ribociclib and abemaciclib

The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard of care for hormone receptor-positive (HR + ) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer, improving survival outcomes compared to endocrine therapy alone. Abemaciclib and ribociclib, in combination with endocrine therapy, have demonstrated significant benefits in invasive disease-free survival for high-risk HR+/HER2- early breast cancer patients. Each CDK4/6i-palbociclib, ribociclib, and abemaciclib-exhibits distinct toxicity profiles. Radiation therapy (RT) can be delivered with a palliative or ablative intent, particularly using stereotactic body radiation therapy for oligometastatic or oligoprogressive disease. However, pivotal randomized trials lack information on concomitant CDK4/6i and RT, and existing preclinical and clinical data on the potential combined toxicities are limited and conflicting. As part of a broader effort to establish international consensus recommendations for integrating RT and targeted agents in breast cancer treatment, we conducted a systematic review and meta-analysis to evaluate the safety profile of combining CDK4/6i with palliative and ablative RT in both metastatic and early breast cancer settings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinases; Female; Humans; Protein Kinase Inhibitors; Radiosurgery

The approval of CDK4/6 inhibitors has dramatically improved care for the treatment of HR+/HER2- advanced breast cancer, but navigating the rapidly-expanding treatment evidence base is challenging. In this narrative review, we provide best-practice recommendations for the first-line treatment of HR+/HER2- advanced breast cancer in Canada based on relevant literature, clinical guidelines, and our own clinical experience. Due to statistically significant improvements in overall survival and progression-free survival, ribociclib + aromatase inhibitor is our preferred first-line treatment for de novo advanced disease or relapse ≥12 months after completion of adjuvant endocrine therapy and ribociclib or abemaciclib + fulvestrant is our preferred first-line treatment for patients experiencing early relapse. Abemaciclib or palbociclib may be used when alternatives to ribociclib are needed, and endocrine therapy can be used alone in the case of contraindication to CDK4/6 inhibitors or limited life expectancy. Considerations for special populations-including frail and fit elderly patients, as well as those with visceral disease, brain metastases, and oligometastatic disease-are also explored. For monitoring, we recommend an approach across CDK4/6 inhibitors. For mutational testing, we recommend routinely performing ER/PR/HER2 testing to confirm the subtype of advanced disease at the time of progression and to consider

Topics: Aged; Aminopyridines; Breast Neoplasms; Female; Humans; Neoplasm Recurrence, Local

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are standard-of-care therapy for hormone receptor-positive advanced or metastatic breast cancer, based on randomized trials showing improved progression-free survival for all 3 drugs and overall survival for ribociclib and abemaciclib. Results in early breast cancer are discordant, with sustained improvement in invasive disease-free survival demonstrated for abemaciclib but not other CDK4/6 inhibitors to date. We review nonclinical studies exploring mechanistic differences between the drugs, the impact of continuous dosing on treatment effect, and translational research into potential resistance mechanisms and prognostic and predictive markers. We focus particularly on how emerging findings may help us understand similarities and differences between the available CDK4/6 inhibitors. Even at late-stage clinical development, there remains much to learn about how agents in this class exert their varying effects.

Topics: Aminopyridines; Breast Neoplasms; Cyclin-Dependent Kinase 4; Female; Humans

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

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Protein Kinase Inhibitors; Receptor, ErbB-2; Triple Negative Breast Neoplasms

This network meta-analysis aimed to assess the comparative efficacy and safety of combinations involving three cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapies (ETs) in patients with metastatic or advanced breast cancer (BC) who are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-).. We initially identified relevant studies from previous meta-analyses and then conducted a comprehensive search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases to locate additional studies published between February 2020 and September 2021. Essential data were extracted, and a network meta-analysis was performed using R 4.1.1 software with a random-effects model. Furthermore, we assigned rankings to all available treatment combinations by calculating their cumulative probability.. Data analysis included ten reports from nine studies. Pooled results demonstrated that each treatment combination significantly reduced the hazard risk of progression-free survival (PFS) compared to treatment with an aromatase inhibitor (AI) or fulvestrant alone. However, there were no differences observed in PFS or overall survival (OS) among the different treatment combinations. Additionally, patients receiving palbociclib plus AI and abemaciclib plus AI or fulvestrant experienced more severe adverse events (AEs), with hazard ratios (HRs) of 10.83 (95% confidence interval [CI] = 2.3 to 52.51) and 4.8 (95%CI = 1.41 to 16.21), respectively. The HR for ribociclib plus AI was 9.45 (95%CI = 2.02 to 43.61), and the HR for palbociclib plus fulvestrant was 6.33 (95%CI = 1.03 to 39.86). Based on the ranking probabilities, palbociclib plus fulvestrant had the highest probability of achieving superior PFS (37.65%), followed by abemaciclib plus fulvestrant (28.76%). For OS, ribociclib plus fulvestrant ranked first (34.11%), with abemaciclib plus fulvestrant in second place (25.75%). In terms of safety, palbociclib plus AI (53.98%) or fulvestrant (51.37%) had the highest probabilities of being associated with adverse events.. Abemaciclib plus fulvestrant or ribociclib plus AI appear to be effective and relatively safe for the treatment of HR+/HER2- metastatic or advanced BC patients. However, given the reliance on limited evidence, our findings require further validation through additional studies.

Topics: Aromatase Inhibitors; Breast Neoplasms; Cyclin-Dependent Kinase 4; Female; Fulvestrant; Humans; Network Meta-Analysis

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone-positive metastatic breast cancers (mBCs). They are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC populations. In the first-line metastatic setting, the median progression-free survival for the three currently approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, with aromatase inhibitors is greater than 2 years (palbociclib 27.6 months; ribociclib 25.3 months; and abemaciclib 28.18 months). Although CDK4/6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are expensive and can be associated with drug toxicities. Here, we have performed a systemic review of the reported molecular markers predictive of drug response including intrinsic and acquired resistance for CDK4/6 inhibition in mBC. The rapidly emerging molecular landscape is captured through next-generation sequencing of breast cancers (DNA with or without RNA), liquid biopsies (circulating tumor DNA), and protein analyses. Individual molecular candidates with robust and reliable evidence are discussed in more depth.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Biomarkers, Tumor; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Resistance, Neoplasm; Female; Humans; Piperazines; Prognosis; Purines; Pyridines

Evaluation of health-related quality of life (HR-QoL) among cancer patients has gained an increasing importance and is now a key determinant of anticancer treatments' value. HR-QoL has been assessed in trials testing cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in breast cancer (BC), using various questionnaires at different timepoints. HR-QoL reports from BC patients treated with CDK4/6i in the real-world setting are also available.. We systematically reviewed the literature, searching for full-length articles, and selected conference abstracts reporting data on HR-QoL in BC patients at any stage and of any molecular subtype treated with abemaciclib, palbociclib or ribociclib.. A total of 533 full-length articles and 143 abstracts were retrieved. After screening for eligibility, 38 records were included (31 clinical trials; 7 real-world reports). Assessment methods were heterogeneous across studies in terms of questionnaires, evaluation timepoints and endpoints. Overall, adding CDK4/6i to endocrine therapy did not worsen patients' HR-QoL, with a positive trend towards pain improvement. Gastrointestinal scores (diarrhea, nausea and appetite loss) statistically favored the control arm among metastatic BC patients receiving abemaciclib, whereas they were superimposable in the early setting. The combination of palbociclib and endocrine therapy showed similar HR-QoL outcomes compared with endocrine therapy alone, but determined better scores compared with chemotherapy. HR-QoL was specifically assessed in premenopausal patients treated with ribociclib, showing similar scores compared with postmenopausal patients.. Despite methodological heterogeneity does not allow a proper comparison, HR-QoL was generally maintained with CDK4/6i. However, differences between abemaciclib, palbociclib and ribociclib exist and mainly rely on the distinct safety profiles of the compounds. These differences should be acknowledged and taken into account in the clinical practice.

Topics: Aminopyridines; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Protein Kinase Inhibitors; Quality of Life

The cyclin-dependent kinase (CDK) 4/6 inhibitors belong to a new class of drugs that interrupt proliferation of malignant cells by inhibiting progression through the cell cycle. Three such inhibitors, palbociclib, ribociclib, and abemaciclib were recently approved for breast cancer treatment in various settings and combination regimens. On the basis of their impressive efficacy, all three CDK4/6 inhibitors now play an important role in the treatment of patients with HR+, HER2- breast cancer; however, their optimal use still needs to be established. The three drugs have many similarities in both pharmacokinetics and pharmacodynamics. However, there are some differences on the basis of which the choice for a particular CDK4/6 inhibitor for an individual patient can be important. In this article, the clinical pharmacokinetic and pharmacodynamic profiles of the three CDK4/6 inhibitors are reviewed and important future directions of the clinical applicability of CDK4/6 inhibitors will be discussed.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

HER2-positive (HER2+) breast cancer represents a heterogeneous breast cancer subtype, including both oestrogen receptor (ER) positive and negative tumours. A deeper understanding of the crosstalk between ER and HER2 receptor pathways has led to the development of treatment strategies consisting of a simultaneous blockade of both signalling pathways, as a reasonable approach to prevent the onset of mechanisms of resistance.. This review was based on the material searched on PubMed, MEDLINE and Embase databases and on conference proceedings from major oncology conferences up to 15 December 2020. The search strategy included the following keywords: 'HER2-positive breast cancer', 'CDK4-6 inhibitors' and 'PI3K inhibitors', and was adapted for use with different bibliographic databases.. CDK4/6 and PI3K inhibitors are two classes of agents already approved in patients with hormone receptor positive, HER2-negative breast cancer. Recently, promising data with their use have been also shown in HER2+ disease. Results from preclinical and clinical studies are shedding light on the role of these classes of agents in HER2+ breast cancer, and are paving the road for a forthcoming change in clinical practice.. Treatment landscape for HER2+ breast cancer is rapidly changing, and CDK4/6 and PI3K inhibitors represent a new promising strategy to improve patients' outcomes.

Topics: Aminopyridines; Anastrozole; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Fulvestrant; Humans; Letrozole; Phosphoinositide-3 Kinase Inhibitors; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Trastuzumab

The historical median survival of advanced luminal breast cancer does not exceed four years. The deciphering of the mechanisms of resistance to hormone therapy has led to the development of inhibitors of cyclin D dependent kinases (CDK4 and 6). Three drugs, palbociclib, ribociclib and abemaciclib, very similar pharmacologically, have been evaluated in the context of pivotal, randomized phase III trials. Strikingly and regardless of the endocrine therapy backbone, and in both hormone-sensitive and hormone-resistant patients, the addition of a CDK4 / 6 inhibitor doubles progression-free survival with a hazard ratio always around 0.55. The benefit in overall survival begins to be demonstrated. This review presents all published results, as well as the main safety data.

Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cell Cycle; Clinical Trials, Phase III as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Progression-Free Survival; Proportional Hazards Models; Protein Kinase Inhibitors; Purines; Pyridines; Randomized Controlled Trials as Topic; Retinoblastoma Binding Proteins; Ubiquitin-Protein Ligases

Topics: Alopecia; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Estrogen Receptor alpha; Female; Fulvestrant; Germany; Humans; Incidence; Neoplasm Metastasis; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Quality of Life; Randomized Controlled Trials as Topic; Receptors, Progesterone; Survival Rate; Tamoxifen

Palbociclib, ribociclib and abemaciclib have all been approved in combination with endocrine therapy in hormone-receptor positive, HER2 negative metastatic breast cancer. While the efficacy of these drugs appears similar, differences in safety and tolerability are apparent.. We searched PubMed and ASCO, ESMO and SABCS proceedings to identify randomized trials of palbociclib, ribociclib and abemaciclib. Data on common and serious adverse events (AE) were extracted for each approved drug. The odds ratio for each AE and the hazard ratio for progression-free survival were calculated relative to endocrine therapy alone. A network meta-analysis was then performed for each endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib.. 8 trials were included in the analysis and comprised 2799 patients receiving cyclin-dependent kinase 4/6 inhibitors palbociclib: 873 patients; ribociclib: 1153 patients; abemaciclib: 773 patients. In 5 trials (1524 patients), the endocrine therapy backbone was an AI and in 3 trials (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 3-4 neutropenia, but significantly higher GI toxicity. Treatment discontinuation was higher with abemaciclib than other drugs. Efficacy of the 3 drugs was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 0.98 and for abemaciclib 1.02. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively.. Palbociclib, ribociclib and abemaciclib have comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to GI toxicity.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Neoplasm Metastasis; Network Meta-Analysis; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Randomized Controlled Trials as Topic

Palbociclib, ribociclib, and abemaciclib are inhibitors of the cyclin-dependent kinases 4 and 6 approved for the treatment of locally advanced or metastatic breast cancer. In this review, we provide an overview of the available clinical pharmacokinetic and pharmacodynamic characteristics of these novel drugs, summarize the results of food-effect and drug-drug interaction studies, and highlight exposure-response and exposure-toxicity relationships. All three drugs exhibit a large inter-individual variability in exposure (coefficient of variation range 40-95% for minimum plasma concentration), are extensively metabolized by cytochrome P450 3A4, and have their brain penetration limited by efflux transporters. Abemaciclib has three active metabolites with similar potency that are clinically relevant (i.e., M2, M20, M18), whereas the metabolites of palbociclib and ribociclib are not of clinical significance. Pharmacokinetic exposure increases in a dose-proportional manner for palbociclib, whereas exposure increases under- and over-proportionally with an increasing dose for abemaciclib and ribociclib, respectively. High exposure is associated with an increased risk of neutropenia, and for ribociclib also to corrected QT prolongation. For abemaciclib, a clear exposure-efficacy relationship has been described, while for palbociclib and ribociclib exposure-response analyses remain inconclusive. Future studies are needed to address exposure-efficacy relationships to further improve dosing.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

The role of cyclin-dependent kinases (CDKs) in regulating the transition of cell cycle steps makes this class of enzymes a suitable target for cancer therapy. Three different generations of CDKs inhibitors have been developed so far. Third-generation compounds (i.e. selective CDK4/6 inhibitors) are the most promising ones, due to their limited toxicity and high in vivo activity. To date, three compounds have entered the therapy, namely Palbociclib, Ribociclib and Abemaciclib. Herein we review the medicinal chemistry aspects of these drugs, with some references to very similar analogues that have been published.

Topics: Aminopyridines; Benzimidazoles; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Dose-Response Relationship, Drug; Humans; Molecular Structure; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Structure-Activity Relationship

Sustained proliferative capacity and gene dysregulation are hallmarks of cancer. In mammalian cells, cyclin-dependent kinases (CDKs) control critical cell cycle checkpoints and key transcriptional events in response to extracellular and intracellular signals leading to proliferation. Significant clinical activity for the treatment of hormone receptor positive metastatic breast cancer has been demonstrated by palbociclib, ribociclib and abemaciclib, dual CDK4/6 inhibitors recently FDA-approved. SY-1365, a CDK7 inhibitor has shown initial encouraging data in phase I for solid tumors treatment. These results have rejuvenated the CDKs research field. This review provides an overview of relevant advances on CDK inhibitor research since 2015 to 2019, with special emphasis on transcriptional CDK inhibitors, new emerging strategies such as target protein degradation and compounds under clinical evaluation.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cell Cycle Checkpoints; Cyclin-Dependent Kinases; Drug Discovery; Humans; Indoles; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Pyrimidines; Transcription Factors

Although international guidelines support the administration of hormone therapies with or without targeted therapies in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, upfront use of chemotherapy remains common even in the absence of visceral crisis. Because first-line or second-line treatments, or both, based on chemotherapy and on hormone therapy have been scarcely investigated in head-to-head randomised controlled trials, we aimed to compare these two different approaches.. We did a systematic review and network meta-analysis with a systematic literature search on PubMed, Embase, Cochrane Central Register of Clinical Trials, Web of Science, and online archives of the most relevant international oncology conferences. We included all phase 2 and 3 randomised controlled trials investigating chemotherapy with or without targeted therapies and hormone therapies with or without targeted therapies as first-line or second-line treatments, or both, in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, published between Jan 1, 2000, and Dec 31, 2017. Additional recently published randomised controlled trials relevant to the topic were also subsequently added. No language restrictions were adopted for our search. A Bayesian network meta-analysis was done to compare hazard ratios (HRs) for progression-free survival (the primary outcome), and to compare odds ratios (ORs) for the proportion of patients achieving an overall response (the secondary outcome). All treatments were compared to anastrozole and to palbociclib plus letrozole. This study is registered in the Open Science Framework online public database, registration DOI 10.17605/OSF.IO/496VR.. We identified 2689 published results and 140 studies (comprising 50 029 patients) were included in the analysis. Palbociclib plus letrozole (HR 0·42; 95% credible interval [CrI] 0·25-0·70), ribociclib plus letrozole (0·43; 0·24-0·77), abemaciclib plus anastrozole or letrozole (0·42; 0·23-0·76), palbociclib plus fulvestrant (0·37; 0·23-0·59), ribociclib plus fulvestrant (0·48; 0·31-0·74), abemaciclib plus fulvestrant (0·44; 0·28-0·70), everolimus plus exemestane (0·42; 0·28-0·67), and, in patients with a PIK3CA mutation, alpelisib plus fulvestrant (0·39; 0·22-0·66), and several chemotherapy-based regimens, including anthracycline and taxane-containing regimens, were associated with better progression-free survival than was anastrozole alone. No chemotherapy or hormone therapy regimen was significantly better than palbociclib plus letrozole for progression-free survival. Paclitaxel plus bevacizumab was the only clinically relevant regimen that was significantly better than palbociclib plus letrozole in terms of the proportion of patients achieving an overall response (OR 8·95; 95% CrI 1·03-76·92).. In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than standard hormone therapies in terms of progression-free survival. Moreover, no chemotherapy regimen with or without targeted therapy is significantly better than CDK4/6 inhibitors plus hormone therapies in terms of progression-free survival. Our data support treatment guideline recommendations involving the new combinations of hormone therapies plus targeted therapies as first-line or second-line treatments, or in both settings, in women with hormone-receptor-positive, HER2-negative metastatic breast cancer.. None.

Topics: Aminopyridines; Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bevacizumab; Breast Neoplasms; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Female; Fulvestrant; Humans; Letrozole; Network Meta-Analysis; Paclitaxel; Piperazines; Postmenopause; Progression-Free Survival; Purines; Pyridines; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone

Dysregulation of the cell cycle is a hallmark of cancer that leads to aberrant cellular proliferation. CDK4/6 are cyclin-dependent kinases activated in response to proliferative signaling, which induce RB hyper-phosphorylation and hence activation of E2F transcription factors, thus promoting cell cycle progression through the S phase. Pharmacologic inhibition of CDK4/6 by palbociclib, ribociclib, or abemaciclib has been showing promising activity in multiple cancers with the best results achieved in combination with other agents. Indeed, CDK4/6 inhibitors are currently approved in combination with endocrine therapy for the treatment of estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. Moreover, a number of clinical trials are currently underway to test the efficacy of combining CDK4/6 inhibitors with different drugs not only in breast but also in other types of cancer. Beyond the inhibition of cell proliferation, CDK4/6 inhibitors have recently revealed new effects on cancer cells and on tumor microenvironment. In particular, it has been reported that these agents induce a senescent-like phenotype, impact on cell metabolism and exert both immunomodulatory and immunogenic effects. Here we describe recent data on the anti-tumor effects of CDK4/6 inhibitors as single agents or in combined therapies, focusing in particular on their metabolic and immunomodulatory activities.

Topics: Aminopyridines; Animals; Antineoplastic Agents, Immunological; Benzimidazoles; Cell Cycle Checkpoints; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Immunomodulation; Neoplasms; Piperazines; Purines; Pyridines

Both palbociclib and abemaciclib are, oral, highly selective inhibitors of cyclin-dependent kinase 4 and 6, which are proteins involved in cell differentiation and growth. In pivotal phase III trials (PALOMA and MONARCH), they demonstrated a significant improvement in median progression-free survival in combination with a nonsteroidal aromatase inhibitor in the first-line, and with a fulvestrant in the second-line in hormone receptor-positive and HER2-negative metastatic breast cancer, respectively. Both palbociclib and abemaciclib were approved, however, ribociclib, the third cyclin-dependent kinase 4/6 inhibitor, has not been approved in Japan. The overall benefits from palbociclib and abemaciclib seem to be equivalent. Subsets analyses suggest that clinical benefits of palbociclib are associated with bone-only disease at baseline, no measurable disease, sensitive to previous endocrine therapy and longer disease-free interval. In contrast, additional benefits from abemaciclib in combination with nonsteroidal aromatase inhibitor or fulvestrant seem to have a relationship with visceral disease, liver metastasis, primary resistant to endocrine therapy, and short treatment-free interval. Abemaciclib induces senescence and apoptosis more than palbociclib does in a time-dependent manner and has potential to produce tumor shrinkage by single use. Neutropenia is more frequent in palbociclib, in contrast, diarrhea, nausea, and liver dysfunction are frequent in abemaciclib. In this review, we provide an overview of the two kinds of cyclin-dependent kinase 4/6 inhibitor, which were already approved in Japan. These differences might be useful information for the proper use in daily practice.

