ribociclib 2025-10-02 02:33:14

ribociclib

Ribociclib: Mechanism of Action, Clinical Efficacy, and Therapeutic Role

Introduction

Ribociclib (brand name Kisqali®) is a selective, orally bioavailable cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor used primarily in the management of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. It is a targeted therapy designed to disrupt cell cycle regulation in cancer cells, thereby inhibiting proliferation and improving clinical outcomes. Ribociclib has received regulatory approval for use in both early and advanced/metastatic breast cancer, in combination with hormone therapies such as aromatase inhibitors and fulvestrant, and is indicated for both female and male patients (Mayo Clinic, 2024); (Gao et al., 2023).

Mechanism of Action

The cell cycle is tightly regulated by cyclin–CDK complexes, with the cyclin D–CDK4/6–p16–retinoblastoma (Rb) pathway governing the critical G1-to-S phase transition. In cancer, dysregulation of this pathway (often through overactivation of CDK4/6 or loss of p16/Rb function) leads to unchecked cellular proliferation (Tripathy et al., 2017).

Ribociclib selectively inhibits CDK4 and CDK6, preventing phosphorylation of Rb, and thereby halting progression from G1 to S phase. This results in cell cycle arrest and reduced tumor cell proliferation (Tripathy et al., 2017); (Novartis Pro Portal, n.d.).

Clinical Indications and Approvals

Early Breast Cancer

As of September 2024, the FDA has approved ribociclib in combination with an aromatase inhibitor for adjuvant treatment of HR-positive, HER2-negative stage II and III early breast cancer at high risk of recurrence. This approval is based on the phase 3 NATALEE trial, which demonstrated a statistically significant improvement in invasive disease-free survival (iDFS) compared to endocrine therapy alone (Targeted Oncology, 2024).

NATALEE Trial Highlights: Ribociclib (400 mg daily, 3-weeks-on/1-week-off for 3 years) plus aromatase inhibitor resulted in an iDFS benefit across subgroups (e.g., menopausal status, prior chemotherapy), with distant recurrence rates of 6.9% versus 9.6% for endocrine therapy alone (Targeted Oncology, 2024).

Advanced or Metastatic Breast Cancer

Ribociclib is approved as first-line and subsequent therapy for HR-positive, HER2-negative advanced or metastatic breast cancer in combination with:

Aromatase inhibitors (as initial endocrine-based therapy)
Fulvestrant (as initial therapy or after progression on endocrine therapy)
In both postmenopausal women and men (Gao et al., 2023); (Tripathy et al., 2017).

MONALEESA Clinical Trials

MONALEESA-2: Ribociclib + letrozole vs placebo + letrozole in postmenopausal women with advanced breast cancer. Median progression-free survival (PFS) was not reached (95% CI, 19.3–NR) in the ribociclib arm vs 14.7 months (95% CI, 13.0–16.5) in placebo (HR 0.56; P = 3.29 × 10^−6). The overall response rate (ORR) was 41% vs 28% (P < 0.001) (Tripathy et al., 2017).
MONALEESA-3: Ribociclib + fulvestrant in postmenopausal women and men. Median PFS was 20.5 months (95% CI, 18.5–23.5) for ribociclib + fulvestrant vs 12.8 months (95% CI, 10.9–16.3) for placebo (HR 0.593, 95% CI 0.480–0.732, p < 0.0001) (Gao et al., 2023).
MONALEESA-7: Pre-/perimenopausal women, ribociclib + non-steroidal aromatase inhibitor (NSAI) or tamoxifen + goserelin. Median PFS benefit of 13.7 months over placebo (HR 0.569, 95% CI 0.436–0.743). Median overall survival (OS) not reached in ribociclib arm vs 40.7 months in placebo (HR 0.699, 95% CI 0.501–0.976) (Gao et al., 2023).

Male Breast Cancer

Ribociclib's approval was expanded to include male patients with HR-positive, HER2-negative advanced or metastatic breast cancer, based primarily on extrapolated efficacy and safety data from MONALEESA studies and supported by the COMPLEEMENT-1 trial:

COMPLEEMENT-1: 39 male patients enrolled out of a cohort of 3,246. The ORR in males with measurable disease at baseline was 46.9% (95% CI, 29.1–65.3), consistent with the ORR of 43.6% (95% CI, 41.5–45.8) in the overall population. Adverse event profile was similar to that in females (Gao et al., 2023); (Gao et al., 2024).

Dosing and Administration

Early Breast Cancer: 400 mg once daily for 21 consecutive days, followed by 7 days off (28-day cycle), usually for 3 years (Mayo Clinic, 2024).
Advanced/Metastatic Breast Cancer: 600 mg once daily for 21 consecutive days, followed by 7 days off (28-day cycle), continued until disease progression or unacceptable toxicity.
Combination partners: Always combined with an aromatase inhibitor or fulvestrant; ovarian suppression required for premenopausal women (Breast Cancer Now, 2024).
Administration: Oral tablets, taken with or without food; avoid grapefruit and St. John’s Wort due to interaction risks (MedlinePlus, 2025).

Pharmacokinetics and Selectivity

Half-life: 33–42 hours.
Tmax: 1–5 hours; rapid absorption.
Food effect: None – can be taken with or without food.
Selectivity: More selective towards CDK4/6 than palbociclib, with less off-target kinase inhibition (Tripathy et al., 2017).

Safety and Adverse Effects

Ribociclib is generally well-tolerated, with a predictable side effect profile:

Hematologic: Neutropenia (59% in MONALEESA-2), leukopenia, anemia.
Non-hematologic: Fatigue, nausea, diarrhea, AST/ALT elevation, QT interval prolongation (requires ECG monitoring).
Serious AEs: Grade 3/4 neutropenia is frequent but usually uncomplicated; dose modifications may be necessary.

Adverse reactions in male patients are similar to those in females (Gao et al., 2023); (Tripathy et al., 2017).

Clinical Impact and Combinatorial Strategies

Ribociclib enhances the efficacy of endocrine therapies, improves PFS and OS, and delays resistance development. It is also being investigated in combination with:

PI3K inhibitors (e.g., alpelisib): Enhanced tumor regression and PFS in preclinical and early-phase clinical studies.
mTOR inhibitors (e.g., everolimus): Acceptable safety and preliminary efficacy.
Other tumor types: Ongoing studies in melanoma, lung cancer, neuroblastoma, and gynecologic cancers (Tripathy et al., 2017).

Summary

Ribociclib is a cornerstone of HR-positive, HER2-negative breast cancer therapy, with robust data supporting its efficacy and safety across diverse patient populations—including both women and men, and across early and advanced disease settings. Its high selectivity, manageable toxicity, and combinatory potential with other targeted agents position ribociclib as a key player in precision oncology (Tripathy et al., 2017); (Gao et al., 2023); (Targeted Oncology, 2024).

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: 2025-10-02

KISQALI® (ribociclib) Mechanism of Action | Novartis Pro Portal - last accessed: 2025-10-02

Kisqali®(ribociclib) CDK4/6 inhibitor (Oncology) – Astex - last accessed: 2025-10-02

Ribociclib (oral route) - Side effects & dosage - Mayo Clinic - last accessed: 2025-10-02

Ribociclib: MedlinePlus Drug Information - last accessed: 2025-10-02

Side Effects | mBC | KISQALI® (ribociclib) - last accessed: 2025-10-02

Ribociclib (Kisqali®) | Macmillan Cancer Support - last accessed: 2025-10-02

Ribociclib (Kisqali) - Uses, How to Take and Side Effects | Breast Cancer Now - last accessed: 2025-10-02

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC - last accessed: 2025-10-02

FDA Approves Ribociclib With an Aromatase Inhibitor in Early Breast Cancer | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways - last accessed: 2025-10-02

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PubMed - last accessed: 2025-10-02

Sources used

QUERY: ribociclib AND clinical trial

A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial.
Annals of oncology : official journal of the European Society for Medical Oncology. 2024/7/1; Impact Factor: 18.4, Quartile: Q1
DOI: 10.1016/j.annonc.2024.10.015
PMID: 39442617
Abstract
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.

