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Cdk4/6 Inhibitors In Early Breast Cancer

Palbociclib Adjuvant Clinical Trials

CDK4/6 Inhibitors in Metastatic Breast Cancer

Palbociclib had been tested in two clinical trials in two different settings. The first, the PALLAS trial, used palbociclib as an addition to the routinely used ET in regular adjuvant settings, while in the other trial, the PENELOPE-B, palbociclib was given following neoadjuvant chemotherapy and surgery to minimize the chance of recurrence in patients with residual disease.

The PALLAS was a Phase III open-label clinical trial designed to evaluate the potential efficacy of the CDK4/6 inhibitor, palbociclib, in the adjuvant setting of EBC. In this study, 5761 patients with HR-positive, HER2-negative stage IIIII breast cancer were randomized, within one year from the diagnosis, and within 6 months of receiving adjuvant ET, to palbociclib 125 mg daily, 3 weeks on/1 week off for two years, in combination with adjuvant ET versus ET alone. The primary endpoint was iDFS in an intention to treat analysis. After a median follow-up of 31 months, iDFS was not improved by adding palbociclib. The 4-year iDFS was 84.2% for palbociclib-containing arm versus 84.5% for ET alone arm 0.811.14 P=0.65), crossing a pre-specified futility boundary.

Biomarkers Of Response To Cdk4/6 Inhibitors For Er+ Breast Cancer

Patients with advanced ER+ breast cancer are pre-selected for CDK4/6 inhibitor therapy on the basis that these cancers generally have an intact Rb axis, and indeed the incidence of Rb gene deletion/mutation is very rare in ER+ breast cancer . Studies in pre-clinical models demonstrate a requirement of intact Rb for effective CDK4/6 inhibition, supporting its utility as a biomarker . This finding has also been validated clinically . In an examination of the effects of palbociclib on unselected ex vivo tumour explant breast cancer models , the 2 of 13 models that were insensitive to palbociclib lacked Rb expression. Studies in glioblastoma cell lines and pancreatic cancer patient-derived xenograft models have reached similar conclusions , with even the low expression of Rb sufficient to confer insensitivity to CDK4/6 inhibitors . The use of Rb as a biomarker of CDK4/6 inhibitor response in ER+ breast cancer could be further refined in combination with low molecular weight cyclin E1 . LMWE is a promiscuous cytoplasmic cyclin E1 fragment that when complexed with CDK2 can phosphorylate Rb in the presence of CDK4/6 inhibition . Patients with Rb-/LMWE+ cancers had the shortest PFS in a cohort of 109 patients treated with palbociclib and endocrine therapy .

Cdk4/6 Inhibitors For Metastatic Breast Cancer

CDK4 and CDK6 are enzymes important in cell division. CDK4/6 inhibitors are drugs designed to interrupt the growth of cancer cells.

CDK4/6 inhibitors are used in combination with hormone therapy to treat some hormone receptor-positive breast cancers.

The CDK4/6 inhibitors FDA-approved for metastatic breast cancer treatment are:

Drug name

Kisqali

Pill

Although the CDK4/6 inhibitors abemaciclib, palbociclib and ribociclib have not been compared directly to one another, studies show similar results with each drug in treating metastatic breast cancer .

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Other Critical Trials In The Monarch Series

Given the success of CDK4/6 inhibition combined with ET in the treatment of HR+/HER2 breast cancer, this strategy is also under consideration for HR+/HER2+ advanced breast cancer, with evidence shown that HER2+ breast tumors in resistance to trastuzumab may be partly caused by cyclin D1 overexpression . The phase II monarcHER study evaluated abemaciclib + trastuzumab + fulvestrant vs. trastuzumab + chemotherapy in HR+/HER2+ advanced breast cancer patients who had received at least 2 lines of anti-HER2 therapy. The median PFS and ORR were improved with triple therapy, confirming that this regimen can provide clinical benefit in heavily pretreated patients with HR+/HER2+ breast cancer. These findings suggest that a chemotherapy-free regimen may be an alternative treatment option for HR+/HER2+ advanced breast cancer patients, although further studies are needed.

Patient And Hospital Characteristics

Cyclin dependent kinase 4/6 inhibitors in early breast cancer: what is ...

Patient characteristics and hospital information were summarized during the baseline period. Weight and height information , smoking history, and the results of the 10-item Barthel Activities of Daily Living index were obtained from discharge summaries from the last hospital admission in the baseline period . Patient treatment history was summarized for up to 5 years preceding the index date. Prescription of luteinizing hormone-releasing hormone during the follow-up period was summarized as surrogate for premenopausal status.

