ribociclib

Scientific Summary of Ribociclib: Mechanism, Clinical Efficacy, and Safety

1. Introduction

Ribociclib (LEE011), marketed as KISQALI®, is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor developed by Novartis. It is primarily approved for use in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced or metastatic breast cancer, and is a cornerstone in modern endocrine-based therapeutic regimens. Its indications have been expanded to include both male and female patients, reflecting its mechanism-based applicability across genders (FDA, 2023); (Tripathy et al., 2018).

2. Mechanism of Action

2.1 Molecular Target and Pathway

Ribociclib selectively inhibits CDK4 and CDK6, kinases pivotal for cell cycle progression from G1 to S phase. This action is achieved by binding to the ATP-binding sites of CDK4/6, preventing phosphorylation of the retinoblastoma (Rb) protein. In its unphosphorylated state, Rb sequesters E2F transcription factors, blocking the transcription of genes essential for S-phase entry and cell proliferation. Dysregulation of the cyclin D–CDK4/6–p16–Rb pathway is a hallmark of many cancers, particularly HR+ breast cancer (Tripathy et al., 2018); (KISQALI MOA, Novartis Pro Portal); (What is the mechanism of action of Ribociclib Succinate?, 2025).

2.2 Selectivity and Pharmacodynamics

Ribociclib demonstrates high selectivity for CDK4/6 over other CDKs (e.g., CDK1, CDK2, CDK5). The reported IC50 values for CDK4–cyclin D1 and CDK6–cyclin D1/2/3 are 10 nM and 39 nM, respectively, with markedly higher (less potent) values for other CDKs (e.g., >10,000 nM for CDK2) (Tripathy et al., 2018). This selectivity minimizes off-target effects and contributes to a favorable safety profile.

3. Clinical Efficacy

3.1 Breast Cancer

a. Preclinical Insights
Ribociclib inhibits proliferation in ER+ breast cancer cell lines and suppresses tumor growth in xenograft models (Tripathy et al., 2018).

b. MONALEESA Clinical Trials
- MONALEESA-2: In postmenopausal women with HR+, HER2– advanced breast cancer, ribociclib plus letrozole significantly improved median progression-free survival (PFS), which was not reached (95% CI 19.3–NR) versus 14.7 months (95% CI 13.0–16.5) for placebo plus letrozole (HR 0.56, p=3.29×10⁻⁶). The objective response rate (ORR) was 41% vs. 28% (p<0.001), with a clinical benefit rate (CBR) of 80% vs. 72% (p=0.02) (Tripathy et al., 2018); (FDA, 2023).

  • MONALEESA-3: In postmenopausal women and men with HR+, HER2– disease, ribociclib plus fulvestrant achieved a median PFS of 20.5 months (95% CI 18.5–23.5) versus 12.8 months (95% CI 10.9–16.3) for placebo plus fulvestrant (HR 0.593, p<0.0001). Median overall survival (OS) was not reached for ribociclib versus 40.0 months for placebo (HR 0.724, p=0.00455) (FDA, 2023).

  • MONALEESA-7: In premenopausal women, ribociclib plus non-steroidal aromatase inhibitor (NSAI) or tamoxifen plus goserelin resulted in a 13.7-month improvement in median PFS (HR 0.569, 95% CI 0.436–0.743), and a median OS not reached vs. 40.7 months for placebo (HR 0.699, 95% CI 0.501–0.976) (FDA, 2023).

c. Extension to Male Patients
Given the rarity of male breast cancer, efficacy in males is extrapolated from female data and supported by the open-label COMPLEEMENT-1 trial, where male patients receiving ribociclib+letrozole+goserelin/leuprolide achieved an ORR of 46.9% (95% CI 29.1–65.3), aligning with outcomes in females (FDA, 2023).

d. Combination Strategies
Ribociclib is effective in doublet (with endocrine therapy) and triplet (adding PI3K or mTOR inhibitors) regimens. For instance, ribociclib plus the PI3K inhibitor alpelisib yielded enhanced tumor regression in preclinical models (–57% vs. –9% for ribociclib and –15% for alpelisib alone) (Tripathy et al., 2018).

3.2 Other Tumor Types

Ribociclib is under investigation for BRAF- and NRAS-mutant melanoma, non-small cell lung cancer, neuroblastoma, and more. Synergistic effects with MEK and BRAF inhibitors have been demonstrated in melanoma models with improved response rates and delayed resistance (Tripathy et al., 2018).