QUERY: ribociclib AND breast cancer

Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018/6/5; Impact Factor: 16.3, Quartile: Q1
DOI: 10.1200/JCO.2018.78.9909
PMID: 29860922
Abstract
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.

QUERY: ribociclib AND adverse effects

Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021/9/1; Impact Factor: 9.75, Quartile: Q1
DOI: 10.1158/1078-0432.CCR-21-3032
PMID: 34965945
Abstract
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).

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

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PubMed

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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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

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

FDA Approves Ribociclib With an Aromatase Inhibitor in Early Breast Cancer | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways

events in each arm were linked with distant recurrence (6.9% vs 9.6%). The iDFS benefit with the ribociclib-based combination also extended across all key prespecified subgroups based on characteristics such as menopausal status, prior chemotherapy, region, and prior endocrine therapy. In addition to this approval, the FDA also approved the ribociclib and letrozole co-pack for the same indication. 1 REFERENCES: 1. FDA approves Kisqali with an aromatase inhibitor and Kisqali Femara Co-Pack for early high-risk breast cancer. News release. FDA. September 17, 2024. Accessed September 17, 2024. https://tinyurl.com/njts3tvy 2. FDA approves Novartis Kisqali® to reduce risk of recurrence in people with HR+/HER2- early breast cancer. News release. Novartis. September 17, 2024. Accessed September 17, 2024. https://tinyurl.com/5n8d6mne 3. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol . 2023;41(suppl 17):LBA500. doi:10.1200/JCO.2023.41.17_suppl.LBA500 4. Fasching PA, Stroyakovskiy D, Yardley DA, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor in patients with HR+/HER2– early breast cancer: 4-year outcomes from the NATALEE trial. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. LBA13. Newsletter Stay up to date on practice-changing data in community practice. Subscribe Now! Advertisement Related Content Advertisement Early Split Between Responders and Others Shown With CAR T in DLBCL By Targeted Oncology Staff October 1st 2025 CAR T Deepens Myeloma Response Over Time, Could Overcome High Risk By Targeted Oncology Staff October 1st 2025 Novel In Vivo CAR T Receives FDA Fast Track Designation By Sabrina Serani October 1st 2025 Beamion LUN

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

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

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

Use with caution. The effects may be increased because of slower removal of the medicine from the body. Lung problems (eg, interstitial lung disease, pneumonitis)—Use with caution. May make these conditions worse. Back to top Proper Use Medicines used to treat cancer are very strong and can have many side effects. Before receiving this medicine, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment. Take this medicine exactly as directed by your doctor . Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This medicine comes with a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions. Ribociclib is taken together with an aromatase inhibitor or fulvestrant. It is important that you take both medicines at the same time each day, preferably in the morning . Follow your doctor's instructions on when to take these medicines. Your doctor may also give you luteinizing hormone-releasing hormone medicine together with this medicine. Swallow the tablet whole. Do not crush, break, or chew it. Do not take this medicine if it is broken, cracked, or looks damaged. You may take this medicine with or without food. Do not eat grapefruit or drink grapefruit juice while you are using this medicine. Dosing The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so. The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine. For oral dosage form (tablets): For early breast cancer: Adults—400 milligrams (mg) (two 200 mg tablets) taken as a single dose, once a day for 21 consecutive days, followed by 7 days without medicine. Your doctor may adjust your dose as needed and tolerated. Children—Use and dose must be determined by your doctor. For advanced or metastatic breast cancer: Adults—600 milligrams (mg) (three 200 mg tablets) taken as a single dose,

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PubMed

ocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1-65.3], consistent with an ORR of 43.6% (95% CI, 41.5-45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights. ©2023 American Association for Cancer Research. PubMed Disclaimer Conflict of interest statement Disclosure of Potential Conflicts of Interest : The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report. Figures Figure 1:. COMPLEEMENT-1 Single Arm Trial Design Figure 1:. COMPLEEMENT-1 Single Arm Trial Design HER2: human epidermal growth factor receptor 2; ECOG:… Figure 1:. COMPLEEMENT-1 Single Arm Trial Design HER2: human epidermal growth factor receptor 2; ECOG: Eastern
Cooperative Oncology Group Source: Created by FDA based on Applicant’s submission See this image and copyright information in PMC References American Cancer Society, Key Statistics for Breast Cancer in Men, https://www.

FDA Approves Ribociclib With an Aromatase Inhibitor in Early Breast Cancer | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways

THYROID CANCERS Choose Specialty Spotlight - Myeloma | Chronic Lymphocytic Leukemia | Gynecologic Cancers | Genomic Testing | Melanoma | Genitourinary Cancers Your AI-Trained Oncology Knowledge Connection! Advertisement News | Articles | September 17, 2024 FDA Approves Ribociclib With an Aromatase Inhibitor in Early Breast Cancer Author(s) Jordyn Sava Fact checked by: Sabrina Serani Adjuvant ribociclib plus an aromatase inhibitor is now an FDA-approved treatment in HR-positive, HER2-negative stage II and III early breast cancer at a high risk of recurrence. Advertisement The FDA has approved adjuvant ribociclib (Kisqali) plus an aromatase inhibitor (AI) in hormone receptor (HR)-positive, HER2-negative stage II and III early breast cancer at high risk of recurrence. This indication includes patients with node-negative disease. Data from the phase 3 NATALEE trial (NCT03701334) support this approval as the combination led to an improvement in invasive disease-free survival (iDFS) vs endocrine therapy alone in this patient population. Adjuvant ribociclib plus an AI has been approved by the FDA for the treatment of patients with HR-positive, HER2-negative stage II and III early breast cancer at a high risk of recurrence. 1,2 Findings from the phase 3 NATALEE trial, a multicenter, randomized, open-label, phase 3 study assessing the combination in adult patients with HR-positive/HER2-negative early breast cancer, support this approval. Once enrolled in the study, patients were given ribociclib at a dose of 400 mg daily in a 3-weeks-on-1-week-off manner for 3 years. The combination led to a statistically significant and clinically meaningful improvement in iDFS when used for the treatment of patients with HR-positive, HER2-negative early breast cancer vs endocrine therapy alone. "The FDA approval of [ribociclib] for this early breast cancer population, including those with [node-negative] disease, is a pivotal moment in improving our approach to care," Dennis J. Slamon, MD, director of clinical/translational research, UCLA Jonsson Comprehensive Cancer Center and chairman of the Board of Transl

FDA Approves Ribociclib With an Aromatase Inhibitor in Early Breast Cancer | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways

