.0012) (Hortobagyi et al., 2024).
Consistent benefit across risk subgroups, with favorable trends in distant DFS, recurrence, and emerging overall survival signals (Slamon et al., 2024); (OncoDaily, 2025).
5-year iDFS benefit (HR=0.716, nominal P<0.0001) and 28% relative reduction in recurrence risk (Novartis, 2025).

Monotherapy in Non-Breast Cancers

Ribociclib (and palbociclib) monotherapy in solid tumors with CDK4/cyclin D pathway alterations provided limited clinical benefit (objective response rate 0%, clinical benefit rate 15%, median PFS 4 months) (Zeverijn et al., 2023).

Comparative Pharmacology and Dosing

Ribociclib is usually administered as 600mg orally, once daily, on a 3-weeks-on/1-week-off schedule.
The drug shows potent selectivity towards CDK4/6 with limited off-target effects compared to palbociclib and abemaciclib; has a half-life of approximately 33–42 hours, supporting once-daily dosing.
In adjuvant trials, a lower dose (400mg) is used to improve tolerability during extended therapy (Tripathy et al., 2017).

Safety and Tolerability

The most frequent grade 3/4 adverse events are neutropenia (46–59%), leukopenia (13–21%), and, to a lesser extent, hepatic toxicity (ALT/AST elevation ~6–9%).
Febrile neutropenia is uncommon, and cytopenias are typically reversible and managed by dose modifications (Hortobagyi et al., 2016); (Spring et al., 2017).
Other notable but rare events: QTc prolongation, transaminitis, and, less commonly, pulmonary toxicity.
Discontinuation rates due to adverse events are relatively low (6–8%) (Hortobagyi et al., 2018).

Special Populations and Drug Interactions

Ribociclib has not been studied in pediatric populations, and caution is advised in patients with a history of cardiac arrhythmias due to QT prolongation risk.
Its metabolism via CYP3A4 mandates vigilance with potent inducers/inhibitors (e.g., St John’s wort contraindicated) (MedlinePlus, 2024).

Ongoing Research and Combinations

Ribociclib is being evaluated in a broad range of studies, assessing combinations with other targeted agents (PI3K, mTOR inhibitors), as well as investigational uses in other tumor types. Preclinical and translational research seeks to refine patient selection via biomarkers and harness synergy with other pathway inhibitors (Tripathy et al., 2017).

Summary & Outlook

Ribociclib is a pivotal agent in the contemporary management of HR+/HER2– breast cancer, with robust evidence for significant improvements in progression-free and overall survival in both pre- and postmenopausal women, as well as compelling recent data in the adjuvant early breast cancer setting. Its toxicity profile is manageable with appropriate monitoring and supportive measures. As precision medicine evolves, ribociclib stands as a cornerstone for rational and targeted cell cycle disruption in breast oncology.

Key References:

REFERENCES

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC - last accessed: 2025-10-22

KISQALI® (ribociclib) Mechanism of Action | Novartis Pro Portal - last accessed: 2025-10-22

What is the mechanism of action of Ribociclib Succinate? - last accessed: 2025-10-22

Ribociclib (Kisqali) - Uses, How to Take and Side Effects | Breast Cancer Now - last accessed: 2025-10-22

Kisqali (Ribociclib Tablets): Side Effects, Uses, Dosage, Interactions, Warnings - last accessed: 2025-10-22

Ribociclib: MedlinePlus Drug Information - last accessed: 2025-10-22

Ribociclib (oral route) - Side effects & dosage - Mayo Clinic - last accessed: 2025-10-22

NATALEE Trial 5-Year Analysis at ESMO 2025: Adjuvant Ribociclib Plus Endocrine Therapy Sustains Long-Term Benefit in HR+/HER2− Early Breast Cancer - OncoDaily - last accessed: 2025-10-22

Novartis Kisqali® 5-year NATALEE data demonstrate 28% reduction in risk of recurrence in the broadest early breast cancer patient population | Novartis - last accessed: 2025-10-22

Sources used

QUERY: ribociclib AND breast cancer

Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear.
In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy.
As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals.
Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months).
Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan-Meier methods.
The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61-0.96]. Kaplan-Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug-drug interactions were observed between ribociclib and either NSAI.
Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2- ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

Purpose This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting. Patients and Methods Patients were randomly assigned at a two-to-one ratio to ribociclib plus fulvestrant or placebo plus fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. Results A total of 484 postmenopausal women were randomly assigned to ribociclib plus fulvestrant, and 242 were assigned to placebo plus fulvestrant. Median progression-free survival was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consistent treatment effects were observed in patients who were treatment naïve in the advanced setting (hazard ratio, 0.577; 95% CI, 0.415 to 0.802), as well as in patients who had received up to one line of prior endocrine therapy for advanced disease (hazard ratio, 0.565; 95% CI, 0.428 to 0.744). Among patients with measurable disease, the overall response rate was 40.9% for the ribociclib plus fulvestrant arm and 28.7% for placebo plus fulvestrant. Grade 3 adverse events reported in ≥ 10% of patients in either arm (ribociclib plus fulvestrant v placebo plus fulvestrant) were neutropenia (46.6% v 0%) and leukopenia (13.5% v 0%); the only grade 4 event reported in ≥ 5% of patients was neutropenia (6.8% v 0%). Conclusion Ribociclib plus fulvestrant might represent a new first- or second-line treatment option in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.

NATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) compared with an NSAI alone in a broad population of patients with hormone receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease-free survival (iDFS).
Premenopausal/postmenopausal women and men were randomized 1 : 1 to ribociclib (n = 2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n = 2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS, and overall survival. This final iDFS analysis was planned after ∼500 events.
At data cut-off (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI versus NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone [hazard ratio 0.749, 95% confidence interval (CI) 0.628-0.892; P = 0.0012]. The 3-year iDFS rates were 90.7% (95% CI 89.3% to 91.8%) versus 87.6% (95% CI 86.1% to 88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (positive/negative). Distant DFS and RFS favored ribociclib plus NSAI. Overall survival data were immature. No new safety signals were observed.
With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable.