4. Pharmacokinetics and Dosing

  • Absorption: Rapid, with a Tmax of 1–5 hours.
  • Half-life: 33–42 hours, supporting once-daily dosing on a 3-weeks-on/1-week-off schedule.
  • Food Effect: Ribociclib can be administered with or without food.
  • Metabolism: Primarily hepatic via CYP3A4 (Tripathy et al., 2018).

5. Safety and Tolerability

5.1 Adverse Events (AEs)

  • Hematologic: Neutropenia is the most common AE (59% in MONALEESA-2), but febrile neutropenia is rare. Other hematologic AEs include leukopenia, lymphopenia, and anemia.
  • Non-Hematologic: QTc prolongation (mainly Grade 1–2), hepatic transaminase elevations, fatigue, diarrhea, and hot flushes.
  • Management: AEs are generally manageable with dose adjustments or interruptions. Discontinuation rates due to AEs are low (7.5% in MONALEESA-2) (Tripathy et al., 2018); (FDA, 2023).

5.2 Comparison with Other CDK4/6 Inhibitors

  • Ribociclib is more selective for CDK4/6 than palbociclib, which targets more kinases and may cause more off-target effects.
  • Compared to abemaciclib, ribociclib has a lower incidence of gastrointestinal toxicity but a higher incidence of hematologic AEs (Tripathy et al., 2018).

6. Ongoing Research and Future Directions

  • Multiple clinical trials are exploring ribociclib in various solid tumors, novel combinations (including immunotherapy), and settings beyond breast cancer.
  • Translational research focuses on biomarker identification to better predict responders and manage resistance.
  • Future formulations and delivery systems are under investigation to further enhance its therapeutic index (Tripathy et al., 2018); (What is the mechanism of action of Ribociclib Succinate?, 2025).

7. Conclusion

Ribociclib is a highly selective, potent CDK4/6 inhibitor that has revolutionized the management of HR+, HER2– advanced breast cancer, demonstrating substantial survival benefits and a favorable safety profile in both sexes. Its mechanism-based specificity, robust clinical efficacy, and manageable toxicity have led to its integration into standard-of-care regimens and ongoing research is poised to expand its application into other malignancies and combination therapies, supporting its central role in the era of precision oncology.

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: 2025-09-21

KISQALI® (ribociclib) Mechanism of Action | Novartis Pro Portal - last accessed: 2025-09-21

What is the mechanism of action of Ribociclib Succinate? - last accessed: 2025-09-21

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer - PMC - last accessed: 2025-09-21

No Title Found - last accessed: 2025-09-21

FDA Approves Adjuvant Ribociclib in HR+/HER2– Breast Cancer | OncLive - last accessed: 2025-09-21

FDA Approves Ribociclib With an Aromatase Inhibitor in Early Breast Cancer | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways - last accessed: 2025-09-21

Ribociclib (Kisqali) - Uses, How to Take and Side Effects | Breast Cancer Now - last accessed: 2025-09-21

Ribociclib (oral route) - Side effects & dosage - Mayo Clinic - last accessed: 2025-09-21

KISQALI® (ribociclib) Safety Profile | Novartis Pro Portal - last accessed: 2025-09-21

Ribociclib Plus Letrozole Safety Profile Has Some Surprising Adverse Effects - last accessed: 2025-09-21

Web Sources

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

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

Ribociclib (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

What is the mechanism of action of Ribociclib Succinate?

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

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

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

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

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

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

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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

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

What is the mechanism of action of Ribociclib Succinate?

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

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 (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

What is the mechanism of action of Ribociclib Succinate?