FDA Approves Ribociclib With an Aromatase Inhibitor in Early Breast Cancer | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways NEWS Special Reports All News FDA Briefs Oncology Icons The Targeted Pulse Voices from the Field CONFERENCES Conference Coverage Conference Listing Data Dialogue with the Oncology Brothers MEDIA All Videos Case-Based Peer Perspectives Evolving Paradigms in Oncology Expert Perspective Virtual Tumor Board Interviews Investigator Perspectives Medical World News Personalized Medicine Pivotal Practice Views with the Oncology Brothers Podcasts Speaking Out PUBLICATIONS All Publications Evolving Paradigms Peers & Perspectives in Oncology Targeted Therapies in Oncology More CASE-BASED ROUNDTABLE PARTNERS RESOURCES CME/CE Clinical Trials Events Precision Medicine Perspectives Press Releases Sponsored Content Treatment Resources SUBSCRIBE NEWS Special Reports All News FDA Briefs Oncology Icons The Targeted Pulse Voices from the Field CONFERENCES MEDIA PUBLICATIONS CASE-BASED ROUNDTABLE PARTNERS RESOURCES SUBSCRIBE BRAIN CANCER BREAST CANCER HER2 Breast Cancer GENITOURINARY CANCERS Bladder Cancer Prostate Cancer Renal Cell Carcinoma GENOMIC TESTING Liquid Biopsies GI CANCERS Colorectal Cancer Gastric Cancer GIST HCC GYNECOLOGIC CANCERS Cervical Cancer Endometrial Cancer Ovarian Cancer HEAD & NECK CANCERS HEMATOLOGY Bone Marrow & Stem Cell Transplant IMMUNOTHERAPY CAR T-Cell Therapy LEUKEMIAS AML Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia LUNG CANCER MET-Targeted Therapy Small Cell Lung Cancer Biomarker-Driven Lung Cancer EGFR+ Lung Cancer LYMPHOMAS DLBCL Follicular Lymphoma Mantle Cell Lymphoma MPNs MULTIPLE MYELOMA NTRK GENE FUSIONS SARCOMA SKIN CANCERS Melanoma THYROID CANCERS Choose Specialty Spotlight - Myeloma | Chronic Lymphocytic Leukemia | Gynecologic Cancers | Genomic Testing | Melanoma | Genitourinary Cancers Your AI-Trained On

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

Ribociclib (Kisqali®) | Macmillan Cancer Support

Online Community Contact us > Home > Treatments and drugs > Ribociclib (Kisqali®) > Ribociclib (Kisqali®) Ribociclib (Kisqali ® ) is a cancer drug. It is used to treat some types of breast cancer. On this page What is ribociclib (Kisqali®)? How ribociclib is given About side effects Very common side effects Other side effects Other information How we can help What is ribociclib (Kisqali®)? Ribociclib is also called Kisqali ® It is a type of targeted therapy drug called a cancer growth inhibitor. Ribociclib is used to treat breast cancer that is oestrogen-receptor positive (ER positive) and HER2 negative. It may be used if the cancer has spread: to the tissues and lymph nodes close to the breast ( locally advanced ), and surgery is not possible from the breast to other parts of the body ( metastatic or secondary breast cancer ). It is best to read this information with our general information about targeted therapy drugs and the type of cancer you have. Your cancer team will talk to you about this treatment and its possible side effects before you agree ( consent ) to have treatment. More information about this treatment This information is correct at time of publishing. But sometimes the types of cancer this treatment is used for, or treatment side effects, may change between revision dates. You can talk to your cancer team if you want more detailed information about this treatment. Or visit the electronic Medicines Compendium (eMC) website, which has patient information leaflets (PIL) for individual drugs. How ribociclib is given Ribociclib is given as tablets, so you can take it at home. You take ribociclib with a hormonal therapy drug . Ribociclib works with the hormonal therapy drug to slow the cancer growing and spreading. During a course of treatment, you will meet someone from your cancer team, such as a: cancer doctor specialist nurse specialist pharmacist. This is who we mean when we mention doctor, nurse or pharmacist in this information. During your course of treatment, you will have regular blood tests. This is to check that it is safe for you to have treatment. You will meet with a doctor, nurse or pharmacist before you have treatment. They will talk to you about your blood results and ask how you have been feeling

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC

(n=3,246 total patients) received ribociclib+letrozole+goserelin/leuprolide. The
ORR based on confirmed responses in male patients with measurable disease at
baseline was 46.9% (95% CI: 29.1, 65.3), consistent with an ORR 43.6% (95% CI:
41.5, 45.8) in the overall population. Overall, adverse reactions occurring in
male patients were similar to those occurring in female patients treated with
ribociclib+ET. The efficacy of ribociclib+fulvestrant for male patients was
primarily based on the previous findings of a favorable benefit-risk assessment
from the MONALEESA-3 trial, supported by FDA review of clinical data of a
limited number of male patients treated in clinical practice receiving
ribociclib+fulvestrant. The known mechanism of action, biologic rationale, and
clinical information available adequately demonstrate that the efficacy and
safety of ribociclib+AI/fulvestrant are similar in male and female patients.
This article summarizes the FDA’s decision-making and data supporting the
approval of ribociclib in male patients with breast cancer, and discusses
regulatory insights. Introduction Male breast cancer is rare, with approximately 2800 new cases and 530 deaths
estimated in 2023. 1 In contrast,
there are an estimated 297,790 new cases of and 43,700 deaths from female breast
cancer in 2023. 2 The majority of
male patients are diagnosed in their mid-60s, and most tumors (>99%) are
hormone receptor (HR)-positive. 3 Although the incidence of male breast cancer has increased over the past few
decades, it remains a rare disease, accounting for less than 1% of all cancers in
men and approximately 1% of all breast cancers. 3 Historically, male patients have been excluded from participation in clinical
trials of breast cancer therapies because the incidence and prevalence are low. This
has led not only to limited FDA-approved therapies for male patients with breast
cancer, but also the reliance on extrapolated data from the treatment of female
patients with breast cancer to inform clinical management of male patients with
breast cancer. In August 2020, the FDA Oncology Center of Excellence (OCE) released
a final

Ribociclib (Kisqali) - Uses, How to Take and Side Effects | Breast Cancer Now

primary breast cancer, and who now have locally advanced or secondary breast cancer, may be offered ribociclib with an aromatase inhibitor or fulvestrant. This will depend on their circumstances. Taking ribociclib with an aromatase inhibitor You take three ribociclib tablets a day for 21 days, followed by a seven-day break. This is known as a cycle. The cycle is then repeated. You take an aromatase inhibitor drug once a day continually throughout the cycle. Taking ribociclib with fulvestrant You take three ribociclib tablets a day for 21 days, followed by a seven-day break. This is known as a cycle. The cycle is then repeated. Fulvestrant is given in two injections, one into the muscle (intramuscular injections) of each buttock. They are usually given every 14 days for the first three doses, then every 28 days for as long as you are taking ribociclib. If you have not been through the menopause Aromatase inhibitors and fulvestrant are suitable for women who have been through the menopause (when your periods stop). If you have not been through the menopause, you will also have treatment to stop the ovaries producing oestrogen, either temporarily or permanently. This is known as ovarian suppression . What happens if I miss a dose? If you miss a dose of ribociclib or you are sick (vomit) soon after taking it, do not take an extra dose to make up for the one you missed. Keep to your usual amount and speak to someone in your treatment team. How long will I take ribociclib for? For primary breast cancer, you’ll have ribociclib alongside hormone therapy for 3 years. For locally advanced or secondary breast cancer, you’ll have ribociclib alongside hormone therapy for as long as your treatment team feels you’re benefiting from the treatment and any side effects are manageable. Medicines and food to avoid when taking ribociclib When taking ribociclib: Do not take anything that contains St John’s Wort Do not eat grapefruit or drink grapefruit juice Some drugs should not be taken with ribociclib. These include some commonly prescribed antibiotics, antifungal and anti-epileptic drugs. Tell your specialist about any prescribed or over-the-counter medicines you’