The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2).
In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10^-5.
The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10^-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively.
Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).

The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study.
A total of 668 postmenopausal women with HR+, HER2- recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point.
At the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months [95% confidence interval (CI) 23.0-30.3] for ribociclib plus letrozole and 16.0 months (95% CI 13.4-18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457-0.704; log-rank P = 9.63 × 10-8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517-1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity.
The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy.
NCT01958021.

In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known.
Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings.
After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed.
First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.).

In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer.
This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18-59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients.
Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigator's assessment, median progression-free survival was 23·8 months (95% CI 19·2-not reached) in the ribociclib group compared with 13·0 months (11·0-16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44-0·69; p<0·0001). Grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (203 [61%] of 335 patients in the ribociclib group and 12 [4%] of 337 in the placebo group) and leucopenia (48 [14%] and four [1%]). Serious adverse events occurred in 60 (18%) of 335 patients in the ribociclib group and 39 (12%) of 337 in the placebo group, of which 15 (4%) and six (2%), respectively, were attributed to the study regimen. 12 (4%) of 335 patients in the ribociclib group and ten (3%) of 337 in the placebo group discontinued treatment because of adverse events. No treatment-related deaths occurred. 11 deaths occurred (five [1%] in the ribociclib group and six [2%] in the placebo group) during or within 30 days after treatment, most of which were due to progression of the underlying breast cancer (three [1%] and six [2%]). The remaining two deaths in the ribociclib group were due to an intracranial haemorrhage in an anticoagulated patient, and a pre-existing wound haemorrhage in another patient.
Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients.
Novartis.

A head-to-head comparison of efficacy between a cyclin-dependent kinase 4/6 inhibitor plus endocrine therapy (ET) versus combination chemotherapy (CT) has never been reported in patients with clinically aggressive hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC).
In this open-label, multicenter, randomized phase II trial, pre/perimenopausal women with clinically aggressive HR+/HER2- ABC were randomly assigned 1:1 to first-line ribociclib (600 mg once daily; 3 weeks on, 1 week off) plus letrozole/anastrozole and goserelin or investigator's choice of combination CT (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine). The primary end point was progression-free survival (PFS).
Among 222 patients randomly assigned to ribociclib plus ET (n = 112) or combination CT (n = 110), 150 (67.6%) had symptomatic visceral metastases, 41 (18.5%) had rapid disease progression per investigator's judgment, and 31 (14.0%) had symptomatic nonvisceral disease. Overall, 106 (47.7%) patients had investigator-assessed visceral crisis. The median follow-up time was 37.0 months. At data cutoff, 31.3% (ribociclib arm) and 15.5% (CT arm) of patients had completed study treatment and transitioned to post-trial access. The median PFS was 21.8 months (ribociclib plus ET; [95% CI, 17.4 to 26.7]) and 12.8 months (combination CT; [95% CI, 10.1 to 18.4); hazard ratio, 0.61 [95% CI, 0.43 to 0.87]; P = .003. The overall response rates and the median time to response in the ribociclib versus CT arms, respectively, were 66.1% and 61.8% and 4.9 months and 3.2 months (hazard ratio, 0.76 [95% CI, 0.55 to 1.06]). Lower rates of symptomatic adverse events were observed in the ribociclib versus CT arm.
First-line ribociclib plus ET showed a significant PFS benefit, similar response rates, and better tolerability over combination CT in patients with clinically aggressive HR+/HER2- ABC.

Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed.
A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI).
Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib.
Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.

QUERY: ribociclib AND clinical trials

Aberrations of the cell cycle are pervasive in cancer, and selective cell cycle inhibition of cancer cells is a target of choice for a number of novel cancer therapeutics. Cyclin-dependent kinases (CDKs) are key regulatory enzymes that control cell cycle transitions and the commitment to cell division. Palbociclib and ribociclib are both orally active, highly selective reversible inhibitors of CDK4 and CDK6 that are approved by the U.S. Food and Drug Administration (FDA) for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies. A third oral CDK4/6 inhibitor, abemaciclib, received Breakthrough Therapy designation status from the FDA and is also being developed in breast cancer. The most common adverse events associated with palbociclib and ribociclib are hematologic, particularly neutropenia. However, the neutropenia associated with CDK4/6 inhibitors is distinct from chemotherapy-induced neutropenia in that it is rapidly reversible, reflecting a cytostatic effect on neutrophil precursors in the bone marrow. Most hematologic abnormalities seen with CDK4/6 inhibitors are not complicated and are adequately managed with standard supportive care and dose adjustments when indicated. Cytopenias are less prevalent with abemaciclib, although fatigue and gastrointestinal toxicity is more common with this agent. This review focuses on the clinical management of potential toxicities and drug interactions seen with the use of CDK4/6 inhibitors in breast cancer, with a focus on palbociclib and ribociclib, and summarizes practical management strategies for an oncologist.
The emergence of modern cyclin-dependent kinase (CDK) inhibitors has changed the treatment paradigm for metastatic hormone receptor (HR)-positive breast cancer. Palbociclib, ribociclib, and abemaciclib are highly selective reversible inhibitors of CDK4 and CDK6. Palbociclib is U.S. Food and Drug Administration (FDA)-approved in the first- and second-line settings in combination with endocrine therapy for HR-positive metastatic breast cancer. Ribociclib is FDA-approved in the first-line setting. Abemaciclib has received FDA Breakthrough Therapy designation status. This review focuses on the clinical management of potential toxicities and drug interactions seen with the use of CDK4/6 inhibitors in breast cancer.

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.

QUERY: ribociclib AND adverse effects

Uncontrolled cellular proliferation, mediated by dysregulation of the cell-cycle machinery and activation of cyclin-dependent kinases (CDKs) to promote cell-cycle progression, lies at the heart of cancer as a pathological process. Clinical implementation of first-generation, nonselective CDK inhibitors, designed to inhibit this proliferation, was originally hampered by the high risk of toxicity and lack of efficacy noted with these agents. The emergence of a new generation of selective CDK4/6 inhibitors, including ribociclib, abemaciclib and palbociclib, has enabled tumour types in which CDK4/6 has a pivotal role in the G1-to-S-phase cell-cycle transition to be targeted with improved effectiveness, and fewer adverse effects. Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge that, although unwelcome, might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response, and the use of combination therapies in order to optimize CDK4/6 targeting.