What is the mechanism of action of Ribociclib Succinate? Products Data Feature Plans Request Demo Sign Up for Free What is the mechanism of action of Ribociclib Succinate? 7 March 2025 Introduction to Ribociclib Succinate Ribociclib Succinate is a small molecule drug developed by Novartis Pharma AG that belongs to a new generation of cyclin‐dependent kinase (CDK) 4/6 inhibitors. As a succinate salt formulation, Ribociclib Succinate is optimized for oral administration with improved solubility and bioavailability, which is critical for its effective delivery in the human body. The chemical composition is designed such that the core structure of ribociclib interacts selectively with its intended molecular targets, and the succinate counterion aids in enhancing its pharmacokinetic properties. Although the detailed chemical structure (including molecular formula and stereochemistry) is not elaborated in the references provided, its classification as a small molecule drug ensures that it has the low molecular weight and structural characteristics needed for oral delivery and efficient tissue penetration. Chemical Composition and Structure Ribociclib Succinate is structured as a small molecule inhibitor that exerts its function by specifically targeting the ATP-binding pocket of CDK4 and CDK6 enzymes . This selective interaction is mediated by its unique chemical moieties which confer high specificity relative to other kinases involved in cell cycle regulation. The succinate salt form not only stabilizes the drug but also improves its solubility characteristics in gastrointestinal fluids, enabling reliable absorption after oral dosing. The rational drug design involved modifying chemical groups to ensure optimal binding affinity, selectivity, and metabolic stability, which together contribute to its favorable pharmacodynamic and pharmacokinetic profiles. Overview of Clinical Use Ribociclib Succinate is primarily approved for the treatment of hormone receptor-positive (HR+) , human epidermal growth factor receptor 2-negative (HER2–) advanced or metastatic breast cancer. The drug is administered orally and is often used in combination with endocrine therapies, such as aromatase inhibitors or fulvestrant, to improve patient outcomes by delaying disease progression. Clinical studies have shown that ribociclib significantly improves progression-free survival while demonstrating a manageable safety profile, making it a vital component in the modern treatment regimens for advanced breast cancer. Its use, however, is not restricted solely to breast cancer, as ongoing clinical investigations are evaluating its role in other tumor types

What is the mechanism of action of Ribociclib Succinate?

. Given the increasing prominence of immunotherapy in cancer treatment, studies are exploring combination regimens that include ribociclib with immune checkpoint inhibitors to determine whether CDK4/6 inhibition might enhance anti-tumor immune responses. The interplay between cell cycle arrest and immune activation offers a promising avenue for achieving durable responses in cancers that have a high propensity for immune evasion. Conclusion In summary, the mechanism of action of Ribociclib Succinate is multifaceted and highly specific, underpinned by its selective inhibition of CDK4 and CDK6. By targeting these molecular kinases, ribociclib disrupts the cyclin D-CDK4/6-Rb pathway, thereby preventing the phosphorylation of the retinoblastoma protein and effectively arresting tumor cells in the G1 phase of the cell cycle. This targeted disruption of cell cycle progression not only inhibits cancer cell proliferation but also plays a critical role in delaying the onset of endocrine resistance when used in combination with standard hormone therapies. From a clinical perspective, the efficacy of ribociclib in improving progression-free survival in hormone receptor-positive, HER2-negative advanced breast cancer has been well established through rigorous clinical trials. Its relatively manageable toxicity profile, characterized primarily by reversible hematologic adverse events like neutropenia, further underscores its utility as a frontline therapy in this setting. Ongoing research continues to expand our understanding of ribociclib’s mechanism, aiming to optimize its use through combination strategies, overcome potential resistance mechanisms, and explore its applicability in a broader range of malignancies. Future developments in formulation, biomarker identification, and integration with immunotherapy promise to further leverage the therapeutic benefits of ribociclib. Ultimately, the world of cancer therapeutics is moving increasingly towards precision medicine, with ribociclib playing a significant role in the targeted treatment of cancers driven by cell cycle dysregulation. Its ability to combine with endocrine therapies, delay resistance, and maintain a favorable safety profile makes it one of the most promising and well-studied CDK4/6 inhibitors in clinical oncology today. The continued investigation and evolution of ribociclib-based regimens signal a robust future where the intersection of molecular biology, pharmacology, and clinical oncology converges to provide improved outcomes and enhanced quality of life for cancer patients worldwide. Discover Eureka LS: AI Agents Built for Biopharma Efficiency Stop wasting time

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

What is the mechanism of action of Ribociclib Succinate?