Topics: Aminopyridines; Antineoplastic Agents; Apoptosis; Aromatase Inhibitors; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Fulvestrant; Humans; Japan; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

Cyclin-dependent kinase 4/6 inhibitors, which act by inhibiting progression from the G1 to S phases of the cell cycle, include palbociclib, ribociclib, abemaciclib, and trilaciclib. Palbociclib and ribociclib are currently food and drug administration-approved for use in combination with aromatase inhibitors in postmenopausal women with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Palbociclib is also food and drug administration-approved for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Abemaciclib is the newest cyclin-dependent kinase 4/6 inhibitor to gain Food and Drug Administration (FDA) approval, specifically as monotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer previously treated with chemotherapy and endocrine therapy. Abemaciclib also shares a similar indication with palbociclib for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Trilaciclib use remains largely investigational at this time. However, despite FDA-approval for only metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, all four cyclin-dependent kinase 4/6 inhibitors have shown promise in hematologic malignancies and non-breast solid tumors. Although further research is needed, cyclin-dependent kinase 4/6 inhibitors represent intriguing developments in the treatment of various malignancies, including those with such poor prognoses as glioblastoma multiforme, mantle cell lymphoma, and metastatic melanoma. We discuss the approved indications, current research, and areas of future exploration for palbociclib, ribociclib, abemaciclib, and trilaciclib.

Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Forecasting; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptor, ErbB-2; Treatment Outcome

Despite the recent advances in breast cancer early detection and awareness, a significant portion of patients present with an advanced-stage disease and more patients will progress to stage IV despite adequate treatment of their initial early-stage disease. Hormone receptor (HR)-positive, Human Epidermal Growth Factor Receptor-2 (HER2)-negative subtype is the commonest among all breast cancer subtypes. The management of the advanced-stage disease of this subtype has evolved significantly over the past few years. The emergence of estrogen receptor down regulators (fulvestrant), mTOR-inhibitors and the recent introduction of CDK4/6 inhibitors, like palbociclib, abemaciclib and ribociclib, has resulted in a significant and a historical improvement in treatment outcomes. In this paper, we review many of the recently reported clinical trials that led to the approval of these new drugs in the first-line settings, along with the current international guidelines.

Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Female; Fulvestrant; Humans; Neoplasm Staging; Piperazines; Purines; Pyridines; Receptor, ErbB-2

To evaluate the existing literature regarding the use of cyclin-dependent kinase (CDK) 4/6 inhibitors in the treatment of hormone receptor-positive advanced breast cancer (ABC).. A search of the medical literature was performed using PubMed (2014 to June 2018). Search terms included cyclin-dependent kinase, CDK, breast cancer, palbociclib, ribociclib, abemaciclib, PD0332991, LEE011, and LY2835219. Clinicaltrials.gov was also searched.. Trials with clinical efficacy outcomes evaluating CDK 4/6 inhibitors in the treatment of advanced hormone-positive breast cancer were considered.. Palbociclib, abemaciclib, and ribociclib each demonstrated significant benefit when combined with an aromatase inhibitor, the benefit to patients was similar for each, with an improvement of 42% to 51% in median progression-free survival (PFS). In combination with fulvestrant, CDK 4/6 inhibitors used for the treatment of hormone receptor-positive ABC resulted in a 43% to 58% improvement in median PFS versus fulvestrant alone. CDK inhibitors are relatively well tolerated; however, discontinuation as a result of adverse effects was highest with abemaciclib. Relevance to Patient Care and Clinical Practice: This review considers the use of the 3 commercially available CDK 4/6 inhibitors for treatment of hormone receptor-positive breast cancer, including data on each of the 3 agents in newly advanced and treatment refractory disease.. The CDK inhibitors should be used in combination with endocrine therapies for the treatment of ABC. Efficacy of the 3 agents is similar. Selection within the class should include consideration of adverse effects and drug interactions.

Topics: Aminopyridines; Aromatase Inhibitors; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Disease Progression; Female; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptor, ErbB-2

Metastatic or advanced breast cancer (mBC/ABC) remains incurable despite many different systemic treatment options. Hormone receptor positive (HR+) disease represents the most common subtype in both early and advanced disease. A better understanding of the biology of this BC subtype, in particular regarding potential mechanisms of endocrine resistance, has led to the development of CDK4/6 inhibitors. All three selective CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib have shown to significantly improve progression-free survival (PFS) when combined to endocrine therapy as first-line treatment for patients with HR+/HER-2 negative ABC, who have progressed on or after adjuvant endocrine therapy. All three of them have also shown an improved PFS as 2nd line therapy for HR+/Her2 negative ABC. Their toxicity profile is favorable, with hematological toxicity (mainly neutropenia) being predominant, followed by diarrhea and fatigue. Quality of life has been maintained in the 1st line setting or improved in the 2nd line setting. Overall survival (OS) has been reported so far only in 2 out of 7 trials as first line therapy and the difference did not reach statistical significance. In this article we review the biology of CDK signaling pathway and its inhibitors, preclinical and clinical data of all three investigated selective CDK4/6 inhibitors and their toxicity. We also discuss how these agents are being included in current international guidelines and future directions for these agents in other subtypes of breast cancer, in both advanced disease and early-stage disease.

Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Molecular Targeted Therapy; Piperazines; Progression-Free Survival; Protein Kinase Inhibitors; Purines; Pyridines; Receptors, Estrogen; Receptors, Progesterone; Signal Transduction

Recently, new targeted agents have been developed, which can prolong the effect of endocrine treatment (ET) by targeting resistance pathways in HR+/HER2- advanced breast cancer. This review examines available studies of everolimus, an mTOR inhibitor, and the CDK 4/6 inhibitors ribociclib, palbociclib and abemaciclib in terms of efficacy, tolerability and safety.. A systematic literature search was performed in Pubmed. Evaluation of the quality of the identified studies was based on selected elements from the GRADE guidelines.. The literature search yielded eight randomized trials that all presented a significant increase in the progression free survival (PFS)/time to progression (TTP) for the targeted agents plus ET vs ET only. The improvement was evident as first-line therapy with an increase in PFS of 10-11 months when adding a CDK4/6 inhibitor to ET, as well as in patients previously treated for metastatic disease, with an increase of 5-6 months. The common adverse events (AEs) of the CDK 4/6 inhibitors were due to myelosuppression. In addition, abemaciclib was associated with liver toxicity and diarrhea, and ribociclib with liver toxicity and QTcF prolongation. The most common grade 3/4 AE of everolimus was stomatitis. The majority (five) of the trials had no serious limitations, and thus the quality of evidence was high.. The new targeted agents are all associated with an improvement of the PFS with an acceptable tolerability, and they should be offered to women with advanced HR+/HER2- breast cancer both as first-line therapy as well as among patients previously treated in metastatic regimens. However, further data regarding the impact on overall survival are required to evaluate the full benefit for patients. Price and differences in AEs could become substantial arguments for the choice of therapy for the individual patient.

Topics: Aminopyridines; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Disease Progression; Drugs, Investigational; Everolimus; Female; Humans; Molecular Targeted Therapy; Piperazines; Purines; Pyridines; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Cytoplasmic and Nuclear; Treatment Outcome

Adding cyclin-dependent kinase (CDK) 4/6 inhibitor to endocrine therapy improves progression-free survival (PFS) in advanced breast cancer but the impact of ethnicity on efficacy and toxicity is unclear. We aimed to estimate the relative treatment efficacy and toxicity of endocrine therapy with and without CDK4/6 inhibitors, and compare between Asian/non-Asian subgroups.. This meta-analysis included published first-line randomized trials comparing CDK4/6 inhibitor-endocrine therapy versus endocrine monotherapy. Hazard ratios (HR) and 95% confidence intervals (CI) for the overall population and Asian/non-Asian subgroups were extracted. The inverse-variance-weighted method was used to pool treatment estimates of PFS.. Four trials (N = 2499) were included. Patients received combination CDK4/6 inhibitor-endocrine therapy (N = 1441; ribociclib, [46.4%]; palbociclib, [30.8%]; or abemaciclib, [22.8%]) versus endocrine monotherapy (N = 1058). CDK4/6 inhibitor-endocrine therapy was associated with prolonged PFS compared with endocrine monotherapy (HR 0.56; 95% CI 0.50-0.62). In Asians (N = 492), PFS HR was 0.39 (95% CI 0.29-0.51, P < 0.0001). In non-Asians (N = 2007), PFS HR was 0.62 (95% CI 0.54-0.71, P < 0.0001). There was a significant treatment-by-ethnicity interaction (P = 0.002). Toxicity data by ethnic subgroup were only available from two trials (n = 1334) with no convincing evidence that the risk of toxicity between CDK4/6 inhibitor-endocrine therapy and endocrine monotherapy varied by ethnicity.. Adding CDK4/6 inhibitor to endocrine therapy prolongs PFS compared to endocrine therapy alone as first-line treatment in advanced breast cancer. The magnitude of PFS benefit is ethnicity-dependent but there is no interethnic differences in relative treatment-related toxicities. These findings may assist in the design and interpretation of trials, inform economic analyses, and stimulate pharmacogenomic research.