Combination therapy with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i: palbociclib, ribociclib, abemaciclib) and endocrine therapy (ET) has been a major advance for the treatment of hormone receptor-positive (HR+), ERBB2 (formerly HER2)-negative (ERBB2-) advanced or metastatic breast cancer.
Randomized phase 3 studies demonstrated that the addition of CDK4/6i reduced the hazard risk of disease progression by approximately half compared with hormonal monotherapy (an aromatase inhibitor, tamoxifen, or fulvestrant) in the first-line (1L) and/or second-line (2L) setting. Hence, the US Food and Drug Administration and European Medicines Agency approved 3 CDK4/6i, in both 1L and 2L settings. However, differences among the CDK4/6i regarding mechanisms of action, adverse effect profiles, and overall survival (OS) are emerging. Both abemaciclib and ribociclib have demonstrated efficacy in high-risk HR+ early breast cancer. While ET with or without CDK4/6i is accepted as standard treatment for persons with advanced HR+ ERBB2- metastatic breast cancer, several key issues remain. First, why are there discordances in OS in the metastatic setting and efficacy differences in the adjuvant setting? Additionally, apart from HR status, there are few biomarkers predictive of response to CDK4/6i plus ET, and these are not used routinely. Despite the clear OS advantage noted in the 1L and 2L metastatic setting with some CDK4/6i, a subset of patients with highly endocrine-sensitive disease do well with ET alone. Therefore, an unanswered question is whether some patients can postpone CDK4/6i until the 2L setting, particularly if financial toxicity is a concern. Finally, given the lack of endocrine responsiveness following progression on some CDK4/6i, strategies to optimally sequence treatment are needed.
Future research should focus on defining the role of each CDK4/6i in HR+ breast cancer and developing a biomarker-directed integration of these agents.

Web Sources

Ribociclib (oral route) - Side effects & dosage - Mayo Clinic

of Continuous Professional Development Mayo Clinic College of Medicine and Science Giving to Mayo Clinic Give Now Giving to Mayo Clinic Frequently Asked Questions Contact Us to Give Make a Donation Drugs & Supplements Drugs & Supplements Ribociclib (oral route) Brand Name US Brand Name Kisqali Back to top Description Ribociclib is used to treat hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER-2)-negative breast cancer. It is used in combination with an aromatase inhibitor to treat stage II and III early breast cancer with a high risk of coming back. This medicine is also used to treat advanced (has gotten worse) or metastatic (has spread throughout the body) breast cancer in combination with an aromatase inhibitor as the first endocrine-based treatment or with fulvestrant as the first endocrine-based treatment or after disease has gotten worse on endocrine treatment. Ribociclib belongs to the group of medicines called antineoplastics. It interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells may also be affected by the medicine, other unwanted effects will also occur. Some of these may be serious and must be reported to your doctor. This medicine is available only with your doctor's prescription. This product is available in the following dosage forms: Tablet Back to top Before Using In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered: Allergies Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully. Pediatric Appropriate studies have not been performed on the relationship of age to the effects of ribociclib in the pediatric population. Safety and efficacy have not been established. Geriatric Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of ribociclib in the elderly. Breastfeeding There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding. Drug Interactions Although certain medicines should

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official
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the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Clin Cancer Res . Author manuscript; available in PMC: 2018 Jul 1. Published in final edited form as: Clin Cancer Res. 2017 Mar 28;23(13):3251–3262. doi: 10.1158/1078-0432.CCR-16-3157 Search in PMC Search in PubMed View in NLM Catalog Add to search Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors Debu Tripathy Debu Tripathy 1 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Find articles by Debu Tripathy 1, * , Aditya Bardia Aditya Bardia 2 Department of Hematology/Oncology, Massachusetts General Hospital Cancer Center/Harvard Medical School, Boston, MA

Ribociclib (oral route) - Side effects & dosage - Mayo Clinic

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Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

inhibitor investigated in a clinical trial of neuroblastoma. Ongoing trials with ribociclib Multiple trials of ribociclib are ongoing across different tumor types, including BRAF v600 - and NRAS -mutant melanoma, non-small cell lung cancer, teratoma, liposarcoma, myelofibrosis, and gynecologic cancers; these are summarized in Supplementary Table 2 . The most advanced trials are investigating ribociclib combinations in HR+ breast cancer. MONALEESA-3 is evaluating the addition of ribociclib to fulvestrant in patients with HR+ ABC who have received no or only one line of prior endocrine therapy. MONALEESA-7 is investigating the combination of ribociclib and tamoxifen or non-steroidal aromatase inhibitors plus goserelin in pre/perimenopausal women with HR+ ABC. MONALEESA-7 is the only trial entirely dedicated to investigating CDK4/6 inhibition in the pre/perimenopausal setting. In addition, based on preclinical rationale, a number of additional doublet and triplet combination studies are underway, including combinations of ribociclib with endocrine therapy and PI3K pathway inhibition ( Supplementary Table 2 ). Ribociclib in perspective The clinical data for ribociclib adds to the wealth of emerging information supporting use of CDK4/6 inhibitors in the treatment of cancer. Certain differences among ribociclib, palbociclib, and abemaciclib, including PK factors, target selectivity, and toxicities, are likely to influence their activity or utility in individual settings. PK data with ribociclib demonstrate a long half-life compared with palbociclib and abemaciclib ( Table 2 ). While the half-lives of ribociclib and palbociclib enable once-daily, 3-weeks-on/1-week-off dosing ( 14 ), the PK/pharmacodynamic profile of abemaciclib favors twice-daily, continuous dosing ( 29 , 70 ). The convenience of intermittent versus continuous dosing and its impact on treatment adherence and outcomes remains to be explored. Once-daily, continuous dosing of ribociclib in combination with endocrine therapies is being evaluated in ongoing breast cancer trials ( NCT02088684 , NCT02712723 , NCT02732119 ) ( 42