free survival while demonstrating a manageable safety profile, making it a vital component in the modern treatment regimens for advanced breast cancer. Its use, however, is not restricted solely to breast cancer, as ongoing clinical investigations are evaluating its role in other tumor types where dysregulation of the cyclin D-CDK4/6- retinoblastoma (Rb) pathway is observed. Mechanism of Action Ribociclib Succinate’s mechanism of action is grounded in its ability to specifically inhibit cyclin-dependent kinases 4 and 6 (CDK4/6), which are essential regulators of the cell cycle. By directly binding to the ATP-binding sites of these kinases, ribociclib prevents their activity, thereby halting the phosphorylation of the retinoblastoma (Rb) protein. This inhibition interrupts the cell cycle progression from the G1 (gap 1) phase to the S (synthesis) phase, ultimately causing cell cycle arrest and inhibition of tumor cell proliferation. Molecular Targets At its core, ribociclib is a selective inhibitor of CDK4 and CDK6. These kinases are pivotal in regulating the progression of cells through the G1 phase by forming complexes with D-type cyclins (mainly cyclin D1). In normal cells, the cyclin D-CDK4/6 complex phosphorylates the retinoblastoma (Rb) protein, which then releases E2F transcription factors. These E2F transcription factors subsequently initiate the transcription of genes necessary for S-phase entry and DNA replication. Ribociclib binds with high affinity to the catalytic sites of CDK4 and CDK6, thereby preventing their ability to phosphorylate Rb. As a direct result, the release of E2F is inhibited, and the transcription of critical S-phase genes is reduced, effectively imposing a block at the G1 phase of the cell cycle. This highly selective inhibition is essential in ensuring that only the proliferative signals mediated by the CDK4/6 pathway are targeted, leaving many other cellular functions intact. This specificity is particularly crucial in minimizing off-target effects commonly associated with less selective kinase inhibitors. The focus on CDK4/6 rather than a broader inhibition of multiple kinases results in a more manageable safety profile—a beneficial aspect that supports prolonged administration in a patient setting. Cellular Pathways Affected The primary cellular pathway affected by

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

What is the mechanism of action of Ribociclib Succinate?

well as with other targeted agents, to overcome resistance mechanisms that may arise during treatment. For example, studies combining ribociclib with fulvestrant or aromatase inhibitors in early and metastatic settings are actively exploring ways to improve progression-free survival and overall response rates in patients. Furthermore, ongoing research focuses on the identification of biomarkers that can predict response to CDK4/6 inhibitors or signal emerging resistance. Molecular profiling of tumors to identify the presence or absence of the Rb protein and other regulatory factors in the CDK4/6 pathway can support personalized treatment strategies, ensuring that only those patients likely to benefit are treated with ribociclib. Future Research Directions Future research directions for ribociclib are focused on several key areas. First, there is a need for a deeper understanding of the molecular mechanisms underlying acquired resistance to CDK4/6 inhibitors. Although ribociclib is highly effective in patients with intact Rb function, a subgroup of patients may develop resistance through alternative pathways, such as activation of cyclin E/CDK2 complexes or compensatory signaling through the PI3K-AKT-mTOR axis. Unraveling these resistance mechanisms will allow for the development of rational combination therapies that further extend the therapeutic benefit of ribociclib. Second, expanding the clinical indications of ribociclib remains a central goal. Research is being directed at exploring its efficacy in other malignancies such as melanoma, non-small cell lung cancer, and even certain types of hematological malignancies, where aberrations in cell cycle control similarly contribute to disease progression. Preclinical models and early phase trials are expected to provide the necessary rationale for these expanded indications, potentially offering new treatment options for patients with tumors that are currently difficult to treat. Additionally, novel drug delivery technologies and formulation improvements are under investigation to further enhance the pharmacokinetic profile and reduce potential side effects of ribociclib. For instance, nanoparticle-based delivery systems or other advanced formulations might enable a more targeted release of the drug into tumor tissues, thereby increasing its therapeutic index and minimizing systemic exposure. Finally, translational research is geared towards integrating ribociclib within multi-modal treatment strategies. Given the increasing prominence of immunotherapy in cancer treatment, studies are exploring combination regimens that include ribociclib with immune checkpoint inhibitors to determine whether CDK4/6 inhibition might enhance anti-tumor immune responses. The interplay

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 (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.