Topics: Aminopyridines; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Asian People; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Progression-Free Survival; Protein Kinase Inhibitors; Purines; Pyridines

Several trials have demonstrated the benefit of anti-CDK4/6 inhibitors plus endocrine therapy in estrogen receptor-positive (ER+) advanced breast cancer (BC), in first or subsequent lines of therapy. However, due to the lack of direct/indirect comparisons, there are no data demonstrating the superiority of one drug over the other. We compared the effectiveness of palbociclib, ribociclib, and abemaciclib in advanced ER + BC via an indirect adjusted analysis.. We performed electronic searches in the PubMed, EMBASE, and Cochrane databases for prospective phase 3 randomized trials evaluating anti-CDK4/6 inhibitors plus endocrine agents. We compared the results with an adjusted indirect analysis of randomized-controlled trials. Outcomes of interest were progression-free survival (PFS), overall response rate (ORR) and G3-4 toxicities occurring in ≥ 5% of patients.. Six trials and six treatment arms including a total of 3743 participants, were included. For PFS and ORR analysis, the three agents were similar in both first- and second-line studies. All G3-4 toxicities were similar, with reduced risk of diarrhea for palbociclib versus abemaciclib (relative risk [RR] 0.13, 95% CI 0.02-0.92; P = 0.04) and of QTc prolongation for palbociclib versus ribociclib (RR 0.02, 95% CI 0-0.83; P = 0.03). Despite different inclusion criteria and length of follow-up, similar features were noticed among second-line studies with the exception of increased risk of anemia G3-4 and diarrhea G3-4 for abemaciclib.. Based on PFS and ORR results of this indirect meta-analysis, palbociclib, ribociclib, and abemaciclib are equally effective in either first- or second-line therapy for advanced ER + BC. They, however, ported different toxicity profiles.

Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Clinical Trials, Phase III as Topic; Female; Humans; Piperazines; Prospective Studies; Purines; Pyridines; Randomized Controlled Trials as Topic; Receptors, Estrogen; Survival Analysis; Treatment Outcome

The majority of patients with metastatic breast cancer (MBC) have hormone receptor-positive HER2-negative disease. For this subgroup, endocrine therapy is the key therapeutic option. Recently, therapeutic options have been expanded by introduction of the inhibitors of cyclin-dependent kinases 4/6 (CDK4/6i). Three compounds, palbociclib, ribociclib, and abemaciclib, have already been approved by the FDA for use together with endocrine therapy such as aromatase inhibitors (AIs) or fulvestrant; abemaciclib is also approved as a single agent. In the first-line setting, all three agents-together with an AI-substantially prolonged progression-free survival with a consistent hazard ratio of around 0.5 in all phase III trials. The data for second-line settings and beyond is also quite consistent, with again a substantial prolongation of progression-free survival demonstrated for fulvestrant together with palbociclib, ribociclib, or abemaciclib. Treatment with CDK4/6i is well tolerated and side effects are manageable. With palbociclib and ribociclib, hematological toxicities are most frequent. Abemaciclib has a lower incidence of neutropenia and a much greater incidence of all grades of diarrhea compared with other CDK4/6i, making diarrhea the key toxicity for abemaciclib. Patient quality of life is maintained under therapy and, particularly in later line settings, deterioration of quality of life is slowed down and symptoms such as pain are better controlled by CDK4/6i. Their consistent and clinically relevant efficacy makes these drugs an important improvement in our armamentarium against MBC and, potentially, ideal candidates in early breast cancer (EBC). This review summarizes the available clinical data for CDK4/6i and current research activities, particularly in EBC.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Randomized Controlled Trials as Topic

Several endocrine therapies are available for postmenopausal women with hormone receptor-positive (HR +) advanced breast cancer (ABC). Given the absence of direct comparisons between fulvestrant and cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with aromatase inhibitors (AIs), which are both used as standard first-line treatments for ABC, an indirect comparison using a network meta-analysis may be advantageous for decision making.. We performed a network meta-analysis to compare the efficacies of fulvestrant and CDK4/6is plus AIs as the first-line treatment of postmenopausal breast cancer patients.. In order to compare these treatments, we searched the PubMed, Cochrane Library, and EMBASE databases for randomized controlled trials of first-line endocrine treatment for advanced or metastatic breast cancer until October 2018. We included a total of 11 eligible trials with 5448 patients. The hazard ratios (HRs) for the efficacies of the different treatments were used as inputs in the network meta-analysis.. In the overall analysis, CDK4/6is plus AIs, including palbociclib plus letrozole, ribociclib plus letrozole, and abemaciclib plus nonsteroidal AI (letrozole or anastrozole), are all superior to 500 mg fulvestrant (HR = 0.50, 95% confidence interval [CI] 0.37-0.68; HR = 0.50, 95% CI 0.35-0.71; and HR = 0.49, 95% CI 0.34-0.71; respectively).. Within the limitations of this network meta-analysis, the comparison indicates that CDK4/6is plus AIs might represent a better option for HR+ ABC as a first-line endocrine treatment compared with fulvestrant.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biomarkers, Tumor; Breast Neoplasms; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Fulvestrant; Humans; Letrozole; Network Meta-Analysis; Piperazines; Purines; Pyridines; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone

The pharmacology, clinical activity, safety, and place in therapy of the cyclin-dependent kinase (CDK) inhibitors palbociclib, ribociclib, and abemaciclib are reviewed.. CDK 4 and CDK 6 are downstream agents in the estrogen signaling pathway that control entry into the cell cycle. CDK4/6 inhibition may prevent tumor cell progression in the cell cycle. Three CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are available for women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. These medications' indications in the treatment of HR+/HER2- advanced breast cancer include use with an aromatase inhibitor (AI) as initial therapy in postmenopausal women and with fulvestrant in women whose disease progressed during endocrine therapy. Ribociclib is also indicated as initial therapy with an AI in premenopausal or perimenopausal women and as initial therapy with fulvestrant in postmenopausal women. Abemaciclib is also indicated as monotherapy in women with disease progression after endocrine therapy and prior chemotherapy. A significant increase in progression-free survival (PFS) was seen with use of all 3 agents as initial therapy with an AI in controlled trials. Each agent also was demonstrated to produce a significant increase in PFS when used with fulvestrant in women whose disease progressed with prior endocrine therapy. Neutropenia is a dose-limiting adverse effect of palbociclib and ribociclib. Fatigue is more common with use of palbociclib and abemaciclib, and gastrointestinal effects are more common with abemaciclib use.. CDK4/6 inhibitors have significant demonstrated clinical activity in combination with AIs or fulvestrant in women with HR+/HER2- advanced or metastatic breast cancer and are becoming a standard of care in these patients.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Dose-Response Relationship, Drug; Fatigue; Female; Gastrointestinal Diseases; Humans; Molecular Targeted Therapy; Neoplasm Staging; Neutropenia; Piperazines; Progression-Free Survival; Protein Kinase Inhibitors; Purines; Pyridines; Randomized Controlled Trials as Topic

Endocrine therapy is the mainstay of treatment for patients with estrogen receptor positive (ER+)/HER2-negative (HER2-) metastatic breast cancer (MBC). Many clinicians consider the sequential endocrine therapy is gold standard strategy because of better outcome and the maintenance of a better quality of life (QOL) for MBC patients. However, clinical practice shall be changed according to development of CDK4/6 inhibitor in current. CDK4/6 is key kinase which promote the cell cycle, and especially the expression of cyclin D1 and the activation of CDK4/6 to drive breast cancer proliferation. Currently positive data of several clinical trials using three CDK4/6 inhibitors (palbocilcib, ribociclib, abemaciclib) were published and primary endpoint were met in all phase III studies. Therefore, practice change of endocrine therapy has been achieved in ER positive MBC. This review will present clinical trial data, including both the efficacy and safety of CDK4/6 inhibitors for MBC, and describe the designs of the mainly ongoing clinical trials examining CDK4/6 inhibitors for the treatment of MBC and EBC.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptors, Estrogen

To compare the efficacy and toxicity of the combination of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and nonsteroidal aromatase inhibitors (AI) versus AI alone as first-line therapy for patients with advanced hormone receptor-positive breast cancer.. Phase III randomized clinical trials (RCT) were identified after a systematic review of electronic databases. A random-effect model was used to determine the pooled hazard ratio (HR) for progression-free survival (PFS) using the inverse-variance method. The Mantel-Haenszel method was used to calculate the pooled odds ratio (OR) for overall response, clinical benefit rate and treatment-related side effects. Heterogeneity was measured using the tau-squared and I. After a systematic search, three phase III RCT (n = 1827) were included. The use of CDK 4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) in combination with an AI was significantly associated with longer PFS compared to the use of letrozole or anastrozole alone (HR: 0.57; 95% CI 0.50-0.65; p < 0.00001), with no significant heterogeneity among trials. Similarly, overall response rate and clinical benefit rate were higher for patients who received the combination therapy than for patients allocated to AI alone. Grade 3 or higher treatment-related side effects were more frequently reported for patients who received CDK 4/6 inhibitors (OR: 7.51; 95% CI 6.01-9.38; p < 0.00001), these included mainly neutropenia, leukopenia and anemia.. The addition of CDK 4/6 inhibitors (either abemaciclib, palbociclib, or ribociclib) to an AI (anastrozole or letrozole) significantly improved PFS, overall response rate, and clinical benefit rate in comparison with a nonsteroidal AI alone.

Topics: Aminopyridines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Benzimidazoles; Breast Neoplasms; Clinical Trials, Phase III as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Postmenopause; Protein Kinase Inhibitors; Purines; Pyridines; Randomized Controlled Trials as Topic; Treatment Outcome

To determine which of the CDK4/6 inhibitors is the optimal treatment in metastatic luminal breast cancer.. A network meta-analysis using the frequentist approach and generalized pairwise modeling was computed.. The associations of aromatase inhibitor with ribociclib, palbociclib and abemaciclib were similar in efficacy. Palbociclib-based regimen was associated with significantly lower treatment discontinuation rates compared with the other approved drugs in this indication.. In the absence of direct comparative evidence, the results of this network meta-analysis represent the best available evidence for decision making in the first-line treatment of metastatic luminal breast cancer.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cell Cycle; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Purines; Pyridines

The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitors (CDK4/6i) induce cell cycle arrest in the G1 phase what eventually can prevent the proliferation of cancer cells. The CDK4/6i have changed the landscape of treatment options for ER-positive, HER2-negative metastatic breast cancer. Currently, palbociclib, ribociclib, and abemaciclib are approved by the US Food and Drug Administration in this setting. This success encouraged the researchers to examine CDK4/6i activity in (neo)adjuvant setting. In this review, clinical data to date and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in the early breast cancer are discussed. A literature search of these topics was carried out using PubMed and data reported at international oncology meetings and clinicaltrials.gov were included. Currently, we have the early promising data from Phase II clinical trials of CDK4/6i efficacy in the neoadjuvant setting in women with HR-positive breast cancer. Moreover, there are numerous studies that are in progress today in (neo)adjuvant setting.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptor, ErbB-2; Receptors, Estrogen