NATALEE Trial 5-Year Analysis at ESMO 2025: Adjuvant Ribociclib Plus Endocrine Therapy Sustains Long-Term Benefit in HR+/HER2− Early Breast Cancer - OncoDaily

2− breast cancer management. The NATALEE trial thus establishes ribociclib as a viable, well-tolerated adjuvant option capable of addressing both node-positive and biologically high-risk node-negative populations—broadening the reach of precision-based therapy in early breast cancer management. Read Full Abstract on ESMO Congress 2025 Website You Can Watch More on OncoDaily Youtube TV Written by Armen Gevorgyan, MD Oncolibrary Adjuvant ribociclib results CDK4/6 inhibitor early breast cancer ESMO ESMO 2025 ESMO Congress 2025 ESMO2025 ESMO25 HR-positive HER2-negative early breast cancer NATALEE trial 5-year results OncoDaily Oncology Ribociclib adjuvant therapy Ribociclib iDFS benefit ribociclib plus endocrine therapy CancerWorld OncoDaily Medical Journal Hemostasis Today OncoDaily IO OncoDaily GI OncoDailyTV Subscribe to newsletter OncoDaily™ | © 2023 - 2025 All rights reserved. Unauthorized reproduction, distribution, or transmission of any content on OncoDaily.com is strictly prohibited. For permission requests or inquiries, please contact OncoDaily directly. By accessing and using OncoDaily.com, you acknowledge and agree to comply with this copyright notice, as well as our Privacy Policy, Editorial Policy, Cookie Policy, and Disclaimer. Continued use of this website constitutes acceptance of all such terms and policies. Phone number: +1 978 717 48 84 Email: [email protected] About Privacy Policy Editorial Policy Cookie Policy Disclaimer Crafted by Matemat OncoDaily Oncology cancer fight against cancer Global fight against cancer Breast Cancer cancer care ASCO Lung cancer Cancer research ESMO MD Anderson Cancer Center NSCLC cancer awareness immunotherapy cancer treatment Headlines Research ASCO24 Childhood Cancer colorectal cancer prostate cancer clinical trials AACR FDA Dana-Farber Cancer Institute UICC European Cancer Organisation American Cancer Society NCI National Cancer Institute SIOP chemotherapy Vivek Subbiah healthcare American Society of Clinical Oncology ASCO25 AI Paolo Tarantino Robert Orlowski IASLC radiation oncology WHO Myeloma Paper of the Day Myeloma Memorial Sloan Kettering Cancer Center multiple myeloma Zainab Shinkafi-Bagudu cervical cancer Pancreatic Cancer European School of Oncology Sitemap

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

, TX, USA Find articles by Debu Tripathy 1, * , Aditya Bardia Aditya Bardia 2 Department of Hematology/Oncology, Massachusetts General Hospital Cancer Center/Harvard Medical School, Boston, MA, USA Find articles by Aditya Bardia 2 , William R Sellers William R Sellers 3 Novartis Institutes for BioMedical Research, Cambridge, MA Find articles by William R Sellers 3 Author information Article notes Copyright and License information 1 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Hematology/Oncology, Massachusetts General Hospital Cancer Center/Harvard Medical School, Boston, MA, USA 3 Novartis Institutes for BioMedical Research, Cambridge, MA * Corresponding author: Professor Debu Tripathy, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1354, Houston, Texas 77030, Phone: (713) 792-2817, Fax: (713) 563-0903, dtripathy@mdanderson.org Issue date 2017 Jul 1. PMC Copyright notice PMCID: PMC5727901 NIHMSID: NIHMS863046 PMID: 28351928 The publisher's version of this article is available at Clin Cancer Res Abstract The cyclin D–cyclin-dependent kinase (CDK) 4/6–p16–retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which was granted priority review by the US Food and Drug Administration in November 2016, and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib. Here we describe the mechanism of action of ribociclib, and review preclinical and clinical data from Phase I, II, and III trials of ribociclib across different tumor types, within the context of other selective CDK4/6 inhibitors. The pharmacokinetics, pharmacodynamics, safety, tolerability, and clinical responses with ribociclib as a single agent or in

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

rozole: 2.5 mg/day All AEs were mild/moderate with no Grade 3/4 AEs Ribociclib 400 mg/day + letrozole: 96% decrease in Ki67 Ribociclib 600 mg/day + letrozole: 92% decrease in Ki67 Letrozole only: 69% decrease in Ki67 MONALEESA-2/ NCT01958021 ( 46 ) Letrozole III Postmenopausal women with HR+, HER2− ABC who have received no prior treatment for advanced disease ( N= 668) Ribociclib: 600 mg/day (3-weeks-on/1-week-off) Letrozole: 2.5 mg/day Ribociclib + letrozole arm vs placebo + letrozole arm: Neutropenia (59% vs 1%), leukopenia (21% vs 1%), hypertension (10% vs 11%), increased ALT (9% vs 1%), lymphopenia (7% vs 1%), and increased AST (6% and 1%) Ribociclib + letrozole arm vs placebo + letrozole arm: Median PFS NR (95% CI, 19.3–NR) vs 14.7 months (95% CI, 13.0–16.5); HR=0.56; P =3.29×10 −6 ORR 41% vs 28% ( P <0.001) CBR 80% vs 72% ( P= 0.02) NRAS - or BRAF -mutant melanoma CMEK162X2114/ NCT01781572 ) ( 62 ) Binimetinib Ib/II Patients with advanced NRAS - mutant melanoma ( N= 22 received ribociclib + binimetinib) MTD: Ribociclib: 200 mg/day (3-weeks-on/1-week-off) Binimetinib: 45 mg BID RP2D: ongoing CPK elevation (18%), neutropenia (9%), acneiform (4%), dermatitis (4%), and rash (4%) 7 PR, 11 SD, 33% had 20–30% tumor shrinkage, CBR 86% CLEE011X2105/ NCT01777776 ( 61 ) Encorafenib Ib/II Patients with advanced BRA

What is the mechanism of action of Ribociclib Succinate?