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

with peritoneal cancer, one with esophageal cancer, and one with breast cancer ( 32 ). These data suggest that ribociclib, through its specific mechanism of action, has activity in humans. Preclinical and clinical experience with ribociclib in individual indications Ribociclib has demonstrated antitumor activity in preclinical and clinical studies of a wide variety of tumor types, including breast cancer, melanoma, and neuroblastoma. While single-agent activity has been demonstrated for ribociclib, it has also been shown to enhance the activity of combination partners and delay the development of treatment resistance in preclinical and clinical studies. Breast cancer Preclinical Breast tumors frequently harbor aberrations of the cyclin D–CDK4/6–p16–Rb pathway ( 34 – 36 ) ( Supplementary Table 1 ), and this pathway is also implicated in resistance to endocrine therapy ( 3 ). Therefore, targeting both the cyclin D–CDK4/6–p16–Rb and ER pathways may delay the development of resistance. In a preclinical study of 50 breast cancer cell lines, ribociclib demonstrated inhibitory activity predominantly against ER+ cell lines ( 37 ), suggesting that ER+ breast cancer cells might be particularly susceptible to CDK4/6 inhibition. In vivo , ribociclib showed significant tumor growth inhibition in xenograft mouse models of ER+ breast cancer ( 37 ). A preclinical study in CDK4/6 inhibitor-resistant breast cancer cell lines suggests that mechanisms of resistance differ between ribociclib and palbociclib. Ribociclib resistant clones demonstrated increased E2F1, compared with increased cycle E protein levels in palbociclib resistant clones ( 38 ). Combinations of ribociclib with endocrine therapies was also associated with potent antitumor effects in ER+ breast cancer models compared with the respective single agents ( 38 , 39 ). The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway has also been widely implicated in breast cancer tumorigenesis and treatment resistance ( 8 ). As cyclin D1 is frequently regulated in a PI3K/AKT/mTOR-dependent manner, combinations of upstream and downstream inhibitors might act cooperatively. Indeed, combination of ribociclib with the PI3K inhibitor alpelisib (BYL719

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC

, peripheral edema), and no cases of
Hy’s law. There were four cases of grade 1–2 QT prolongation. There
was one case of grade 3 QT prolongation requiring dose reduction of ribociclib: this
patient ultimately discontinued ribociclib at a later time due to personal reasons.
All cases of QT prolongation were identified by ECG monitoring, and QT prolongation
is a known adverse reaction of ribociclib, already included in section 5 of the
ribociclib labeling as a Warning and Precaution. 5 Table 2: COMPLEEMENT-1 Summary of Efficacy in Men 1 (Investigator Assessed,
Intent-to-Treat Population) Ribociclib + Letrozole + Goserelin or
Leuprolide Overall Response Rate * , 2 N = 32 (95% CI) 46.9 (29.1, 65.3) Duration of Response
(DoR) 3 N = 15 Median (months, 95% CI) NR (21.3, NR) Patients with DoR ≥ 12 months, n
(%) 12 (80.0%) Open in a new tab Abbreviations: CI, confidence interval, NR, not reached. * Based on confirmed responses. 1 Patients with measurable disease. 2 Investigator Assessment. 3 Patients with complete response or partial response. Source: Ribociclib U.S. Prescribing
Information 5 Regulatory Insights MONALEESA-2, 3, and 7 were large, randomized trials in female patients who
received ribociclib/placebo plus hormonal therapy (AI or fulvestrant). Given the
rarity of male breast cancer, a randomized trial comparing ribociclib plus hormonal
therapy (AI and fulvestrant) vs. placebo plus hormonal therapy would be both
impractical and infeasible, as it would take a significant amount of time to enroll
and to generate efficacy results. More importantly, it would delay availability of
ribociclib, which is not expected to have different efficacy or safety profiles in
males compared to females based on the known mechanism of action, to male patients
with breast cancer. A significant PFS benefit has already been previously
demonstrated in female patients who received ribociclib in addition to hormonal
therapy in MONALEESA-2, 3, and

KISQALI® (ribociclib) Mechanism of Action | Novartis Pro Portal

KISQALI® (ribociclib) Mechanism of Action | Novartis Pro Portal Skip to main content This page is intended for UK healthcare professionals and other relevant decision makers only. If you are a member of the public, please click here . This portal is funded and owned by Novartis Pharmaceuticals UK Ltd and includes content approved by Novartis. Adverse events reporting information can be found in the footer of this page. Main navigation Menu Menu Medicines Cardio-metabolic ENTRESTO (sacubitril/valsartan) LEQVIO®▼ (inclisiran) Dermatology COSENTYX® (secukinumab) XOLAIR® (omalizumab) Haematology FABHALTA®▼ (iptacopan) JAKAVI® (ruxolitinib) SCEMBLIX®▼ (asciminib) Immunology ILARIS® (canakinumab) Neuroscience AIMOVIG® (erenumab) KESIMPTA®▼ (ofatumumab) Oncology KISQALI® (ribociclib) TAFINLAR (dabrafenib) + MEKINIST (trametinib) in non-small cell lung cancer (NSCLC) TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) in melanoma SANDOSTATIN® LAR® (octreotide acetate) Respiratory and Inflammation XOLAIR® (omalizumab) Rheumatology COSENTYX® (secukinumab) Therapy Areas Cardio-metabolic Dermatology Haematology Immunology Neuroscience Oncology Respiratory and inflammation Rheumatology Events Resources Healthcare Systems Support Disease area service resources Service resources: Oncology Breast Cancer Inequalities Tool Collaborative Working Contact us Login Navigation Navigation Navigation KISQALI® (ribociclib) Kisqali in aBC Safety profile in aBC Efficacy of KISQALI in aBC Pre- and perimenopausal women Treating older patients Quality of life NCCN recommendations Kisqali in eBC Safety profile in eBC Efficacy of KISQALI

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

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, and a half-life (t 1/2 ) of 33–42 hours ( Table 2 ) ( 31 , 32 ). In Japanese patients, ribociclib exposure appeared higher on average than in non-Japanese patients, although considerable inter-patient variability was observed ( 31 , 32 ). In a separate, healthy volunteer study, overall exposure of a single oral dose of 600 mg ribociclib was unaffected in fed versus fasted states, indicating that ribociclib may be taken with or without food ( 33 ). Safety analyses from the Phase I studies indicated that single-agent ribociclib is associated with a manageable safety profile. The most common treatment-related adverse events (AEs) were hematologic, particularly neutropenia, consistent with on-target CDK4/6 inhibitor toxicity ( 31 , 32 ). Non-hematologic AEs included nausea and fatigue ( 31 , 32 ). Grade 1/2 QTc prolongation was reported in patients receiving the RP2D and subsequent trials included additional cardiac monitoring ( 31 ). AEs were generally mild-to-moderate in severity, and were reversible upon ribociclib interruption ( 31 , 32 ). Preliminary antitumor activity was observed in the Phase I studies ( 31 , 32 ). Among US/European patients, the large majority of whom were heavily pretreated, three had partial responses (PRs) and 41 had stable disease (SD); eight patients had SD for >6 months ( 31 ). The PRs occurred in a patient with head and neck acinar carcinoma and CDKN2A loss, another with PIK3CA -mutant, CCND1 -amplified, estrogen receptor-positive (ER+) breast cancer, and another with BRAF/NRAS -wild-type, CCND1 -amplified melanoma ( 31 ). In the Japanese population, who were also heavily pretreated, SD was observed in four patients treated at the RP2D: two with peritoneal cancer, one with esophageal cancer, and one with breast cancer ( 32 ). These data suggest that ribociclib, through its specific mechanism of action, has activity in humans. Preclinical and clinical experience with rib