Dysregulation of the cyclin dependent kinase pathway in luminal breast cancer creates a new therapeutic opportunity for estrogen receptor positive breast cancer. Initial pan-CDK inhibitors were associated with extensive toxicities but in recent years, the development of potent specific CDK inhibitors with favorable tolerability has driven renewed interests in this class of targeted therapies. Palbociclib, ribociclib and abemaciclib are specific CDK4/6 inhibitors that have been approved by the U.S. Food and Drug Administration for use in combination with endocrine therapy for women with advanced hormone receptor positive breast cancer. These three anticancer therapeutics were approved based on progression free survival benefit seen on phase III trials with the most common grade 3 treatment-related side effects being neutropenia, fatigue, nausea and diarrhea. Except for estrogen receptor positivity, no biomarkers predictive of response to CDK4/6 inhibitors have been identified to date. Based on mechanistic insights here described, CDK4/6 inhibitors are currently being explored in combination with other agents, including targeted therapies, immunotherapy and chemotherapy.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

Deregulated cell division, resulting in aberrant cell proliferation, is one of the key hallmarks of cancer. Cyclin-dependent kinases (CDKs) play a central role in cell cycle progression in cancer, and the clinical development of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has changed clinical practice in the setting of endocrine-receptor positive breast cancer. Results of pivotal phase II and III trials investigating these CDK4/6 inhibitors in patients with endocrine receptor-positive, advanced breast cancer have demonstrated a significant improvement in progression-free survival, with a safe toxicity profile. No validated biomarkers of sensitivity or resistance exist at the moment. Future development of CDK4/6 inhibitors in breast cancer should focus on the identification of predictive biomarkers, the development of drug combinations to overcome resistance, and the application of CDK4/6 inhibitors to other breast cancer subtypes.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cell Proliferation; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Resistance, Neoplasm; Female; Humans; Molecular Targeted Therapy; Piperazines; Progression-Free Survival; Protein Kinase Inhibitors; Purines; Pyridines

Aberrant cellular proliferation due to dysregulation of the cyclin-dependent kinase (CDK) retinoblastoma (Rb)-pathway occurs in several cancers. Selective inhibition of CDK4/6 is an attractive target particularly in hormone-receptor positive (HR+) metastatic breast cancer (MBC), where it has transformed the treatment of these cancers in recent years. Three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved for the treatment of HR+, HER2 negative (HER2-) MBC. Areas covered: We reviewed and compared the pharmacology, clinical efficacy, and toxicity profiles of the three CDK4/6 inhibitors and discussed several challenges in the use of these drugs, particularly in identifying biomarkers, optimizing dosing strategies, and finding best combinations with other therapies. Expert opinion: All three CDK4/6 inhibitors have shown remarkable efficacy when added to endocrine therapy in the treatment of HR+/HER2- MBC with consistent improvements in progression-free survival across all phase III trials. As efficacy appears similar between the drugs, differences in toxicities, dosing schedule, and monitoring requirements may influence the choice of CDK4/6 inhibitor. There is a paucity of predictive biomarkers that have been identified thus far, but a few promising biomarkers have been studied in the preclinical setting and results of ongoing clinical studies are awaited to validate their utility.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzimidazoles; Biomarkers, Tumor; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Progression-Free Survival; Protein Kinase Inhibitors; Purines; Pyridines

Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapies have shown great promise in improving clinical outcomes for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer.. 1. Discuss the mode of action of the three CDK4/6 inhibitors in late clinical development: palbociclib (PD-0332991; Pfizer), ribociclib (LEE011; Novartis), and abemaciclib (LY2835219; Lilly). 2. Describe the efficacy and safety data relating to their use in HR+, HER2- advanced breast cancer. 3. Discuss the key side effects associated with CDK4/6 inhibitors along with considerations for adverse event management and patient monitoring.. Relevant information and data were assimilated from manuscripts, congress publications, and online sources.. CDK4/6 inhibitors have demonstrated improved progression-free survival in combination with endocrine therapy compared with endocrine therapy alone. The side-effect profile of each agent is described, along with implications for patient monitoring, and considerations for patient care providers and pharmacists.. Addition of a CDK4/6 inhibitor to endocrine therapy increases efficacy and delays disease progression. Insight into the unique side-effect profiles of this class of agents and effective patient monitoring will facilitate the successful use of CDK4/6 inhibitor-based therapies in the clinic.

Topics: Aminopyridines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Liver; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptor, ErbB-2; Transcription Factors

Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6), which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Food and Drug Administration has approved palbociclib and ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer, and recent clinical trial data suggest that palbociclib significantly improved clinical outcome when combined with letrozole or fulvestrant. Besides, the favorable effects of abemaciclib on prolonging survival of breast cancer patients have also been observed in clinical trials both for single-agent and combination strategy. In this review, we outline the preclinical and clinical advancement of these three orally bioavailable and highly selective CDK4/6 inhibitors in breast cancer.

Topics: Aminopyridines; Antineoplastic Agents, Immunological; Benzimidazoles; Breast Neoplasms; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Screening Assays, Antitumor; Female; Humans; Molecular Targeted Therapy; Neoplasm Proteins; Piperazines; Purines; Pyridines; Therapies, Investigational

Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates.. A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; "palbociclib", "abemaciclib", "ribociclib", "cyclin-dependent kinase inhibitors" and "CDK 4/6" in metastatic breast cancer (MBC). The last search was on 10 June 2017.. CDKs and cyclins are two molecules that have a key role in cell cycle progression. Today, there are three highly selective CDK4/6 inhibitors in clinical development - palbociclib, ribociclib and abemaciclib. Palbociclib and ribociclib were recently approved by the US FDA in combination with letrozole for the treatment of MBC in a first-line setting, as well as palbociclib in combination with fulvestrant for hormone-receptor (HR)-positive MBC that had progressed while on previous endocrine therapy according to the PALOMA-1, MONALEESA-2 and PALOMA-3 trials, respectively. In the recently published randomized phase III MONARCH 2 trial, abemaciclib plus letrozole had longer progression-free survival and higher objective response rates with less serious adverse events in advanced HR-positive breast cancer previously treated with hormonal treatment.. CDK4/6 inhibition is a new and promising target for patients with hormone-receptor-positive MBC. Both palbociclib and ribociclib showed significant additive benefit for patients receiving first-line treatment for HR-positive, epidermal growth factor receptor-2-negative advanced breast cancer. Palbociclib and abemaciclib also had significant activity in combination with fulvestrant for patients with MBC that progressed on previous endocrine therapy.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Disease-Free Survival; Estradiol; Female; Fulvestrant; Humans; Letrozole; Nitriles; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Randomized Controlled Trials as Topic; Triazoles

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

Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Interactions; Female; Humans; Molecular Targeted Therapy; Neutropenia; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway plays a crucial role in cell cycle progression and its dysregulation is an important contributor to endocrine therapy resistance. CDK4/6 inhibitors trigger cell cycle arrest in Rb protein (pRb)-competent cells. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising results of efficacy and manageable safety profiles. The main objective of this review is to discuss preclinical and clinical data to date, and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in breast cancer.. A literature search of above topics was carried out using PubMed and data reported at international oncology meetings and clinicaltrials.gov were included.. The highly selective oral CDK4/6 inhibitors have been tested in combination with endocrine therapy in Phase III studies in metastatic breast cancer. Results led to the US Food and Drug Administration approval of palbociclib (PD0332991) and ribociclib (LEE011), and abemaciclib (LY2835219) is in development. Studies of these agents, in combination with endocrine therapy, are also underway in ER-positive early breast cancer in the neoadjuvant and adjuvant settings. Moreover, they are also being investigated with other agents in the advanced setting and in triple negative breast cancer.. After having demonstrated impressive activity in ER-positive, HER2-negative metastatic breast cancer, currently CDK4/6 inhibitors are in further development. It is obvious that this class of agents with their efficacy, low and easily manageable toxicity, and oral dosage is a very important treatment option for breast cancer patients.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Biomarkers, Tumor; Breast Neoplasms; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Staging; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Randomized Controlled Trials as Topic; Treatment Outcome

A burst of recent activity has surrounded the study of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors for the treatment of metastatic breast cancer. The success of these drugs in the metastatic setting has pushed the evaluation of these agents in early-stage disease. The use of CDK 4/6 inhibitors as neoadjuvant and adjuvant therapy is a hot topic and several studies are underway.. Ongoing studies are exploring the addition of CDK 4/6 inhibitors to endocrine therapy in early breast cancer.. Identification of the optimal treatment combinations is the goal of current research. Finding biomarkers for patients' selection will be the goal of future research.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Neoadjuvant Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Randomized Controlled Trials as Topic

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinases; Estradiol; Female; Fulvestrant; Humans; Letrozole; Nitriles; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Estrogen; Risk Assessment; Triazoles

Dysregulated cellular proliferation, one of the hallmarks of cancer, is mediated by aberrant activation of the cell cycle machinery through the biological effects of cyclin-dependent kinases (CDKs). The clinical development of non-selective CDK inhibitors failed due to combined lack of efficacy and excessive toxicity reported by clinical trials across different cancer types. The clinical development of second generation, CDK4/6-selective inhibitors, namely palbociclib, abemaciclib and ribociclib, led to practice-changing results in the setting of breast cancer. Areas covered: This review illustrates how CDK4/6-selective inhibitors got approval for the treatment of patients with either newly diagnosed or pretreated advanced hormone receptor positive, HER2-negative breast cancer. Furthermore, data about potential predictive biomarkers, as well as preclinical and preliminary clinical evidence for potential antitumor activity of CDK4/6 inhibition in other breast cancer subtypes is provided. Expert opinion: Future clinical development of CDK4/6 inhibitors in breast cancer will focus on the following aspects: i) optimization of treatment sequencing for patients with advanced disease, ii) early-stage disease, iii) other subtypes of breast cancer in rationally chosen therapeutic combinations and iv) the identification of predictive biomarkers.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cell Proliferation; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Design; Female; Humans; Neoplasm Staging; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

Cyclin dependent kinase (CDK) 4/6 inhibitors have advanced the treatment of metastatic breast cancer by targeting the cell cycle machinery, interrupting intracellular and mitogenic hormone signals that stimulate proliferation of malignant cells. Preclinical evidence demonstrated that derangements of cyclin D1, CDK4/6, and retinoblastoma expression are common in breast cancer, and suggested a therapeutic benefit from interrupting this axis required for cell cycle progression. Studies of cell lines and animal models of breast cancer have demonstrated the complex interplay between the cell cycle and estrogen receptor and human epidermal growth receptor 2 signaling, which informs our understanding of synergistic use of CDK4/6 inhibitors with endocrine therapy, as well as mechanisms of resistance to endocrine therapy. Interestingly, estrogen receptor activity leads to upregulation of cyclin D1 expression, but the estrogen receptor is also in turn activated by cyclin D1, independent of estrogen binding. Early CDK inhibitors were nonspecific and limited by systemic toxicities, while the current generation of CDK4/6 inhibitors have shown promise in the treatment of hormone receptor-positive breast cancer. Preclinical investigations of the three CDK4/6 inhibitors approved by the US Food and Drug Administration (palbociclib, ribociclib, and abemaciclib) lend further insight into their mechanism of action, which will hopefully inform the future use and refinement of these therapies. Finally, we summarize evidence for additional novel CDK4/6 inhibitors currently in development.