DNA replication, repair, and cellular metabolism. This broad-spectrum impact on the cellular transcriptome and proteome contributes significantly to the anti-proliferative and, in some cases, pro-apoptotic effects observed in cancer cells treated with ribociclib. Clinical Implications Ribociclib’s mechanism of action translates into significant clinical benefits, particularly in the treatment of advanced hormone receptor-positive, HER2-negative breast cancer. Its ability to specifically target the CDK4/6-Rb pathway yields robust inhibitory effects on cancer cell proliferation, which is reflected in improved clinical outcomes and survival metrics in multiple clinical trials. Efficacy in Cancer Treatment Multiple clinical studies have demonstrated that ribociclib, when used as a monotherapy or in combination with endocrine agents, leads to a significant prolongation of progression-free survival in patients with advanced breast cancer. By halting cell cycle progression and preventing the transition from G1 to S phase, ribociclib effectively controls tumor growth in hormone receptor-positive cancers. The effectiveness of ribociclib is not only supported by its clinical trial outcomes but also by its preclinical profile. Studies detailing its molecular interactions have shown that ribociclib exerts potent growth inhibition in a variety of cancer cell lines that rely on a functional Rb protein. In patient-derived xenograft models, administration of ribociclib led to marked tumor growth suppression, emphasizing its translational potential from bench to bedside. Moreover, the strategic combination of ribociclib with endocrine therapies is crucial. Hormone receptor-positive breast cancers often develop resistance through mechanisms involving upregulation of cyclin D1 and subsequent activation of CDK4/6. By interrupting this resistance mechanism, ribociclib restores sensitivity to endocrine therapies. This synergy not only delays disease progression but also contributes to overall disease control, making the combination a cornerstone in the treatment landscape of luminal breast cancers. Side Effects and Safety Profile One of the notable clinical implications of ribociclib’s precise mechanism of action is its manageable toxicity profile. Since ribociclib selectively targets CDK4/6 and spares other kinases, the associated adverse effects are typically less severe compared to broader-spectrum kinase inhibitors. The most frequently observed adverse events include hematologic toxicities such as neutropenia, which is generally manageable through dose modifications or appropriate scheduling (for instance, a 21

Ribociclib: MedlinePlus Drug Information

abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. How should this medicine be used? Ribociclib comes as a tablet to take by mouth. It is usually taken with or without food once daily in the morning for the first 21 days of a 28-day cycle. Take ribociclib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take ribociclib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Swallow the tablets whole; do not split, chew, or crush them. Do not take tablets that are broken or crushed. If you vomit after taking ribociclib, do not take another dose. Continue your regular dosing schedule. Your doctor may decrease your dose of ribociclib or permanently or temporarily stop your treatment. This depends on how well the medication works for you and the side effects you experience. Be sure to tell your doctor how you are feeling during your treatment with ribociclib. Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient. Other uses for this medicine This medication may be prescribed for other uses; ask your doctor or pharmacist for more information. What special precautions should I follow? Before taking ribociclib, tell your doctor and pharmacist if you are allergic to ribociclib, any other medications, or any of the ingredients in ribociclib tablets. Ask your pharmacist for a list of the ingredients. tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take while taking ribociclib. Your doctor may need to change the doses of your medications or monitor you carefully for side effects. the following herbal product may interact with ribociclib: St. John's wort. Be sure to let your doctor and pharmacist know that you are taking this medication before you start taking ribociclib. Do not start this medication while taking ribociclib without discussing with your healthcare provider. tell your doctor if you or anyone in your family has or has ever had a prolonged QT interval (a rare heart problem that may cause irregular heartbeat, fainting, or sudden death). Also, tell your doctor if you

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

remains to be explored. Once-daily, continuous dosing of ribociclib in combination with endocrine therapies is being evaluated in ongoing breast cancer trials ( NCT02088684 , NCT02712723 , NCT02732119 ) ( 42 ). PK data indicate that ribociclib can be taken with or without food, whereas palbociclib must be administered with food ( 20 , 33 ), and that ribociclib may be absorbed more rapidly than palbociclib and abemaciclib ( Table 2 ) ( 70 , 71 ). Preclinically, ribociclib appears to have less toxicity against bone marrow mononuclear cells compared with palbociclib and abemaciclib ( Table 2 ) ( 26 ), which may potentially translate into fewer hematologic toxicities. Hematologic toxicities were reported with ribociclib plus letrozole in MONALEESA-2 and with palbociclib plus letrozole in PALOMA-2 ( 18 , 46 ). Differences in target selectivity also lead to variations in safety: with abemaciclib demonstrating increased frequency of gastrointestinal AEs versus ribociclib or palbociclib ( Table 1 ) ( 14 ). Ribociclib is generally well tolerated, with predictable AEs that are easily manageable by dose adjustment or treatments. Finally, preclinical data suggest that both ribociclib and abemaciclib can cross the blood–brain barrier, supporting further exploration with central nervous system tumors ( 72 , 73 ). Conclusion Ribociclib is a promising, selective CDK4/6 inhibitor in the late stages of clinical development, demonstrating preclinical and clinical activity across a range of tumor types, including HR+ breast cancer. The preclinical, clinical, and PK profiles of ribociclib in a variety of tumor types make it an important addition to the class of CDK4/6 inhibitors. Given the selectivity of ribociclib towards CDK4/6, the addition of ribociclib to existing anticancer therapies in doublet and triplet combinations has been successful, enhancing efficacy of existing therapies with minimal increases in toxicity in preclinical and clinical studies. This result is being explored extensively across a range of tumor types and in combination with a variety of anticancer agents ( Supplementary Table 2 ). Establishing validated biomarkers of clinical response to ribociclib will help define patient populations