What is the mechanism of action of Ribociclib Succinate?

inhibitors. The focus on CDK4/6 rather than a broader inhibition of multiple kinases results in a more manageable safety profile—a beneficial aspect that supports prolonged administration in a patient setting. Cellular Pathways Affected The primary cellular pathway affected by ribociclib is the cyclin D-CDK4/6-Rb pathway. This pathway is frequently dysregulated in many cancers due to overexpression of cyclin D1, loss of regulatory proteins, or other mechanisms that lead to unchecked cell division. By inhibiting CDK4 and CDK6, ribociclib maintains the Rb protein in an unphosphorylated, active state. In its active form, Rb sequesters E2F transcription factors, thereby preventing the transcription of genes involved in cell cycle progression. Consequently, this disruption leads to G1 cell-cycle arrest, which reduces the proliferation of cancer cells. Furthermore, ribociclib’s effect on the cell cycle does more than simply halt proliferation: it acts as a sensitizing agent when used in combination with endocrine therapies. Endocrine resistance in hormone receptor-positive breast cancer is often mediated by alterations in the CDK4/6-Rb signaling axis. By inhibiting this pathway, ribociclib not only induces cell cycle arrest but also delays the development of resistance to endocrine therapy, thereby enhancing the overall anti-tumor effect. In addition, there is an interplay between the inhibition of CDK4/6 and other signaling cascades such as the PI3K-AKT-mTOR pathway. Although ribociclib does not directly target these pathways, its action in blocking cell cycle progression creates a cellular environment in which other targeted therapies can work more efficiently. For example, in some preclinical models, combining ribociclib with inhibitors of growth factor signaling pathways has led to increased apoptosis and delayed resistance development. On the molecular level, ribociclib’s inhibition of CDK4/6 affects various downstream cellular processes. The decrease in Rb phosphorylation results in altered regulation of E2F-dependent gene transcription, which affects not only cell cycle-related proteins but also other factors involved in DNA replication, repair, and cellular metabolism. This broad-spectrum impact on the cellular transcriptome and proteome contributes significantly to the anti-proliferative and, in some cases, pro-apoptotic effects observed in cancer cells treated

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 ,

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

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 ). QT prolongation has been observed following ribociclib treatment in combination with endocrine therapy; cases were predominantly Grade 1–2 in severity with prolongation limited by proactive dose modifications ( 31 , 46 ). AEs were manageable and reversible upon treatment interruption ( 46 , 47 ). In the Phase III MONALEESA-2 study of ribociclib plus letrozole in the first-line treatment of postmenopausal women with HR+, HER2− ABC, ribociclib dose intensity was 88% despite dose interruptions, and only 7.5% of patients discontinued ribociclib plus letrozole treatment due to AEs ( 46 ). Table 3. Clinical experience with ribociclib combinations. Study name/ID Combination drug Phase Population MTD/RP2D/dose Reported Grade 3/4 AEs Clinical activity HR+, HER2− breast cancer CLEE011X2106/ NCT01857193 ( 44 ) Exemestane Ib Postmenopausal women with ER+, HER2− ABC previously treated with letrozole or anastrozole ( N= 14 treated with ribociclib + exemestane) Evaluated dose Ribociclib: 600 mg/day (3-weeks-on/1-week-off) Exemestane: 25 mg/day Neutropenia (71%), leukopenia (36%), lymphopenia (14%), ALT elevation (14%), AST elevation (14%), and anemia (14%) 2 unconfirmed PR, 4 SD CLEE011X2107/ NCT01872260 ( 45 , 47 ) Letrozole Ib Pretreated and treatment-naïve postmenopausal women with ER+, HER2− ABC ( N= 47 treated with ribociclib + letrozole) RP2D: Ribociclib: 600 mg/day (3-weeks-on/1-week-off) Letrozole: 2.5 mg/day All patients: Neutropenia and neutrophil count reduced (60%), ALT elevation (4%), AST elevation (4%), asthenia (2%), constipation