Topics: Aminopyridines; Antineoplastic Agents, Hormonal; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Synergism; Humans; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptor, ErbB-2; Receptors, Estrogen

With 40,920 American women expected to die from breast cancer in 2018 and global health estimates that more than 508,000 women died in 2011 from this disease, the identification of novel therapeutic strategies for the treatment of breast cancer cannot be ignored. A breakthrough class of cancer drugs that has emerged in recent years and has had an impact in the treatment of breast cancer are the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, with palbociclib the first in class to have received regulatory approval for breast cancer. In this article we will compare and contrast three CDK4/6 inhibitors - palbociclib, ribociclib and abemaciclib - that have received regulatory approval for the treatment of metastatic breast cancer. Ribociclib and abemaciclib developed after the success of palbociclib represent examples of "me-too" therapies increasingly being deployed in oncology.

Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

For millions of women, breast cancer remains a potentially life-endangering diagnosis. With advances in research, new therapies targeted to tumor biology are emerging to treat the most common form of this disease. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of therapeutic agents that have the potential to improve the outcomes of patients with hormone receptor-positive (HR(+)) breast cancer. Three CDK 4/6 inhibitors have been investigated for the treatment of HR(+) breast cancer, including palbociclib (PD 0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Palbociclib recently received accelerated Food and Drug Administration approval for the treatment of HR(+) metastatic breast cancer in combination with letrozole, and recent data suggest improved outcome when combined with fulvestrant. In this article, the mechanism of action of CDK 4/6 inhibitors, preclinical studies on their efficacy, ongoing clinical trials in breast cancer, and toxicity profiles are reviewed.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

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

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cell Cycle; Clinical Trials as Topic; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Forecasting; Humans; Molecular Targeted Therapy; Neoplasms; Piperazines; Purines; Pyridines

Breast cancer remains a major cause of morbidity and mortality worldwide. Given the central role of cyclin-dependent kinases in regulating cell division, there has been a longstanding interest in developing compounds which target the cyclin D1: CDK4/6 axis in breast cancer. The recent discovery of potent and selective CDK4/6 inhibitors (CDK4/6i) was an important breakthrough.. There are three CDK4/6i in clinical development (palbociclib, ribociclib and abemaciclib). Phase II and III studies using palbociclib in combination with endocrine therapy demonstrated remarkable clinical activity in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, resulting in two separate FDA approvals in 2015 and 2016. In this article, we review the preclinical and clinical development of these compounds as well as discussing the role for novel applications of these agents outside the arena of HR-positive, HER2-negative advanced breast cancer.. In combination with endocrine therapy, CDK4/6i have shown promising efficacy in patients with advanced HR-positive, HER2-negative advanced breast cancer. Numerous trials in a variety of clinical settings and in different tumor types are ongoing or planned.

Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptor, ErbB-2

Dysregulation of the cell cycle is a classic hallmark of cancer growth and metastatic potential. Re-establishing cell cycle control through CDK inhibition has emerged as an attractive option in the development of targeted cancer therapy. Three oral agents selectively targeting CDK4/6 have been developed: palbociclib, abemaciclib, and LEE011. Preclinical models show optimal activity in hormone receptor positive breast cancer, which may display biologic features suggesting particular dependence on the CDK4/cyclin D1/Rb interaction. Palbociclib has been studied in a randomized phase 2 clinical trial in metastatic hormone receptor positive breast cancer in which the combination of palbociclib and endocrine therapy significantly prolonged progression-free survival over endocrine therapy alone. The toxicity profile of palbociclib and the other CDK 4/6 inhibitors in early phase I and II trials has been predominantly hematologic, characterized by limited neutropenia, as well as variable gastrointestinal toxicity. Multiple phase II and III studies are ongoing with all three agents, and are designed to explore the role of CDK 4/6 inhibition in metastatic hormone receptor positive breast cancer. The next wave of studies will examine further clinical and scientific topics, including the role of CDK 4/6 inhibition in the neo/adjuvant setting, the combination of CDK 4/6 inhibitors with other targeted therapies, and the activity of CDK 4/6 inhibitors in the HER2 positive subset of breast cancer, as well as in other cancer subtypes. Should ongoing study confirm benefits and tolerability of CDK 4/6 inhibition, combination therapy with endocrine agents may become a new standard of care for hormone receptor positive breast cancer.

Topics: Aminopyridines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

CDK 4/6 inhibitors have given patients with estrogen receptor (ER)-positive/HER2-negative (ER+/HER2ࢤ) advanced metastatic breast cancer important new therapeutic options. Abemaciclib is different to the other two licensed and approved CDK 4/6 inhibitors, palbociclib and ribociclib, both in dosing schedule (continuous vs intermittent) and toxicity profile (less neutropenia, more diarrhea), yet the magnitude of clinical benefit seen in first- and second-line studies is very similar. One of the key issues for clinicians is when to use these therapies. Ultimately, the biggest impact of abemaciclib could be in the adjuvant setting if the current MONARCH-E trial in high-risk node-positive patients is positive. The emerging biomarker work in the early breast cancer setting (i.e., neoMONARCH) may determine which tumors are most sensitive to abemaciclib.

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Evaluation; Female; Follow-Up Studies; Humans; Mice; Molecular Targeted Therapy; Neoplasm Metastasis; Piperazines; Prognosis; Purines; Pyridines; Receptors, Estrogen; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib were approved by the U.S. Food and Drug Administration (FDA) and European Medicine Agency for the treatment of breast cancer between 2015 and 2018. Oral tumor therapeutics extend the options for cancer therapy, but also challenge physicians and patients. The aim of the present work was to establish a semi-automated liquid-chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of abemaciclib, its active metabolites abemaciclib M20 and M2, palbociclib, and ribociclib in human serum. Detuning of ribociclib enabled the development of a simultaneous quantification method for abemaciclib, M20, M2, palbociclib, and ribociclib in the respective relevant concentration ranges based on semi-automated sample preparation with isotope dilution LC-MS/MS. The method was validated according to the guidance of the FDA. The LC-MS/MS method was successfully validated according to FDA and showed inaccuracies ≤ 10.7% and imprecisions ≤ 8.51%. Linearity was given from 20 to 800 ng/mL for abemaciclib, 15-600 ng/mL for M20, 10-400 ng/mL for M2 and palbociclib, and 100-4000 ng/mL for ribociclib. Normalized matrix factors and process efficiency showed no significant matrix effects regardless of the analytes. To demonstrate the applicability of the method, authentic samples were also analyzed. This novel semi-automated LC-MS/MS method covering all previously approved CDK4/6 inhibitors as well as the similarly pharmacologically active metabolites in human serum simultaneously was developed for potential future use in routine analysis in order to improve personalized therapy, patient safety, and treatment success.

Topics: Aminopyridines; Breast Neoplasms; Chromatography, Liquid; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Monitoring; Female; Humans; Protein Kinase Inhibitors; Tandem Mass Spectrometry

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, palbociclib, ribociclib, and abemaciclib, are standard-of-care agents for patients with hormone receptor-positive human epidermal growth factor receptor 2-negative metastatic breast cancer. In support of therapeutic drug monitoring and clinical pharmacokinetic studies, a liquid chromatography coupled with tandem mass spectrometry assay for the simultaneous quantitation of CDK4/6 inhibitors and the major active metabolite M2 of abemaciclib in human plasma has been developed.. Analytes were extracted from 50 μL of human plasma by precipitating proteins with methanol and then collecting the supernatant. Reversed-phase high-performance liquid chromatography was performed for analyte separation using a biphasic gradient at a flow rate of 0.25-0.5 mL/min. The total run time was 9.5 minutes. The analytes were detected using MS/MS with electrospray ionization operating in positive ion mode.. Validation according to the US Food and Drug Administration's guidance showed that the new assay produced accurate (94.7%-107%) and precise (within-run: 1.2%-8.2%; between-run: 0.6%-7.5%) measurements of all analytes over a concentration range of 5-2000 ng/mL. Overall, analyte recoveries were consistent (mean values: 110%-129%). The analytes were also stable in human plasma and the final extract under various storage conditions. Finally, the clinical applicability of the assay was confirmed by quantitation of all analytes in plasma samples obtained from patients treated with CDK4/6 inhibitors. Reproducibility of the measured analyte concentrations in study samples was confirmed successfully by incurred sample reanalysis.. A sensitive liquid chromatography coupled with tandem mass spectrometry method to measure CDK4/6 inhibitors was developed and validated according to the Food and Drug Administration criteria. Quantitation of all analytes in clinical plasma samples confirmed that the assay is suitable for therapeutic drug monitoring and clinical pharmacokinetic studies of CDK4/6 inhibitors.