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

): 2 PR, 7 SD, 5 NCRNPD CLEE011X2106/ NCT01857193 ( 52 ) Everolimus + exemestane Ib Postmenopausal women with ER+, HER2− ABC previously treated with letrozole or anastrozole ( N= 77 treated with ribociclib + everolimus + exemestane) RP2D: Ribociclib: 300 mg/day (3-weeks-on/1-week-off) Everolimus: 2.5 mg/day Exemestane: 25 mg/day Neutropenia (31%), neutrophil count reduced (18%), leukocyte count reduced (12%), anemia (7%), thrombocytopenia (7%), lymphopenia (7%), ALT elevation (5%), AST elevation (4%), and lymphocyte reduced (4%) ORR 9%, DCR 73%, CBR 26% CLEE011X2107/ NCT01872260 ( 51 ) Alpelisib + letrozole Ib Pretreated and treatment-naïve postmenopausal women with ER+, HER2− ABC ( N= 46 treated with ribociclib + alpelisib + letrozole) RP2D: Ribociclib: 300 mg/day (3-weeks-on/1-week-off) Alpelisib: 200 mg/day Letrozole: 2.5 mg/day Increased ALT (30%), increased AST (26%), hyperglycemia (17%), neutropenia (17%), fatigue (13%), reduced neutrophil count (4%), anemia (4%), thrombocytopenia (2%), vomiting (2%), and nausea (2%) ORR 16%, DCR 70%, CBR 26% CLEE011A2201/ NCT01919229 ( 43 ) Letrozole II Postmenopausal women with HR+, HER2− Grade II/III, invasive, early breast cancer who have received no prior breast cancer treatment ( N= 14) Ribociclib: 600 mg/day or 400mg/day Letrozole: 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

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

/6 inhibitor ribociclib (LEE011) in non-tumor bearing mice and mice bearing orthotopic pediatric brain tumors. Neuro Oncol. 2016;18(suppl 6) Abstract PDTB-12. [ Google Scholar ] 74. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol. 2015;16:25–35. doi: 10.1016/S1470-2045(14)71159-3. [ DOI ] [ PubMed ] [ Google Scholar ] 75. DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, et al. CDK4/6 inhibitor palbociclib (PD0332991) in rb+ advanced breast cancer: Phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res. 2015;21:995–1001. doi: 10.1158/1078-0432.CCR-14-2258. [ DOI ] [ PubMed ] [ Google Scholar ] 76. Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood. 2012;119:4597–607. doi: 10.1182/blood-2011-10-388298. [ DOI ] [ PubMed ] [ Google Scholar ] 77. Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31:2024–8. doi: 10.1200/JCO.2012.46.5476. [ DOI ] [

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

regulated in a PI3K/AKT/mTOR-dependent manner, combinations of upstream and downstream inhibitors might act cooperatively. Indeed, combination of ribociclib with the PI3K inhibitor alpelisib (BYL719) resulted in enhanced tumor regression (−57%) versus single-agent treatments with ribociclib (−9%) and alpelisib (−15%) ( 39 ). More recently, large-scale, patient-derived breast cancer xenografts (PDX) were used to evaluate such combinations in mouse preclinical trials. Treatment of 38 PDX mouse models with ribociclib plus alpelisib demonstrated increased response rates and progression-free survival (PFS) with this combination compared with the single agents ( 40 ). Interestingly, the ribociclib plus alpelisib combination appeared more active in PDX models than in cell lines, suggesting a possible disconnect between in vitro cell-based assays and in vivo PDX-based results ( 40 ). Furthermore, the addition of PI3K inhibitors to ribociclib and either letrozole or fulvestrant demonstrated increased antitumor activity, including some complete regressions, without significant toxicity in mouse models of ER+ breast cancer ( 37 ). These regressions were sustained for ~4 weeks post treatment and occurred in both PI3K/PTEN -wild-type and -altered backgrounds. Taken together, the synergistic activity of ribociclib in combination with various anticancer therapies suggest that ribociclib may complement existing breast cancer treatments in the clinic. Clinical The combination of ribociclib and endocrine therapies in HR+, HER2− breast cancer is being investigated in Phase Ib–III studies ( Table 3 and Supplementary Table 2 ). These studies have demonstrated that ribociclib exposure is unaffected by combinations with exemestane, letrozole, or fulvestrant in patients with HR+ ABC ( 41 , 42 ). Similarly, letrozole exposure when combined with ribociclib was within the range of values observed from single-agent letrozole ( 41 , 43 ). The addition of ribociclib to exemestane, letrozole, or fulvestrant was also associated with manageable tolerability profiles in all studies ( Table 3 ). The most common AEs were hematologic, and Grade 3/4 neutropenia was frequent but uncomplicated ( 42 , 44 – 46

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC

the reliance on extrapolated data from the treatment of female
patients with breast cancer to inform clinical management of male patients with
breast cancer. In August 2020, the FDA Oncology Center of Excellence (OCE) released
a final guidance document entitled “Male Breast Cancer: Developing Drugs for Treatment”, encouraging the
inclusion of both male and female patients in clinical trials of breast
cancer. 4 For certain
clinical trials of oncology products where inclusion of male patients has been rare
or none at all, it may be possible to extrapolate the findings to include male
patients in the FDA-approved indication, if no difference in efficacy or safety is
expected based on the mechanism of action, using data from earlier stages of
development, literature, or both. In situations where there may be a concern for
differential efficacy or safety between male and female patients, additional
supportive data may be generated through a variety of trial designs using different
data sources. 4 Ribociclib, a cyclin-dependent kinase (CDK) 4 and 6 inhibitor (CDKI), was
first approved on March 13, 2017, in combination with an aromatase inhibitor for the
treatment of postmenopausal women with HR-positive, HER2-negative advanced or
metastatic breast cancer, based on the MONALEESA-2 study 5 ( Table
1 ). On July 18, 2018, the indication for ribociclib in combination with
an aromatase inhibitor was expanded to include pre- and perimenopausal women, and
ribociclib also received approval in combination with fulvestrant for the treatment
of postmenopausal women, as initial endocrine based therapy or following disease
progression on endocrine therapy, based on the MONALEESA-7 and 3 studies,
respectively 5 ( Table 1 ). In this article, we present the
FDA’s rationale for the approval of ribociclib for use in combination with
aromatase inhibitors and fulvestrant for the treatment of male patients with breast
cancer, and discuss regulatory insights. Table 1: Overview of Ribociclib + Hormonal Therapy MONALEESA Clinical Trials (at
time of FDA review) MONALEESA-2 MONALEESA-3 MONALEESA-7 Initial FDA regular approval
date March 13, 2017 July 18, 2018 July 18, 2018 Hormonal

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC

CDK 4/6 inhibitor; PFS = progression free
survival; OS = overall survival; HR = hazard ratio; CI = confidence
interval Source: Ribociclib U.S. Prescribing
Information 5 Clinical Trial Design and Results The data from the following sources were reviewed to support the expansion of
the existing ribociclib indications to include male patients (based on available
data at the time of FDA’s review). MONALEESA-2 was a randomized (1:1), double-blind, placebo-controlled,
multicenter clinical trial of ribociclib or placebo in combination with letrozole in
postmenopausal women with HR-positive, HER2-negative advanced breast cancer who
received no prior therapy for advanced disease 5 ( Table 1 ). The median
duration of exposure to ribociclib plus letrozole was 13 months, with 58% of
patients exposed for > 12 months. The trial showed a statistically
significant and clinically meaningful improvement in progression free survival (PFS)
with the addition of ribociclib to letrozole. The median PFS was not reached (95% CI
19.3, NR) in the ribociclib arm compared to 14.7 months (95% CI 13.0, 16.5) in the
placebo arm (HR 0.556, 95% CI 0.429, 0.720, p<0.0001). Male patients were not
eligible to enroll in MONALEESA-2. 5 MONALEESA-3 was a randomized (2:1), double-blind, placebo-controlled trial of
ribociclib or placebo in combination with fulvestrant in postmenopausal women, or
men, with HR-positive, HER2-negative advanced breast cancer who had received no or
only one line of prior endocrine treatment for the treatment of advanced breast
cancer 5 ( Table 1 ). While male patients were eligible for
MONALEESA-3, none enrolled. The median duration of exposure to ribociclib plus
fulvestrant was 15.8 months with 58% of patients exposed for ≥ 12 months. The
trial showed a statically significant and clinically meaningful improvement in PFS
and overall survival (OS). The median PFS for ribociclib plus fulvestrant was 20.5
months (95% CI 18.5