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Role Of Muc16 In The Palbociclib Response

Figure 4.MUC16s role in Palbociclib response. MUC16 can serve as a biomarker of palbociclib treatment in MCFDCIS tumors and may play a functional role in tumor growth.

A) Cigar plot of Log2 expression of cDNA array data generated from RNA isolated from vehicle- and palbociclib-treated tumors of cohort two. Points highlighted in red are up-regulated by palbociclib while those in blue are downregulated by drug. B) Top 15 most PD-regulated genes from the cDNA array at two weeks of treatment, ranked by Log2 fold change and significance of P< 0.05. Up-regulated genes are depicted in red, down-regulated genes in blue. C) qPCR analysis of MUC16 expression in MCFDCIS tumors treated as indicated. Mean fold change ± S.E.M. . D) Representative cohort 1 and 2 tumor sections stained by IHC for MUC16, treated with PD as indicated. 10x mag., scale = 200m. E) Tumor growth curves for non-silenced or shMUC16 MCFDCIS tumors following subcutaneous injection of cells, represented as the delta in tumor size normalized to initial tumor size . F) Representative NS and shMUC16 MCFDCIS tumor sections stained by IHC for MUC16. 10x mag., scale = 200m. G) Quantification of MUC16 IHC staining as a percent of tumor area. Mean ± S.E.M. . H) ELISA for circulating MCFDCIS tumor-derived MUC16 in serum taken at day 28 from mice bearing NS or shMUC16 MCFDCIS tumors. I) Representative NS and shMUC16 MCFDCIS tumor sections stained using the PAS method. 10x mag., scale = 200m.

Lilly Announces Details Of Presentations At 2022 San Antonio Breast Cancer Symposium

INDIANAPOLIS, Nov. 21, 2022 /PRNewswire/ — Eli Lilly and Company today announced that study investigators will present data from its breast cancer portfolio and pipeline at the 2022 San Antonio Breast Cancer Symposium , to be held December 6-10, 2022, in San Antonio, Texas, and virtually. These presentations include new results from studies of Verzenio® , imlunestrant , and LOXO-783 .

The Verzenio oral and poster presentations will provide updated clinical data from ongoing studies in early and advanced forms of hormone receptor-positive , human epidermal growth factor receptor 2-negative breast cancer. An oral presentation will provide results from a pre-planned overall survival analysis from the Phase 3 monarchE study in HR+, HER2-, node-positive, high risk early breast cancer, including four-year efficacy outcomes. Updated results at the final OS from the Phase 3 MONARCH 2 trial of Verzenio plus fulvestrant in patients with HR+, HER2- advanced breast cancer will be presented in a spotlight poster discussion. Additional analyses include real-world evidence in early breast cancer with a high risk of recurrence.

A list of the presentations, along with their viewing details, is shared below.

Presentation Title

Presenter: Puca L

About Verzenio® Verzenio® is a targeted treatment known as a CDK4/6 inhibitor. Verzenio is a nonchemotherapy oral tablet.

Verzenio is also indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer:

AL HCP ISI 12OCT2021

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Cdk4/6 Inhibitors And Metastatic Breast Cancer Treatment

CDK4/6 inhibitors are used in combination with hormone therapy .

A CDK4/6 inhibitor in combination with hormone therapy can be used to treat some metastatic breast cancers that are:

Compared to treatment with hormone therapy alone, the combination of hormone therapy and a CDK4/6 inhibitor can give people more time before the cancer spreads and increase overall survival .

The CDK4/6 inhibitor abemaciclib may also be used alone to treat hormone receptor-positive, HER2-negative cancers that have progressed on past hormone therapy and chemotherapy .

For a summary of research studies on CDK4/6 inhibitors and metastatic breast cancer treatment, visit the Breast Cancer Research Studies section.