Topics: Chromatography, Liquid; Cyclin-Dependent Kinase 4; Humans; Reproducibility of Results; Tandem Mass Spectrometry

This study found that CDK4/6 inhibitors rapidly reached many eligible patients with metastatic breast cancer and were adopted gradually over time in the Netherlands. Adoption of innovative medicines may be further optimized, and better transparency of the availability of new medicines during different phases of the postapproval access pathway is needed.. This cohort study reviewed approval and reimbursement decisions of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib and estimated the number of patients with metastatic breast cancer who were eligible for these medicines compared with the actual use in clinical practice. The study used nationwide claims data that were obtained from the Dutch Hospital Data. Claims and early access data for patients with hormone receptor-positive and ERBB2 (formerly HER2)-negative metastatic breast cancer who were treated with CDK4/6 inhibitors from November 1, 2016, to December 31, 2021, were included.. The number of new cancer medicines that are being approved by regulatory agents is increasing exponentially. Yet little is known about the pace at which these medicines reach eligible patients in daily clinical practice during different phases of the postapproval access pathway.. Description of the postapproval access pathway, monthly number of patients who were treated with CDK4/6 inhibitors in clinical practice, and estimated number of patients who were eligible for treatment. Aggregated claims data were used, and patient characteristics and outcomes data were not collected.. To describe the entire postapproval access pathway of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in the Netherlands, from regulatory approval to reimbursement and to investigate the adoption of these medicines in clinical practice among patients with metastatic breast cancer.. Three CDK4/6 inhibitors have received European Union-wide regulatory approval for the treatment of HR-positive and ERBB2-negative metastatic breast cancer since November 2016. In the Netherlands, the number of patients who have been treated with these medicines increased to approximately 1847 (based on 1 624 665 claims over the entire study period) from approval to the end of 2021. Reimbursement for these medicines was granted between 9 and 11 months after approval. While awaiting reimbursement decisions, 492 patients received palbociclib, the first approved medicine of this class, via an expanded access program. By the end of the study period, 1616 patients (87%) were treated with palbociclib, whereas 157 patients (7%) received ribociclib, and 74 patients (4%) received abemaciclib. The CKD4/6 inhibitor was combined with an aromatase inhibitor in 708 patients (38%) and with fulvestrant in 1139 patients (62%). The pattern of use over time appeared to be somewhat lower compared with the estimated number of eligible patients (1847 vs 1915 in December 2021), especially in the first 2.5 years after approval.

Topics: Breast Neoplasms; Cohort Studies; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Netherlands; Protein Kinase Inhibitors

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors improve progression-free survival when combined with endocrine therapies in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, the comparative cost effectiveness of utilizing three US Food and Drug Administration-approved CDK4/6 inhibitors is unknown. Therefore, we aimed to evaluate the cost effectiveness of individual CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) with letrozole versus letrozole monotherapy in the first-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in the USA.. We constructed a Markov-based decision-analytic model to evaluate the cost effectiveness of CDK4/6 inhibitors plus endocrine therapies over a 40-year lifetime from a third-party payer perspective. The model incorporated health states (progression-free disease, progressive disease, and death), major adverse events (neutropenia), and cancer-specific and all-cause mortality. Using clinical efficacy and quality-of-life scores (utility) data from clinical trials, we estimated quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios using Medicare charges reported in US dollars per 2022 valuation and a discount rate of 3% applied to costs and outcomes. We performed deterministic and probabilistic sensitivity analyses to evaluate parametric and decision uncertainty.. Compared to letrozole, the model estimated an increase of 5.72, 5.87, and 6.39 in QALYs and costs of $799,178, $788,168, and $741,102 in combining palbociclib, ribociclib, and abemaciclib plus letrozole, respectively. Palbociclib or ribociclib plus letrozole were dominated by abemaciclib plus letrozole. Compared with letrozole, abemaciclib plus letrozole resulted in an incremental cost-effectiveness ratio of $457,538 per QALY with an incremental cost of $553,621 and an incremental QALY gain of 1.21. The results were sensitive to the cost of abemaciclib, disease progression utility, and patients' age.. At a willingness to pay of $100,000/QALY gained, our model predicts that combining CDK4/6 inhibitors plus letrozole is not cost effective with a marginal increase in QALYs at a high cost. Lowering the cost of these drugs or identifying patients who can receive maximal benefit from CDK4/6 inhibitors would improve the value of this regimen in patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cost-Effectiveness Analysis; Cyclin-Dependent Kinase 4; Female; Humans; Letrozole; Medicare; Postmenopause; Receptor, ErbB-2; United States

CDK4/6 inhibitors (ribociclib, palbociclib and abemaciclib) are 1st line therapy in metastatic breast cancer (MBC). No comparative data exists between agents regarding toxicity or efficacy.. A retrospective study was performed at our tertiary referral centre evaluating patients on a CDK4/6 inhibitor for MBC between July 2017 and December 2021. Toxicity was evaluated along with variability in full blood counts and liver function over the first 12 weeks of therapy.. Two hundred and seventeen patients were treated (palbociclib 59%, abemaciclib 25% and ribociclib 16%). 86% received the agent as 1st line therapy. Most patients were white women with a median age of 61 years (32-95) and ECOG 0/1. Twelve patients were switched to an alternative CDK4/6 inhibitor due to toxicity and two did not tolerate this. Toxicity profiles of agents were consistent with published trials. However, there was greater overlap in hepatitis, diarrhoea and bone marrow suppression. Blood results indicated a minimum of four weeks treatment before development of neutropenia. Forty percent of patients went onto have subsequent lines of therapy. The progression-free survival per agent was palbociclib 27.9 months (95% CI 23-32.5), ribociclib 29 months (95% CI 21.5-37.0) and abemaciclib 20.6 months (95% CI 15.0-26.0). The overall survival was palbociclib 38.0 months (95% CI 33.5-42.5), ribociclib 33.9 months (95% CI 26.7-41.1) and abemaciclib 27.3 months (95% CI 22.5-32.1).. Toxicity across CDK4/6 inhibitors overlaps. The optimal sequence of therapies post CDK4/6 inhibitors remains unknown but rechallenge with an alternative agent is possible.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Cyclin-Dependent Kinase 4; Female; Humans; Middle Aged; Protein Kinase Inhibitors; Retrospective Studies

By the end of 2020, there were more than 8 million women alive who had received a breast cancer diagnosis in the previous 5 years, making it the most prevalent neoplasia in the world. About 70% of breast-cancer cases present positivity for estrogen and/or progesterone receptors and a lack of HER-2 overexpression. Endocrine therapy has traditionally been the standard of care for ER-positive and HER-2-negative metastatic breast cancer. In the last 8 years, the advent of CDK4/6 inhibitors has shown that adding them to endocrine therapy doubles PFS. As a result, this combination has become the gold standard in this setting. Three CDK4/6 inhibitors have been approved by the EMA and the FDA: abemaciclib, palbociclib, and ribociclib. They all have the same indications, and it is at each physician's discretion to choose one or the other. The aim of our study was to perform a comparative efficacy analysis of the three CDK4/6i using real-world data. We selected patients diagnosed with endocrine-receptor-positive and HER2-negative breast cancer who were treated with all three CDK4/6i as first-line therapy at a reference center. After 42 months of retrospective follow up, abemaciclib was associated with a significant benefit in terms of progression-free survival in endocrine-resistant patients and in the population without visceral involvement. In our real-world cohort, we found no other statistically significant differences among the three CDK4/6 inhibitors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Protein Kinase Inhibitors; Retrospective Studies

Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) has been associated with drugs with different mechanisms of action, including anti-hypertensives, tumour necrosis factor-α inhibitors and even some chemotherapy medicines. In the last years, a few reports have been described in patients treated with cyclin-dependent kinase (CDK) 4/6 inhibitors, palbociclib and abemaciclib.. Here, we describe a case of DI-SCLE in association with ribociclib and exemestane in a woman diagnosed with metastatic breast cancer.. Topical mometasone was prescribed for two weeks with complete resolution of lesions, also abemaciclib was substituted for ribociclib, and the patient had stable disease with no relapse of DI-SCLE.. To our knowledge, this is the first report of ribociclib-induced SCLE but based on the DI-SCLE reported cases associated others CDK4/6 inhibitors, the role of this family of drugs in dermatopathology must be further investigated.

Topics: Breast Neoplasms; Female; Humans; Lupus Erythematosus, Cutaneous; Neoplasm Recurrence, Local

The CDK4/6 inhibitors (CDKi) palbociclib, ribociclib, and abemaciclib are currently approved in combination with anti-estrogen therapy for the treatment of advanced and/or metastatic hormone receptor-positive/HER2-neu-negative breast cancer patients. Given the high incidence of bone metastases in this population, we investigated and compared the potential effects of palbociclib, ribociclib, and abemaciclib on the breast cancer bone microenvironment. Primary osteoclasts (OCs) and osteoblasts (OBs) were obtained from human monocyte and mesenchymal stem cells, respectively. OC function was evaluated by tartrate-resistant acid phosphatase assay and real-time PCR; OB activity was assessed by an alizarin red assay. OB/breast cancer co-culture models were generated via the seeding of MCF-7 cells on a layer of OBs, and tumor cell proliferation was analyzed using flow cytometry. Here, we showed that ribociclib, palbociclib, and abemaciclib exerted similar inhibitory effects on the OC differentiation and expression of bone resorption markers without affecting OC viability. On the other hand, the three CDKi did not affect the ability of OB to produce bone matrix, even if the higher doses of palbociclib and abemaciclib reduced the OB viability. In OB/MCF-7 co-culture models, palbociclib demonstrated a lower anti-tumor effect than ribociclib and abemaciclib. Overall, our results revealed the direct effects of CDKi on the tumor bone microenvironment, highlighting differences potentially relevant for clinical practice.

Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor Proteins; Female; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Tumor Microenvironment

Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin-proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins.. We performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts.. We uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C.. Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.

Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Hormones; Humans; Phosphatidylinositol 3-Kinases; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; Purines; RNA, Messenger; Ubiquitin-Conjugating Enzymes; Ubiquitins

Topics: Aminopyridines; Benzimidazoles; Cyclin-Dependent Kinase 4; Electrophoresis, Capillary; Pharmaceutical Preparations; Protein Kinase Inhibitors

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Brain; Brain Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

Lay abstract Palbociclib (PAL), ribociclib (RIB) and abemaciclib (ABM) are used with fulvestrant to treat hormone receptor-positive, HER2-negative advanced breast cancer. This study aims to use data from clinical trials to compare how long patients live after starting treatment with PAL versus RIB and ABM. Since patients who enroll in different trials may have different characteristics, it is important to adjust for these differences for a more accurate comparison. Adjusting for these differences showed that patients with hormone receptor-positive, HER2-negative advanced breast cancer treated with PAL lived for a similar length of time compared with those treated with RIB or ABM.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Humans; Piperazines; Purines; Pyridines; Receptor, ErbB-2

Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy.. In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor.