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

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 who will benefit most from treatment, improve treatment outcomes, and identify effective drug combinations to mitigate treatment resistance. The comprehensive and robust portfolio of unique and ongoing clinical studies of doublet and triplet therapies containing ribociclib are likely to shape the future landscape of cancer therapeutics. Supplementary Material 1 NIHMS863046-supplement-1.docx (24.1KB, docx) 2 NIHMS863046-supplement-2.docx (23.1KB, docx) Acknowledgments Financial support Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. Grant support: The project described was supported in part by award number P30CA014089 from the National Cancer Institute (D. Tripathy). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. A. Bardia is supported by the National Institutes of Health (4K12CA087723-14). The authors thank Abbie Saunders PhD for medical editorial assistance with this manuscript. Footnotes Conflict of interest disclosure statement D Tripathy discloses clinical trial grants and editorial support funded by Novartis Pharmaceuticals Corporation in relation to this submitted work. He also discloses consultancy fees from Nektar Therapeutics outside the submitted work. A Bardia discloses participating in an advisory board for Novartis Pharmaceuticals Corporation. W Sellers was previously employed by, and owns shares in, Novartis Pharmaceuticals Corporation. References 1. Abukhdeir AM, Park BH. P21 and p27: Roles in carcinogenesis and drug resistance. Expert Rev Mol Med. 2008;10:e19. doi: 10.1017/S1462399408000744. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 2. Caldon CE, Daly RJ, Sutherland RL, Musgrove EA. Cell cycle control in breast cancer cells. J Cell Biochem. 2006;97:261–74. doi: 10.1002/jcb.20690. [ DOI ] [ PubMed ] [ Google Scholar ] 3. Lange CA, Y

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC

Food and Drug
Administration, Silver Spring, Maryland. Find articles by Paul G Kluetz 1 , Laleh Amiri-Kordestani Laleh Amiri-Kordestani 2 Center for Drug Evaluation Research, U.S. Food and Drug
Administration, Silver Spring, Maryland. Find articles by Laleh Amiri-Kordestani 2 Author information Copyright and License information 1 Oncology Center of Excellence, Research, U.S. Food and Drug
Administration, Silver Spring, Maryland. 2 Center for Drug Evaluation Research, U.S. Food and Drug
Administration, Silver Spring, Maryland. ✉ Corresponding Author : Jennifer Gao, Oncology Center
of Excellence, U.S. Food and Drug Administration, WO22, 10903 New Hampshire
Avenue, Silver Spring, MD 20993. Phone 204-402-4683. jennifer.gao@fda.hhs.gov This is a U.S. Government work. There are no restrictions on its
use. PMC Copyright notice PMCID: PMC10840597 NIHMSID: NIHMS1921110 PMID: 37594723 The publisher's version of this article is available at Clin Cancer Res Abstract On December 10, 2021, the FDA expanded the indications for ribociclib to
include male patients for the treatment of hormone receptor (HR)-positive,
HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated
in combination with an aromatase inhibitor (AI) as initial endocrine-based
therapy in adult patients, or with fulvestrant as initial endocrine-based
therapy or following disease progression on endocrine therapy (ET), in
postmenopausal women or in men. The efficacy of ribociclib+AI for male patients
was primarily based on previous favorable benefit-risk assessments of ribociclib
from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an
open-label, single arm, multicenter clinical trial, in which 39 male patients
(n=3,246 total patients) received ribociclib+letrozole+goserelin/leuprolide. The
ORR based on confirmed responses in male patients with measurable disease at
baseline was 46

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

inhibitors spare CDK2 activity, avoiding inhibition of general S-phase activity. Three selective CDK4/6 inhibitors are in late-stage clinical development: ribociclib (LEE011, Novartis), palbociclib (Ibrance ® ; PD-0332991; Pfizer), and abemaciclib (LY-2835219; Eli Lilly). Palbociclib combined with letrozole or fulvestrant has demonstrated efficacy in patients with HR+ advanced breast cancer (ABC; Table 1 ) ( 18 , 19 ), and is approved in the USA and Europe for use in these combinations ( 20 , 21 ). Abemaciclib has shown efficacy as a single agent and in combination with endocrine therapies in patients with HR+ ABC, and has entered Phase III development, with an US Food and Drug Administration (FDA) Breakthrough Therapy Designation granted in 2015 for patients with refractory HR+ ABC ( Table 1 ) ( 22 – 24 ). Table 1. Key reported clinical trials with palbociclib and abemaciclib. Study name/ID Combination drug Phase Population Common Grade 3/4 AEs (≥10% of patients) Clinical activity Palbociclib Breast Cancer PALOMA-1/ NCT00721409 ( 74 ) Letrozole II ER+ ABC with no prior treatment for ABC ( N= 165) Neutropenia (54%), leukopenia (19%) Median PFS 20.2 months vs 5.7 months for letrozole monotherapy (HR=0.488; P= 0.0004) PALOMA-2/ NCT01740427 ( 18 ) Letrozole III ER+ ABC with no prior treatment for ABC ( N= 666) Neutropenia (66%), leukopenia (25%) Median PFS 24.8 months vs 14.5 months for letrozole monotherapy (HR=0.58; P< 0.000001) PALOMA-3/ NCT01942135 ( 19 ) Fulvestrant III HR+ ABC after progression on one line of endocrine therapy for ABC ( N= 521) Neutropenia (62%), leukopenia (25%) Median PFS 9.2 months vs 3.8 months for fulvestrant monotherapy (HR=0.42; P< 0.

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

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, and letrozole, PK indices for ribociclib and alpelisib were generally consistent with historic single-agent data ( 51 ). The combination of ribociclib, alpelisib, and letrozole also demonstrated an acceptable safety profile ( Table 3 ) ( 51 ). Both triplet regimens have demonstrated antitumor activity in patients whose ER+ breast cancer tumors harbor PI3K/AKT/mTOR and/or cyclin D–CDK4/6–p16–Rb pathway modifications ( 51 , 52 ). Further evaluation and validation of biomarkers of response is ongoing. Melanoma Preclinical The now-refined genetic landscape of melanoma has highlighted the centrality of RAS signaling in this disease. Indeed, activating mutations occur in critical components of this pathway, including BRAF V600 (35–50%), NRAS (10–25%), and NF1 (~15%) ( 53 , 54 ). The cyclin D–CDK4/6–p16–Rb pathway is also commonly dysregulated in melanomas. Mutations, deletions, or hypermethylation of CDKN2A are key driver alterations in melanomas, and CCND1 (cyclin D1) and CDK4 are frequently amplified ( Supplementary Table 1 ) ( 53 – 57 ). Germline mutations in CDKN2A and CDK4 are also linked to familial melanoma ( 58 ). High CCND1 and low CDKN2A copy numbers have been associated with reduced PFS with BRAF inhibitors ( 59 ). Approved treatments for BRAF -mutant melanoma include targeted therapy with BRAF and/or MEK inhibitors ( 60 ). Binimetinib (MEK162), a MEK inhibitor, and encorafenib (LGX818), a selective BRAF inhibitor, have demonstrated antitumor activity as single agents in NRAS - and BRAF -mutant melanomas, respectively, and in combination in BRAF -mutant melanomas ( 61 – 63 ). The combination of ribociclib and binimetinib demonstrated enhanced tumor regression (34% tumor/control [T/C] ratio) in xenograft