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

Estevez L, Mayer I, Becerra C, Hamilton E, et al. Phase Ib safety, efficacy, and molecular analysis of ribociclib (LEE011) plus letrozole for the treatment of ER+, HER2− advanced breast cancer. San Antonio Breast Cancer Symposium; 2016. Poster P4-22-18. [ Google Scholar ] 46. Hortobagyi G, Stemmer S, Burris H, Yap Y, Sonke G, Paluch-Shimon S, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375:1738–48. doi: 10.1056/NEJMoa1609709. [ DOI ] [ PubMed ] [ Google Scholar ] 47. Juric D, Hamilton E, Garcia-Estevez L, De Boer R, Mayer I, Campone M, et al. Phase Ib/II study of LEE011 and alpelisib (BYL719) and letrozole in ER+, HER2–breast cancer: Safety, preliminary efficacy and molecular analysis. Cancer Res. 2014;75(9 suppl) Abstract P5-19-24. [ Google Scholar ] 48. Burris H, Chan A, Campone M, Blackwell K, Winer E, Janni W, et al. First-line ribociclib + letrozole in patients with HR+, HER2− advanced breast cancer (ABC) presenting with visceral metastases or bone-only disease: A subgroup analysis of the MONALEESA-2 trial. San Antonio Breast Cancer Symposium; 2016. Poster P4-22-16. [ Google Scholar ] 49. O’Shaughnessy J, Petrakova K, Sonke G, André F, Conte P, Arteaga C, et al. First-line ribociclib plus letrozole in patients with de novo HR+, HER2− ABC: A subgroup analysis of the MONALEESA-2 trial. San Antonio Breast Cancer Symposium; 2016. Poster P4-22-05. [ Google Scholar ] 50. Andre F, Stemmer S, Hortobagyi G, Burris H, Shimon S, Campone M, et al. Riboc

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

. 2016;375:1925–36. doi: 10.1056/NEJMoa1607303. [ DOI ] [ PubMed ] [ Google Scholar ] 19. Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373:209–19. doi: 10.1056/NEJMoa1505270. [ DOI ] [ PubMed ] [ Google Scholar ] 20. [Accessed December 2016];IBRANCE® (palbociclib) prescribing information. Available from http://Labeling.pfizer.com/ShowLabeling.aspx?id=2191 . 21. Pfizer. [Accessed December 2016];IBRANCE® (palbociclib) receives approval in European Union for the treatment of women with HR+/HER2− metastatic breast cancer. Available from: http://www.pfizer.com/news/press-release/press-release-detail/ibrance_palbociclib_receives_approval_in_european_union_for_the_treatment_of_women_with_hr_her2_metastatic_breast_cancer . 22. Dickler M, Tolaney S, Rugo H, Cortes J, Diéras V, Patt D, et al. MONARCH 1: Results from a Phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2− breast cancer, after chemotherapy for advanced disease. J Clin Oncol. 2016;34(suppl) Abstract 510 (Oral presentation) [ Google Scholar ] 23. Goetz M, Beeram M, Beck T, Conlin A, Dees E, Dickler M, et al. Abemaciclib, an inhibitor of CDK4 and CDK6, combined with endocrine and HER2-targeted therapies for women with metastatic breast cancer. Cancer Res. 2016;76(4 suppl) Poster P4-13-25. [ Google Scholar ] 24. Lilly. [Accessed December 2016];Lilly receives FDA breakthrough therapy designation for abemaciclib - a CDK

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

biochemical assays ( Table 2 ) ( 26 – 29 ). Interestingly, in a chemoproteomics study of CDK4/6 inhibitor activity in lung carcinoma cell lines and primary tumor samples, ribociclib was found to be significantly more selective towards CDK4 and CDK6 than palbociclib, which interacted with more than twice as many kinases than ribociclib ( 30 ). Table 2. Key characteristics of CDK4/6 inhibitors in clinical development for solid tumors. Ribociclib (LEE011) ( 26 , 27 , 31 , 32 ) Palbociclib (Ibrance ® ; PD-0332991) ( 20 , 26 , 28 ) Abemaciclib (LY2835219) ( 26 , 29 , 70 ) IC 50 (nM) – on target CDKs CDK4–cyclin D1 10 11 2 CDK6–cyclin D1/2/3 39 16 10 IC 50 (nM) – on other CDKs CDK1–cyclin B 113,000 >10,000 1627 CDK2–cyclin A/E 76,000 >10,000 504 CDK5–p25 43,900 >10,000 355 CDK9–cyclin T NR NR 57 Kinase partition index 0.99 0.96 0.88 Lipophilicity (cLogP) 2.3 2.7 5.5 IC 50 against bone marrow mononuclear cells (nM) 1700 ± 231 240 ± 43 230 ± 27 Half-life 33–42 hours 26–27 hours 17–38 hours T max 1–5 hours 6–12 hours 4–6 hours Open in a new tab cLogP, calculated Log of the partition coefficient. Early clinical experience with ribociclib The first Phase I clinical studies evaluated single-agent ribociclib across a range of Rb-positive advanced solid tumors and lymphomas in US/European ( N= 132) and Japanese patients ( N= 17) ( 31 , 32 ). The recommended Phase II dose (RP2D) of single-agent ribociclib was declared as 600 mg/day on a 3-weeks-on/1-week-off schedule ( 31 , 32 ). Pharmacokinetic analyses determined that ribociclib is rapidly absorbed, with a time to maximum concentration (T max ) of 1–5 hours,