Molecular Mechanisms Of Cdk4/6 Inhibitor Efficacy And Resistance

Future Directions: CDK4/6 Inhibitors in Breast Cancer

The cyclin D-CDK4/6-Retinoblastoma protein axis regulates cell cycle progression from G1 to the S phase . Before entering the cell cycle, Rb is hypophosphorylated and bound to the E2F transcription factors , causing their inhibition. When the appropriate mitogenic signals are present, quiescent cells may enter the cell cycle at the G1 phase. These mitogenic signals lead to the expression of cyclin D, which competes with CDKN2 family proteins to bind CDK4/6, forming the cyclin D-CDK4/6 complex. This active complex can then phosphorylate Rb, causing a conformational change and subsequent release of the E2F TFs, which drive S phase entry and further cell cycle progression via downstream transcriptional activation. Furthermore, the cyclin D-CDK4/6 complex triggers the forkhead box protein M1 TF, promoting the advancement of later cell cycle phases . ER+ breast cancer is highly reliant on an intact cyclin D-CDK4/6-Rb axis, as estrogen drives cyclin D1 expression leading to the formation of the cyclin D-CDK4/6 complex, ultimately inducing cell proliferation through the CDK4/6 pathway. CDK4/6 inhibitors leverage this by binding the ATP domain of CDK4/6 and halting progression from the G1 to S phase of the cell cycle.

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Educated Patient Metastatic Breast Cancer Summit Overview Of Management Of Hormone Receptor

Although certain treatments such as Ibrance , Kisqali and Verzenio have become the standard first-line treatment option for hormone receptor-positive breast cancer, recent study findings have shown that they may no longer be interchangeable.

Now, according to Dr. Seth A. Wander, health care providers are actively debating as to why two drugs in this instance, Ibrance and Kisqali could elicit similar improvements in progression-free survival but drastic results in overall survival.

Of note, progression-free survival and overall survival are common endpoints that trial investigators assess when analyzing new treatments.

As part of a larger discussion, Wander, an assistant professor of medicine at Harvard Medical School and a medical oncologist at Massachusetts General Hospital in Boston, highlighted the first- and second-line management of hormone receptor-positive breast cancer during CURE®s recent Educated Patient® Metastatic Breast Cancer Summit.

Most Common Cancer

Wander noted that breast cancer, according to statistics released by the American Cancer Society in 2020, is the most common type of malignancy diagnosed in women.

In fact, more than 275,000 new cases of breast cancer were expected to be diagnosed in women in the U.S. Of those cases, approximately 70% are hormone receptor positive.

Hormone Therapy

CDK4/6 Inhibitors

Mechanisms of Treatment Resistance

Related Content:

Celcuity To Present Additional Data For Gedatolisib At The 2022 San Antonio Breast Cancer Symposium

MINNEAPOLIS, MN / ACCESSWIRE / November 22, 2022 / Celcuity Inc. , a clinical-stage biotechnology company focused on development of targeted therapies for cancer treatment, today announced that an abstract accepted for a Spotlight Poster presentation at the 2022 San Antonio Breast Cancer Symposium is now available on the SABCS website. The 2022 San Antonio Breast Cancer Symposium is being held virtually and in-person from December 6-10, 2022.

The presentation will include updated efficacy and safety data and sub-group analysis by PIK3CA mutation status in the four expansion arms of a Phase 1b study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer. The primary endpoint was investigator assessed objective response rate . Secondary endpoints included safety, duration of response and progression free survival . Promising ORR and PFS were seen in all arms, regardless of PIK3CA mutation status. Arm D, which treated patients whose disease progressed on a CDK4/6 inhibitor, reported ORR of 63% overall, 73% in PIK3CA-mutation patients, and 60% in PIK3CA-wild type patients overall PFS was 12.9 months. Arm A, which evaluated patients who were treatment-naïve in the advanced disease setting, reported ORR of 85% overall, 81% in PIK3CA-wild type patients, and 100% in PIK3CA-mutations patients median PFS was not reached after a median follow-up period of 33.1 months.

Poster presentation details are provided below.

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Liquid Biopsies To Predict Cdk4/6 Inhibitor Efficacy And Resistance In Breast Cancer

Sasha C. Main1,2 David W. Cescon1,3 Scott V. Bratman1,2,4

1Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C1, Ontario, Canada.

2Department of Medical Biophysics, University of Toronto, Toronto M5G 1L7, Ontario, Canada.

3Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto M5S 1A8, Ontario, Canada.

4Department of Radiation Oncology, University of Toronto, Toronto M5T 1P5, Ontario, Canada.

Correspondence to: Dr. Scott Bratman, Princess Margaret Cancer Centre, University Health Network, 101 College Street, PMCRT, Room 13-305, Toronto M5G 1L7, Ontario, Canada. E-mail: scott.bratman@rmp.uhn.ca

Received: Revised: Accepted: Available online:Academic Editor: Copy Editor: Production Editor:

© The Author 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License , which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Discovery And Preclinical Development

Adjuvant CDK4/6 inhibitors combined with endocrine therapy in HR ...