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

, and in combination in BRAF -mutant melanomas ( 61 – 63 ). The combination of ribociclib and binimetinib demonstrated enhanced tumor regression (34% tumor/control [T/C] ratio) in xenograft models of NRAS Q61K -mutant melanoma relative to single-agent binimetinib (12% T/C) or ribociclib (32% T/C) ( 27 , 62 ). In BRAF V600E -mutant melanoma models, low-dose ribociclib exhibited synergistic activity with encorafenib ( 27 , 61 ). The addition of ribociclib to encorafenib also appeared to prevent resistance to encorafenib ( 27 , 61 ), suggesting that simultaneous inhibition of BRAF and cyclin D–CDK4/6–p16–Rb pathways may provide a therapeutic benefit in the clinical setting. The enhanced antitumor activity of ribociclib plus encorafenib relative to single agents was confirmed in a large-scale in vivo screen of PDX melanoma models, where the combination was associated with a 100% response rate, including 87% PR and CR (exceeding the 72% PR and CR for binimetinib plus encorafenib) ( 40 ). The combination also resulted in a significant improvement in PFS and delayed the development of resistance in the tumor models ( P =1.8×10 −3 ), with no drug–drug interactions ( 40 ). Clinical The combinations of ribociclib plus binimetinib or encorafenib have been evaluated in two dose-escalation/expansion Phase Ib/II studies of advanced NRAS - and BRAF -mutant melanoma, respectively ( Table 3 ) ( 61 , 62 ). In patients with advanced NRAS -mutant melanoma, combination of ribociclib and binimetinib did not affect the PK exposures of either drug ( 41 , 62 ). Common AEs experienced with ribociclib plus binimetinib included creatine phosphokinase (CPK) elevation, acneiform dermatitis, nausea, rash, edema, leukopenia, and creatinine elevation, whereas Grade 3/4 AEs included CPK elevation, neutropenia, acneiform dermatitis, and rash ( Table 3 ) ( 62 ). This combination was also associated with preliminary antitum

Ribociclib: MedlinePlus Drug Information

services at 911. What other information should I know? Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests before and during your treatment to check your body's response to ribociclib. Your doctor may also order an electrocardiogram (ECG; test that measures the electrical activity in the heart) before and during your treatment. Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription. Keep a written list of all of the prescription and nonprescription (over-the-counter) medicines, vitamins, minerals, and dietary supplements you are taking. Bring this list with you each time you visit a doctor or if you are admitted to the hospital. You should carry the list with you in case of emergencies. Brand names Kisqali Â® Brand names of combination products Kisqali Â® Femera Â® (as a combination product containing Letrazole and Ribociclib) Last Revised - 01/15/2025 Browse Drugs and Medicines Learn how to cite this page American Society of Health-System Pharmacists, Inc. Disclaimer AHFS Â® Patient Medication Informationâ¢. Â© Copyright, 2025. The American Society of Health-System Pharmacists Â® , 4500 East-West Highway, Suite 900, Bethesda, Maryland. All Rights Reserved. Duplication for commercial use must be authorized by ASHP. About MedlinePlus What's New Site Map Customer Support Subscribe to RSS Connect with NLM NLM Web Policies Copyright Accessibility Guidelines for Links Viewers & Players HHS Vulnerability Disclosure MedlinePlus Connect for EHRs For Developers National Library of Medicine 8600 Rockville Pike, Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health

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

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 combination with other therapies are discussed, and an overview of the broad portfolio of ongoing clinical trials with ribociclib across a wide range of indications is presented. Based on the available data, ribociclib has a manageable tolerability profile and therapeutic potential for a variety of cancer types. Its high selectivity makes it an important partner drug for other targeted therapies and it has been shown to enhance the clinical activity of existing anticancer therapies and delay the development of treatment resistance, without markedly increasing toxicity. Ongoing trials of doublet and triplet targeted therapies containing ribociclib seek to identify optimal CDK4/6-based targeted combination regimens for various tumor types and advance the field of precision therapeutics in oncology. Keywords: ribociclib, LEE011, CDK4/6 inhibitor, cyclin D–CDK4/6–p16–Rb pathway, cancer Introduction Cancer development is often characterized by abnormal cellular proliferation and dysregulation of cell cycle control ( 1 ). The cell cycle is regulated at different stages by various cyclin–cyclin-dependent kinase (CDK) complexes ( Figure 1 ). The G1 (pre-DNA synthesis) to S (DNA synthesis) cell cycle checkpoint is regulated by the cyclin D–CDK4/6–p16–retinoblastoma (Rb) pathway, which ensures conditions are appropriate for cell growth and division before the cell is irreversibly committed to division ( 2 – 4 ). In this pathway, cyclin D is the key entry point at which various mitogenic and growth arrest signaling pathways converge to regulate the cell cycle ( 3 ). In response to mitogenic signaling, levels of D-type cyclins rise and associate with CDK4 or CDK6. The resulting active cyclin D–CDK4/6 complexes phosphorylate Rb, relieving its repression of E2 transcription factors (E2F). The released E2F consequently activates the transcription of genes required for the G1–S transition and cell cycle progression ( 5 , 6 ). The tumor suppressor and negative regulator of the cyclin D–CDK4/6 complex, p16, is a critical mediator

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC

CI NR-NR) in
the ribociclib arm versus 40.7 months (95% CI 37.4, NR) in the placebo arm. Male
patients were not eligible to enroll on MONALEESA-7. 5 COMPLEEMENT-1 ( NCT02941926 ) was an open-label, multicenter, single-arm trial of
ribociclib plus letrozole and goserelin/leuprolide in men and pre- and
postmenopausal women with HR-positive HER2-negative advanced breast cancer who had
received no prior hormonal therapy but could have received ≤1 line of prior
chemotherapy for advanced disease. Patients received ribociclib 600 mg once daily
for 21 consecutive days followed by 7 days off plus letrozole 2.5 mg daily
continuously, until disease progression or unacceptable toxicity. Goserelin 3.6 mg
injectable subcutaneous implant or leuprolide 7.5 mg intramuscular injection were
administered on day 1 of each 28-day cycle to men and premenopausal women. 5 The primary endpoints were safety
and tolerability (adverse events, grade 3–4 adverse events, and serious
adverse events), and secondary endpoints included time-to-progression (TTP), overall
response rate (ORR), clinical benefit rate (CBR), patient reported outcomes, and
long-term safety. The trial design is depicted in Figure 1 . Figure 1: COMPLEEMENT-1 Single Arm Trial Design. Open in a new tab HER2: human epidermal growth factor receptor 2; ECOG: Eastern
Cooperative Oncology Group Source: Created by FDA based on Applicant’s submission COMPLEEMENT-1 enrolled 39 male patients (n=3,246 total patients) between
November 30, 2016 and March 22, 2018. The analysis cut-off date was November 8,
2019, and the database was locked on December 19, 2019. As of the cut-off date, 18
(46%) male patients discontinued treatment (11 due to progressive disease, 4 due to
adverse events). The median age of male patients was 62 years (range 33 to 80). Of
these patients, 39% were 65 years and older, including 10% aged 75 years and older.
The male patients enrolled were White (72%), Asian (

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC

12 months. The
trial showed a statically significant and clinically meaningful improvement in PFS
and overall survival (OS). The median PFS for ribociclib plus fulvestrant was 20.5
months (95% CI 18.5, 23.5) compared to 12.8 months (95% CI 10.9, 16.3) for placebo
plus fulvestrant (HR 0.593, 95% CI 0.480, 0.732, p-value <0.0001). The median
OS for ribociclib plus fulvestrant was not reached (95% CI 42.5, NR) compared to
40.0 months (95% CI 37.0, NR) in the placebo plus fulvestrant arm (HR 0.724, 95% CI
0.568, 0.924, p=0.00455). 5 MONALEESA-7 was a randomized (1:1), double-blind, placebo-controlled trial of
ribociclib or placebo plus non-steroidal aromatase inhibitor (NSAI) or tamoxifen
plus goserelin in pre- or perimenopausal women with HR-positive, HER2-negative
advanced breast cancer who received no prior endocrine therapy and no more than one
line of chemotherapy for advanced disease ( Table
1 ). 5 Due to QT
prolongation, ribociclib is not indicated in combination with tamoxifen. The median
duration of exposure of ribociclib plus NSAI was 15.2 months, with 66% of patients
exposed for > 12 months. In patients who received ribociclib plus NSAI plus
goserelin, the trial demonstrated a statistically significant and clinically
meaningful improvement in PFS and OS. There was a 13.7-month improvement in median
PFS in the ribociclib arm compared to the placebo arm (HR 0.569, 95% CI 0.436,
0.743). Median OS (HR 0.699, 95% CI 0.501, 0.976) was not reached (95% CI NR-NR) in
the ribociclib arm versus 40.7 months (95% CI 37.4, NR) in the placebo arm. Male
patients were not eligible to enroll on MONALEESA-7. 5