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

50 ). In newly diagnosed Grade II/III HR+, HER2− invasive breast cancer, a randomized pre-surgical study demonstrated an enhanced reduction in expression of the Ki67 marker for cell proliferation upon combination of ribociclib and letrozole (≥92%) versus letrozole alone (69%), further supporting a role for ribociclib in enhancing the antitumor effects of its combination partner ( 43 ). An ongoing trial ( NCT02712723 ) is investigating ribociclib plus letrozole in the neoadjuvant setting ( Supplementary Table 2 ). Preliminary clinical activity has also been established with ribociclib plus fulvestrant in pretreated HR+, HER2− ABC, and PRs were observed in patients who received prior fulvestrant ( 42 ). When evaluating potential biomarkers of response, preliminary clinical activity with ribociclib plus letrozole or fulvestrant was reported in patients with ER+ breast cancer tumors carrying alterations in PI3K/AKT/mTOR or cyclin D–CDK4/6–p16–Rb pathways, suggesting a possible benefit in patients whose tumors carry these alterations ( 42 , 45 ). Encouraging preliminary clinical activity has also been demonstrated with triplet therapy of ribociclib, exemestane, and everolimus (mTOR inhibitor), as well as ribociclib, letrozole, and alpelisib (PI3Kα selective inhibitor) in pretreated patients with HR+ ABC ( Table 3 and Supplementary Table 2 ) ( 47 , 51 , 52 ). While ribociclib exposure remained unaltered by combination with everolimus, exposure to everolimus, which is metabolized by cytochrome P450 3A4 (CYP3A4), increased 1.5–3-fold when combined with ribociclib ( 41 ). However, use of lower doses of everolimus (e.g. 2.5 mg/day) resulted in exposures within the ranges achieved with single-agent everolimus dosing (e.g. 5–10 mg/day), with potentially lower toxicity ( 41 , 52 ). Triplet therapy with ribociclib, everolimus, and exemestane in pretreated patients with ER+ ABC was associated with manageable safety ( Table 3 ) ( 52 ). During triplet therapy with ribociclib, alpelisib,

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

; 2016. Poster P4-22-05. [ Google Scholar ] 50. Andre F, Stemmer S, Hortobagyi G, Burris H, Shimon S, Campone M, et al. Ribociclib + letrozole for first-line treatment of HR+, HER2− ABC: Efficacy, safety, and pharmacokinetics. EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics; 2016. Abstract 12LBA. [ Google Scholar ] 51. Juric D, Ismail-Khan R, Campone M, García-Estévez L, Becerra C, De Boer R, et al. Phase Ib study of ribociclib and alpelisib and letrozole in ER+, HER2− advanced breast cancer: Safety, preliminary efficacy, and molecular analysis. Cancer Res. 2016;76(4 suppl) Abstract P3-14-01. [ Google Scholar ] 52. Bardia A, Modi S, Oliveira M, Campone M, Ma B, Dirix L, et al. Triplet therapy with ribociclib, everolimus, and exemestane in postmenopausal women with HR+/HER2− advanced breast cancer. Cancer Res. 2016;76(4 suppl) doi: 10.1158/1078-0432.CCR-20-1068. Abstract P6-13-01. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 53. Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681–96. doi: 10.1016/j.cell.2015.05.044. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 54. Rajkumar S, Watson IR. Molecular characterisation of cutaneous melanoma: Creating a framework for targeted and immune therapies. Br J Cancer. 2016;115:145–55. doi: 10.1038/bjc.2016.195. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 55. Maelandsmo GM, Flørenes VA, Hovig E, Øyjord T, Engebraaten O, Holm R, et al. Inv

Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors - PMC

4%) 7 PR, 11 SD, 33% had 20–30% tumor shrinkage, CBR 86% CLEE011X2105/ NCT01777776 ( 61 ) Encorafenib Ib/II Patients with advanced BRAF V600 -mutant melanoma ( N= 28 received ribociclib + encorafenib) MTD: ongoing R P2D: ongoing Hand–foot syndrome (11%), rash (4%), and myalgia (4%) 2 confirmed PRs, 3 unconfirmed PRs, 10 SD, 1 SD >9 cycles Open in a new tab ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBR, clinical benefit rate; CR, complete response; DCR, disease control rate; NCRNPD, not complete response nor progressive disease; NR, not reached; ORR, overall response rate; UTI, urinary tract infection. Clinical activity of ribociclib was observed in studies of HR+ ABC ( Table 3 ) ( 42 , 44 – 46 ). In MONALEESA-2, where 668 patients with HR+ ABC were randomized to receive ribociclib plus letrozole or placebo plus letrozole, ribociclib plus letrozole significantly increased PFS relative to placebo plus letrozole in the first-line setting (median PFS: not reached vs 14.7 months; hazard ratio=0.56; P =3.29×10 −6 ) ( 46 ). The PFS rate at 12 months was 72.8% versus 60.9% in the ribociclib and placebo groups, respectively ( 46 ). A significant hazard ratio benefit for ribociclib plus letrozole was also observed across all pre-specified patient subgroups, including older patients (≥65 years) and those with visceral metastases, bone-only disease, or de novo ABC ( 46 , 48 , 49 ). In the ribociclib plus letrozole arm, decreased tumor size at the initial evaluation (~Week 8) was observed in 76% of evaluable patients with measurable disease ( 50 ). In newly diagnosed Grade II/III HR+, HER2− invasive breast cancer, a randomized pre-surgical study demonstrated an enhanced reduction in expression of the Ki67 marker for cell proliferation upon combination of ribociclib and letroz

Novartis Kisqali® 5-year NATALEE data demonstrate 28% reduction in risk of recurrence in the broadest early breast cancer patient population | Novartis

Stroyakovskii D, Yardley DA, et al. Adjuvant Ribociclib Plus Nonsteroidal Aromatase Inhibitor Therapy in Patients With HR+/HER2− Early Breast Cancer: NATALEE 5-Year Outcomes. Presented at the European Society for Medical Oncology (ESMO) Congress; October 17-21, 2025; Berlin, Germany. Yardley DA 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. Neven P et al. Updated overall survival (OS) results from the first-line (1L) population in the Phase III MONALEESA-3 trial of postmenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with ribociclib (RIB) + fulvestrant (FUL). Mini oral presented at the European Society for Medical Oncology Breast Cancer Congress. May 4, 2022. Paris, France. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med . 2022;386(10):942-950. doi:10.1056/NEJMoa2114663. Hortobagyi GN et al. Overall survival (OS) results from the phase III MONALEESA (ML)-2 trial of postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib. LBA 17. Proffered paper presented at the European Society of Medical Oncology Congress, September 16-21, 2021. Lugano, Switzerland. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med . 2019;381(4):307-316. doi:10.1056/NEJMoa1903765. Slamon DJ