LY2835219 was discovered by scientists at Eli Lilly and Company Research Laboratories. Abemaciclib binds to inactive kinase conformation of CDK4/6 and establishes a reversible interaction. Two hydrogen bonds are established in the three CDK4/6 inhibitors with residues in the hinge region of CDK4/6 ATP pocket. One hydrogen bond is between the pyridine N atom and His100NH, and another one is between the exocyclic NH of the side chain and Val101CO. The amino side chains of these inhibitors are observed to occupy different positions. Compared with abemaciclib, ribociclib and palbociclib bind differently to CDK4/6 and have larger substituents, while abemaciclib has only a fluorine atom. Therefore, abemaciclib is more deeply buried into the ATP cleft than ribociclib and palbociclib .

Figure 2

In addition to cell-cycle dependent activity, CDK4/6 inhibitors have been shown to increase the frequency of CD8-positive T cell memory precursors and downregulate the expression of MYC target genes, suggesting a potential for augmentation of long-term protective immunity in patients with cancer . Furthermore, abemaciclib has been shown to promote antitumor immunity by simultaneously potentiating tumor antigen presentation, as well as selectively suppressing proliferation of regulatory T cells .

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Residual Effects After Cessation Of Treatment With Palbociclib

Palbociclibs effects in vitro are largely but not entirely reversible as shown above . Thus, we sought to determine if similar residual effects of CDK4/6 inhibition could be detected in vivo in either the tumor cells or stroma after discontinuation of therapy. To study this, we allowed mice an 11-day drug-recovery period following 2 weeks of palbociclib treatment . Upon treatment termination, palbociclib-treated tumors resumed growth but final tumor sizes in the palbociclib recovery group remained significantly smaller than vehicle-treated tumors . Growth rates of tumors during the 11 days of recovery paralleled those of the vehicle-treated tumors notably, in tumors recovering from palbociclib treatment, almost 30% of tumor area remained DCIS while vehicle-treated tumors progressed to invasive disease with only 8.5% of tumor area remaining DCIS . We observed partial re-expression of phosphorylated RB, Ki67 and p63 upon palbociclib withdrawal . p63 expression remained lower in palbociclib-treated and recovered tumors than in vehicle-treated tumors , suggesting that palbociclib has some lasting effects on tumor differentiation status and progression to invasive lesions. Interestingly, the panel of cell cycle genes completely returned to baseline as did the senescence markers LMNB1 and FOXM1 .

Cdk4/6 Inhibition In Early

  • ContactAffiliationsDepartment of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
  • Ying FanAffiliationsDepartment of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China

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A Narrative Review Of The Clinical Development Of Cdk4/6 Inhibitor Abemaciclib In Breast Cancer

Liu Yang#, Yang Chen#, Ning Wang, Weiwei Han

Eli Lilly and Company , China

Contributions: Conception and design: L Yang, Y Chen, N Wang Administrative support: W Han Provision of study materials or patients: L Yang, Y Chen, N Wang Collection and assembly of data: L Yang, Y Chen Data analysis and interpretation: L Yang, Y Chen, W Han Manuscript writing: All authors Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to:

Methods: We reviewed English publications in PubMed related to CDK4/6 inhibitors from 2011 to 2021.

Key Content and Findings: In this review, we summarized the mechanism, results of preclinical and clinical studies of abemaciclib, describing current indications for treatment, ongoing clinical trials, safety and tolerability, and future perspectives.

Abemaciclib is a unique CDK4/6 inhibitor with distinctive characteristics and promising data, which bring benefit to HR+, HER2 breast cancer patients.

Keywords: Cyclin-dependent kinase 4/6 inhibitor abemaciclib hormone receptor positive/human epidermal growth factor receptor 2 negative breast cancer metastatic breast cancer

Received: 07 December 2021 Accepted: 21 January 2022 Published: 31 January 2022.

doi: 10.21037/tbcr-21-36

Cdk4/6 Inhibitors In Combination Therapies: Better In Company Than Alone: A Mini Review

Adjuvant CDK4/6 inhibition in early-stage HR-positive breast cancer | Ruth O’Regan
  • 1Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano , Istituto di Ricovero e Cura a Carattere Scientifico , National Cancer Institute, Aviano, Italy
  • 2Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
  • 3Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, SantAndrea Hospital, University of Rome Sapienza, Rome, Italy

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Cdk4/6 Inhibition In Breast Cancer: Current Practice And Future Directions

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