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC

). The median age of male patients was 62 years (range 33 to 80). Of
these patients, 39% were 65 years and older, including 10% aged 75 years and older.
The male patients enrolled were White (72%), Asian (8%), Black (3%), and 17%
unknown. Nearly all male patients (97%) had an ECOG performance status of 0 or 1.
Most male patients (97%) had 4 or less metastatic sites, which were primarily bone
and visceral (69% each). The median duration of exposure in male patients overall
was 20.8 months (0.5–30.6 months, from the start of treatment to last
treatment per the cut-off date), with median duration of exposure of 19.2 months to
ribociclib (0.5–30.6 months). Twenty-three male patients received ribociclib
for 12 months or longer, and 11 male patients received ribociclib for 24 months or
longer. The median relative dose intensity was 98.6% for ribociclib (range
87.4–100) and 100% for letrozole. The overall response rate based on
confirmed responses in male patients with measurable disease at baseline was 46.9%
(95% CI 29.1–65.3, 15/32 male patients, 1 male patient with complete response
and 14 male patients with partial response). In confirmed responders with measurable
disease at baseline, the median duration of response was not reached. Results are
summarized in Table 2 . Overall, adverse
reactions occurring in male patients were similar to those occurring in female
patients treated with ribociclib plus endocrine therapy. The most common adverse
reactions (incidence ≥ 20%) were neutropenia, hot flush, diarrhea,
arthralgia, fatigue, and asthenia. One male patient died due to grade 3 dyspnea and
progression of disease, with documented new lung lesions and a history of
tuberculosis. There were four male patients who discontinued treatment due to
adverse events (ALT/AST elevation, colon cancer, peripheral edema), and no cases of
Hy’s law. There were four cases of grade 1–2 QT prolongation. There
was one case of grade 3 QT prolongation requiring dose reduction of ribociclib

Ribociclib (Kisqali) - Uses, How to Take and Side Effects | Breast Cancer Now

grapefruit juice Some drugs should not be taken with ribociclib. These include some commonly prescribed antibiotics, antifungal and anti-epileptic drugs. Tell your specialist about any prescribed or over-the-counter medicines you’re taking. If a healthcare professional, such as your GP or dentist, prescribes you a new drug, tell them you’re taking ribociclib. Always ask for advice from your treatment team before taking any herbal medicines or supplements. Ribociclib contains soya lecithin. You should not take ribociclib if you are allergic to peanuts or soya. Close Glossary term Ovarian suppression Sometimes called ovarian ablation. Stopping the ovaries producing oestrogen using surgery, drugs or radiotherapy. 4. Side effects of ribociclib (Kisqali) Healthcare Information Life during treatment Going through breast cancer treatment can affect you physically and emotionally. Read our tips to help you cope. Like any drug, ribociclib can cause side effects. Everyone reacts differently to drugs and some people have more side effects than others. You’ll have regular hospital appointments with your treatment team to check whether you’re experiencing side effects. It can be helpful to keep a diary of how you feel while taking ribociclib to monitor any side effects. Side effects can usually be controlled and those described here will not affect everyone. Because it’s given alongside hormone therapy, you may have side effects from that drug as well. If you’re concerned about any side effects, regardless of whether they’re listed here, tell your treatment team. 5. Common side effects of ribociclib (Kisqali) Common side effects of ribociclib include: Effects on the blood Liver changes Cancer-related fatigue (extreme tiredness) Shortness of breath and cough Sore mouth Nausea and vomiting Loss of appetite Tummy (abdominal) pain Diarrhoea and constipation Rash Hair thinning and hair loss Healthcare Information Life during treatment Going through breast cancer treatment can affect you physically and emotionally. Read our tips to help you cope. Effects on the blood Ribociclib can temporarily affect the number of healthy blood cells in the body. You’ll have regular blood tests both before and throughout your treatment to check your blood count. It’s recommended that blood tests are done before you start treatment, every two

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

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 4 and 6 inhibitor - in advanced breast cancer. Available from: https://Investor.lilly.com/releasedetail.cfm?releaseid=935735 . 25. Novartis. [Accessed December 2016];Novartis LEE011 (ribociclib) granted FDA priority review for first-line treatment of HR+/HER2− advanced breast cancer. Available from: https://www.novartis.com/news/media-releases/novartis-lee011-ribociclib-granted-fda-priority-review-first-line-treatment . 26. Chen P, Lee N, Hu W, Xu M, Ferre R, Lam H, et al. Spectrum and degree of CDK drug interactions predicts clinical performance. Mol Cancer Ther. 2016;15:2273–81. doi: 10.1158/1535-7163.MCT-16-0300. [ DOI ] [ PubMed ] [ Google Scholar ] 27. Kim S, Loo A, Chopra R, Caponigro G, Huang A, Vora S, et al. LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6–reactivating rb in cancer. Mol Cancer Ther. 2013;12(11 suppl) Abstract PR02 (Oral presentation) [ Google Scholar ] 28. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3:1427–38. [ PubMed ] [ Google Scholar ] 29. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: In-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine.

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC

of action, to male patients
with breast cancer. A significant PFS benefit has already been previously
demonstrated in female patients who received ribociclib in addition to hormonal
therapy in MONALEESA-2, 3, and 7, with an OS benefit also demonstrated in
MONALEESA-3 and 7. Given this demonstrated efficacy benefit of the addition of
ribociclib to hormonal therapy in female patients, a trial where male patients are
randomized to receive hormonal therapy without ribociclib would lack equipoise. It is reasonable to rely on efficacy and safety results from the single arm
trial of COMPLEEMENT-1 in male patients with breast cancer treated with ribociclib
and an AI. Acknowledging the limitations of cross-trial, and cross-patient
population, comparisons, ORR in male patients from COMPLEEMENT-1 is comparable with
ORR from female patients in MONALEESA-2, 3, and 7, with overlapping 95% confidence
intervals across all trials. It is further reasonable to extrapolate findings to
expand the indication of ribociclib in combination with fulvestrant to include male
patients based on known disease-based biological plausibility, the drug-based
mechanism of action of ribociclib, the rarity of male breast cancer, and because no
difference in efficacy or safety is anticipated between males and females based on
pharmacological mechanism. The Applicant submitted limited contextual real-world
data in male patients who received ribociclib in combination with fulvestrant. While
no significant safety signals were seen, FDA’s review and approval ultimately
relied on the known data and extrapolation from MONALEESA-2, 3, and 7, and
COMPLEEMENT-1, given the limited interpretability of clinical information available
from the real-world data that was submitted from a very small sample of male
patients. Expanding the existing ribociclib indications in combination with an AI or
fulvestrant to include male patients with breast cancer is reasonable,
scientifically justified, and consistent with FDA’s guidance on developing
therapies for male patients with breast cancer. 4 Currently, all FDA-approved CDK 4/6 inhibitors, abemaciclib,
palbociclib, and ribociclib, are indicated for male and female patients. 5 ,