NATALEE Trial 5-Year Analysis at ESMO 2025: Adjuvant Ribociclib Plus Endocrine Therapy Sustains Long-Term Benefit in HR+/HER2− Early Breast Cancer - OncoDaily

0.716 (95% CI: 0.618–0.829; nominal 1-sided P < .0001). This translates to a 28.4% relative reduction in the risk of invasive disease recurrence compared to NSAI alone. The absolute iDFS rates favored ribociclib across all time points: 3 years: 90.8% (RIB + NSAI) vs 88.0% (NSAI alone) 4 years: 88.3% vs 83.9% 5 years: 85.5% vs 81.0% These figures represent absolute iDFS improvements of 2.7%, 4.4%, and 4.5%, respectively, showing that the magnitude of benefit increased with longer follow-up. Importantly, the iDFS advantage extended across all predefined subgroups, including those with node-negative (N0) disease, where ribociclib achieved an HR of 0.606 (95% CI: 0.372–0.986). This finding underscores the potential role of ribociclib in reducing recurrence risk even among patients traditionally considered to have a favorable prognosis. In addition to the primary endpoint, ribociclib maintained consistent benefit across secondary measures of disease control: DDFS: HR = 0.709 (95% CI: 0.608–0.827) DRFS: HR = 0.699 (95% CI: 0.594–0.824) Both endpoints confirm the combination’s ability to prevent distant metastases, which represent the most clinically meaningful form of relapse in early breast cancer. Furthermore, a positive trend toward overall survival continues to emerge, with HR = 0.800 (95% CI: 0.637–1.003; nominal 1-sided P = .026), suggesting potential long-term mortality benefit that may reach statistical significance with further follow-up. Safety After a median follow-up of approximately two years beyond completion of ribociclib therapy, no new or unexpected safety signals were reported. The long-term safety profile remained consistent with prior analyses and with the established tolerability of ribociclib in the metastatic setting. The 400 mg dosing strategy—lower than the 600 mg dose used in metastatic disease—was designed to balance efficacy with improved tolerability for long-term adjuvant use. The absence of cumulative or delayed toxicity supports the feasibility of prolonged CDK4/6 inhibition

What is the mechanism of action of Ribociclib Succinate?

effects are typically less severe compared to broader-spectrum kinase inhibitors. The most frequently observed adverse events include hematologic toxicities such as neutropenia, which is generally manageable through dose modifications or appropriate scheduling (for instance, a 21-days-on/7-days-off treatment cycle). Importantly, the side effect profile of ribociclib is also influenced by its pharmacokinetic properties. Ribociclib is rapidly absorbed and has a suitable half-life, allowing for once-daily dosing that helps maintain sustained inhibition of CDK4/6 activity without causing excessive toxicity. Clinical trials have confirmed that while hematologic side effects are common, they are rarely associated with febrile neutropenia, and other non-hematologic adverse effects such as hepatic toxicity and QTc interval prolongation are generally manageable with monitoring and dose adjustments. Additionally, the tolerability of ribociclib supports its combination with other agents. When administered together with endocrine therapies, the combined regimen’s adverse effects are often predictable and can be managed with supportive care, allowing patients to receive prolonged treatment periods, which is critical in chronic settings like metastatic breast cancer. Research and Development The ongoing research and development efforts related to ribociclib have broadened our understanding of its mechanism and clinical utility. As the first in a class of highly selective CDK4/6 inhibitors approved for HR+/HER2– advanced breast cancer, ribociclib continues to be the subject of extensive investigation in both preclinical and clinical settings to optimize its use across various cancer types and in combination with other therapeutic modalities. Ongoing Studies Numerous clinical trials are underway to explore the full potential of ribociclib beyond its established indication in breast cancer. One arena of investigation includes evaluating the efficacy of ribociclib in different tumor types where CDK4/6 pathway dysregulation is evident. Preclinical studies have already shown promising synergistic effects when ribociclib is combined with inhibitors targeting other proliferative pathways such as FGFR, PI3K, and mTOR, thereby expanding its therapeutic scope. Clinical trials are currently evaluating combinations of ribociclib with newer endocrine therapies as well as with other targeted agents, to overcome resistance mechanisms that may arise during treatment. For example, studies combining ribociclib with fulvestrant or aromatase inhibitors in early and metastatic settings are actively exploring ways to improve progression-free

Novartis Kisqali® 5-year NATALEE data demonstrate 28% reduction in risk of recurrence in the broadest early breast cancer patient population | Novartis

American Society of Clinical Oncology Annual Meeting. June 2020. Chicago, USA. O’Shaughnessy J et al. Overall survival subgroup analysis by metastatic site from the Phase III MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with HR+/HER2− advanced breast cancer. Presented at the San Antonio Breast Cancer Symposium. December 7-10, 2021. Texas, USA. Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med . 2024;390(12):1080-1091. doi:10.1056/NEJMoa2305488 Clinicaltrials.gov. NCT03701334. A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/ HER2- Early Breast Cancer (NATALEE). Accessed October 2025. https://clinicaltrials.gov/study/NCT03701334 Kisqali. Prescribing Information (US FDA). Novartis Pharmaceuticals Corporation; 2017. Accessed October 2025. https://www.novartis.com/us-en/sites/novartis_us/files/kisqali.pdf Kisqali. Summary of product characteristics (SmPC). Novartis Europharm Limited; 2017. Accessed October 2025. https://www.ema.europa.eu/en/documents/product-information/kisqali-epar-product-information_en.pdf NCCN Guidelines. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) - Breast Cancer. Accessed October 2025. https://www.nccn.org National Medical Products Administration. Drug Evaluation Information Disclosure: Drug Evaluation Approval Results. National Medical Products Administration. Published May 21, 2025. Accessed October 2025. https://www.nmpa.gov.cn/zwfw/sdxx/sdxxyp/yppjfb/20250521151427103.html European Society of Medical Oncology (ESMO). ESMO MCBS scorecards; NATALEE. Accessed October 2025. https://www.esmo.org/guidelines/esmo-mcbs/esmo