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

ukopenia, 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 antitumor activity, including cases of PR (33%) and SD (52%) ( Table 3 ) ( 62 ). In patients with advanced BRAF V600 -mutant melanomas, the combination of ribociclib and encorafenib resulted in reduced ribociclib exposure and increased encorafenib exposure, most likely due to encorafenib-mediated CYP3A4 induction and to ribociclib-mediated CYP3A4 inhibition, respectively ( 41 ). The combination of ribociclib and encorafenib demonstrated clinical activity and an acceptable tolerability profile, with AEs consisting of hand–foot syndrome, nausea, pruritus, rash, and myalgia ( Table 3 ) ( 61 ). Cases of PR and SD were observed in patients receiving ribociclib plus encorafenib whose tumors exhibited p16 loss or CDK4 mutation ( 61 ). There was little evidence of response in patients resistant to BRAF inhibition ( 61 ). The use of ribociclib and binimetinib and/or encorafenib combinations in melanoma is being investigated further in ongoing trials ( Supplementary Table 2 ). Neuroblastoma Preclinical Neuroblastoma is frequently driven by oncogenic activation of anaplastic lymphoma kinase ( ALK ), often resulting in cyclin D1 upregulation and cell proliferation ( 64 ). Consistent with this, extensive overexpression of cyclin D–CDK4/6 components have been observed in neuroblastomas ( 65 ). Array-based data showed that cyclin D1 expression is 3–8 times higher in neuroblastoma tumors than in libraries of 18 other common malignancies, including breast cancer ( 65 ). High expression of CDK4 and CDK6 and deletions of CDKN2A have also been associated with these tumors ( Supplementary Table 1 ) ( 65 – 67 ). Ribociclib activity has been profiled against >500 cell lines in the Cancer Cell Line Encyclopedia study, whereby neuroblastoma cell lines were identified as particularly sensitive to ribociclib ( 27 ). Here, ribociclib induced cytostasis at nanomolar concentrations in 12/17 human neuroblastoma

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

ena 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. Invest New Drugs. 2014;32:825–37. doi: 10.1007/s10637-014-0120-7. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 30. Sumi N, Kuenzi B, Knezevic C, Rix L, Rix U. Chemoproteomics reveals novel protein and lipid kinase targets of clinical CDK4/6 inhibitors in lung cancer. ASC Chem Biol. 2015;10:2680–6. doi: 10.1021/acschembio.5b00368. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 31. Infante J, Cassier P, Gerecitano J, Witteveen P, Chugh R, Ribrag V, et al. A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin Cancer Res. 2016;22:5696–705. doi: 10.1158/1078-0432.CCR-16-1248. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 32. Yamada Y, Ishikawa N, Kakizume T, Tajima T, Hewes B, Doi T. A phase I study of single-agent ribociclib in japanese patients with advanced solid tumors. Mol Cancer Ther. 2015;14(12 suppl) doi: 10.1111/cas.13428. Abstract B31 (Poster) [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 33. Dhuria SV, Siddani R, Kosecki CM, Germa C, Mondal S. A phase I food-effect study of the ribociclib (LEE011) drug-in-capsule (DiC) formulation in healthy subjects. J Clin Oncol. 2015;33(suppl) Abstract e13577. [ Google Scholar ] 34. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature

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

in the Cancer Cell Line Encyclopedia study, whereby neuroblastoma cell lines were identified as particularly sensitive to ribociclib ( 27 ). Here, ribociclib induced cytostasis at nanomolar concentrations in 12/17 human neuroblastoma-derived cell lines ( 67 ). In sensitive neuroblastoma cell line-derived xenograft mouse models, treatment with ribociclib was accompanied by a reduction in phosphorylated Rb, Ki67, and cell proliferation, leading to significant tumor growth delay throughout the treatment period ( P <0.0001) ( 67 ). CDK4/6 is therefore an attractive target for neuroblastoma treatment. Clinical The efficacy and safety of single-agent ribociclib in patients with neuroblastoma was evaluated as part of the Phase I study investigating ribociclib in 31 pediatric patients (median age [range]: 5 [1–20] years) with malignant rhabdoid tumors (MRT), neuroblastoma, or CDK4/6 pathway-activated tumors ( 68 ). Consistent with single-agent data in adults, the maximum tolerated dose (MTD) and RP2D were 470 mg/m 2 /day (adult equivalent dose ≈800 mg/day) and 350 mg/m 2 /day (adult equivalent dose ≈600 mg/day), respectively, on a 3-weeks-on/1-week-off dosing schedule ( 68 ). Ribociclib was rapidly absorbed with a median T max of 2–5 hours, regardless of age ( 69 ). As in adults, ribociclib exposure in pediatric patients appeared to accumulate 2–3-fold in plasma, reaching steady state within 8 days ( 69 ). Clearance was 2–3 times slower in pediatric patients compared with adults, presumably due to their lower body weight ( 69 ). Ribociclib was well tolerated with mild-to-moderate reversible AEs, the majority of which were hematologic ( 68 ). Three patients, two with neuroblastoma and one with MRT, received ribociclib for ≥4 cycles; SD was the best overall response ( 68 ). Ribociclib remains the only CDK4/6 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-

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

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

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