Topics: Aminopyridines; Animals; Benzimidazoles; Carcinoma, Hepatocellular; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Hep G2 Cells; Humans; In Vitro Techniques; Liver Neoplasms; Liver Neoplasms, Experimental; Mice; Neoplasm Transplantation; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Retinoblastoma Protein; Tumor Suppressor Protein p53; Xenopus Proteins

The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the standard treatment for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. Data about the balance between efficacy and toxicity of combined palliative radiotherapy (RT) and CDK4/6 inhibition are lacking.. We undertook a review of 46 patients with metastatic breast cancer on systemic treatment with CDK4/6i who underwent 62 metastases-directed RT. Clinical, laboratory, and RT treatment planning data were collected. Statistical analyses included Student t test, paired sample t test, and logistic regression modeling.. Thirty patients (65.2%) received palbociclib, 15 (32.6%) received ribociclib, and one patient received abemaciclib (2.2%). Median total prescribed RT dose was 20 Gy (range, 8-63 Gy). Sites of RT were bone (n = 50; 80.7%), visceral (n = 7; 11.3%), or brain metastases (n = 3; 4.8%), as well as primary tumor of the breast (n = 2; 3.2%). Overall, the rates of grade 3 or higher adverse events (AEs) were 6.5%, 4.3%, 15.2%, and 23.9% before the start of RT, during RT, 2 and 6 weeks after RT completion, respectively. We found no correlation between dose distribution to organs at risk and the development of AEs. The local control rates for the entire cohort were 98% at 6 months and 90% at 12 months. Overall, pain relief (complete or partial) was experienced by 80% (24/30) of patients who initially reported pain at the treated metastatic site.. We observed a modest increase in the rates of grade 3 or higher AEs after combined RT and CDK4/6i, with maintained efficacy of concomitant RT.

Topics: Adult; Aged; Aminopyridines; Benzimidazoles; Breast Neoplasms; Cancer Pain; Chemoradiotherapy; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Organs at Risk; Pain Measurement; Palliative Care; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Radiotherapy Dosage; Treatment Outcome

Cyclin-dependent kinase inhibitors (CDKIs) and endocrine therapy (ET) are the corner-stone of systemic therapy for patients with hormone-positive (HR+) HER2-negative metastatic breast cancer (MBC). However, limited data exist regarding rechallenge treatment strategies with CDKIs after limiting toxicity. In this report, we provide evidence of the safety and efficacy of sequential treatment with palbociclib or abemaciclib in 6 HR+/HER- MBC patients who experienced grade ≥3 ribociclib-induced hypertransaminasemia. Until results from large observational or randomized studies are communicated, empirical evidence may help make individualized decisions on CDKI rechallenge beyond ribociclib-induced unacceptable liver toxicity.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Substitution; Female; Humans; Middle Aged; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Transaminases; Treatment Outcome

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Lung Diseases; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

Recently three different cyclin-dependent kinase 4 and 6 (CDK4/6) dual inhibitors were approved for the treatment of breast cancer (palbociclib, ribociclib, and abemaciclib), all of which offer comparable therapeutic benefits. Their safety profiles, however, are different. For example, neutropenia is observed at varying incidences in patients treated with these drugs; however, it is the most common adverse event for palbociclib and ribociclib, whereas diarrhea is the most common adverse event observed in patients treated with abemaciclib. To understand the mechanism of diarrhea observed with these drugs and in an effort to guide the development of safer drugs, we compared the effects of oral administration of palbociclib, ribociclib, and abemaciclib on the gastrointestinal tract of rats using doses intended to produce comparable CDK4/6 inhibition. Rats administered abemaciclib, but not palbociclib or ribociclib, had fecal alterations, unique histopathologic findings, and distinctive changes in intestinal gene expression. Morphologic changes in the intestine were characterized by proliferation of crypt cells, loss of goblet cells, poorly differentiated and degenerating enterocytes with loss of microvilli, and mucosal inflammation. In the jejunum of abemaciclib-treated rats, downregulation of enterocyte membrane transporters and upregulation of genes associated with cell proliferation were observed, consistent with activation of the Wnt pathway and downstream transcriptional regulation. Among these CDK4/6 inhibitors, intestinal toxicity was unique to rats treated with abemaciclib, suggesting a mechanism of toxicity not due to primary pharmacology (CDK4/6 inhibition), but to activity at secondary pharmacologic targets.

Topics: Aminopyridines; Animals; Benzimidazoles; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Diarrhea; Disease Models, Animal; Gene Expression Regulation; Male; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Rats; Rats, Sprague-Dawley

Three Cyclin Dependent Kinase 4/6 (CDK) inhibitors have been approved by the United Stated Food and Drug Administration for front line treatment of advanced hormone receptor positive breast cancer based on improvements in progression free survival against endocrine monotherapy. Two clinical trials have so far reported results on overall survival but both are negative. CDK inhibitors are usually tolerated well but they do add to inconvenience and cost - for example, grade III-IV neutropenia occur at a frequency of over 60% requiring frequent blood work at least during the initial months of treatment. These drugs cost over $ 13,500 for a 4-week cycle in the United States, and are responsible for billions of dollars annually in drug cost alone. Importantly, many women with metastatic breast cancer do well for a long time with endocrine therapy alone and CDK inhibitors do not have a predictive marker. Selective use of these agents in later lines may improve substantially the convenience and cost without compromise in overall outcome. However, with results demonstrating impressive improvements in PFS published in major medical journals coupled with patients' natural desire for "best available" options, the trend among oncologists is to prescribe these drugs as the default front-line treatment. In this commentary I caution readers against over interpretation of results from the CDK inhibitor trials, describe adverse consequences of routine front-line use, and explain why selective use in later line may yield a higher value.

Topics: Aminopyridines; Antineoplastic Agents, Hormonal; Benzimidazoles; Breast Neoplasms; Cost-Benefit Analysis; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Costs; Female; Humans; Neutropenia; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptors, Estrogen; Receptors, Progesterone

Palbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) approved for the treatment of some cancers. The main mechanism of action of palbociclib is to induce cell cycle arrest and senescence on responsive cells. Here, we report that palbociclib concentrates in intracellular acidic vesicles, where it can be readily observed due to its intrinsic fluorescence, and it is released from these vesicles upon dilution or washing out of the extracellular medium. This reversible storage of drugs into acidic vesicles is generally known as lysosomal trapping and, based on this, we uncover novel properties of palbociclib. In particular, a short exposure of cells to palbociclib is sufficient to produce a stable cell-cycle arrest and long-term senescence. Moreover, after washing out the drug, palbociclib-treated cells release the drug to the medium and this conditioned medium is active on susceptible cells. Interestingly, cancer cells resistant to palbociclib also accumulate and release the drug producing paracrine senescence on susceptible cells. Finally, other lysosomotropic drugs, such as chloroquine, interfere with the accumulation of palbociclib into lysosomes, thereby reducing the minimal dose of palbociclib required for cell-cycle arrest and senescence. In summary, lysosomal trapping explains the prolonged temporal activity of palbociclib, the paracrine activity of exposed cells, and the cooperation with lysosomotropic drugs. These are important features that may help to improve the therapeutic dosing and efficacy of palbociclib. Finally, two other clinically approved CDK4/6 inhibitors, ribociclib and abemaciclib, present a similar behavior as palbociclib, suggesting that lysosomal trapping is a property common to all three clinically-approved CDK4/6 inhibitors.

Topics: Acridine Orange; Aminopyridines; Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Cellular Senescence; Chloroquine; Cyclin-Dependent Kinase 4; Cytokines; Fluorescent Dyes; Humans; Lysosomal Membrane Proteins; Lysosomes; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

Topics: Aminopyridines; Animals; Benzimidazoles; Carcinoma, Small Cell; Cell Line, Tumor; Cell Survival; Chromatin Immunoprecipitation; Cyclin D1; DNA Helicases; Female; Humans; Hypercalcemia; Mice; Mice, SCID; Nuclear Proteins; Ovarian Neoplasms; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; RNA, Small Interfering; Transcription Factors

A novel method was developed and validated for the quantification of the three approved CDK4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) in both human and mouse plasma and mouse tissue homogenates (liver, kidney, spleen, brain, and small intestine) using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). For all matrices, pretreatment was performed using 50 μL of sample by protein precipitation with acetonitrile, followed by dilution of the supernatant. Chromatographic separation of the analytes was done on a C18 column using gradient elution. A full validation was performed for human plasma, while a partial validation was executed for mouse plasma and mouse tissue homogenates. The method was linear in the calibration range from 2 to 200 ng/mL, with a correlation coefficient (r) ≥0.996 for each analyte. For both human and mouse plasma, the accuracy and precision were within ±15% and ≤15%, respectively, for all concentrations, except for the lower limit of quantification, where they were within ±20% and ≤20%, respectively. A fit-for-purpose strategy was followed for tissue homogenates, and the accuracy and precision were within ±20% and ≤20%, respectively, for all concentrations. Stability of all analytes in all matrices at different processing and storage conditions was tested; ribociclib and palbociclib were unstable in most tissue homogenates and conditions were modified to increase the stability. The method was successfully applied for the analysis of mouse samples from preclinical studies. A new ribociclib metabolite was detected in mouse plasma samples with the same m/z transition as the parent drug.

Topics: Aminopyridines; Animals; Benzimidazoles; Chromatography, Liquid; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Mice; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Tandem Mass Spectrometry

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Biomarkers, Tumor; Breast Neoplasms; Circulating Tumor DNA; Class I Phosphatidylinositol 3-Kinases; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Disease-Free Survival; Drug Resistance, Neoplasm; Estradiol; Female; Fulvestrant; Humans; Mutation; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Retinoblastoma Binding Proteins; Ubiquitin-Protein Ligases

The genes encoding MDM2 and CDK4 are frequently co-amplified in sarcomas, and inhibitors to both targets are approved or clinically tested for therapy. However, we show that inhibitors of MDM2 and CDK4 antagonize each other in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon MDM2 inhibition. Moreover, the p53 response was also attenuated when co-depleting MDM2 and CDK4 with siRNA, compared to MDM2 single knockdown. The complexes of p53 and MDM2, as well as CDK4 and Cyclin D1, physically associated with each other, suggesting direct regulation of p53 by CDK4. Interestingly, CDK4 inhibition did not reduce p53 binding or histone acetylation at promoters, but rather attenuated the subsequent recruitment of RNA Polymerase II. Taken together, our results suggest that caution must be used when considering combined CDK4 and MDM2 inhibition for patient treatment. Moreover, they uncover a hitherto unknown role for CDK4 and Cyclin D1 in sustaining p53 activity.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase 4; Humans; Piperazines; Proto-Oncogene Proteins c-mdm2; Purines; Pyridines; RNA Interference; RNA, Small Interfering; Sarcoma; Tumor Suppressor Protein p53

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Benzimidazoles; Breast Neoplasms; Carcinoma, Lobular; Colonic Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Letrozole; Middle Aged; Neoplasm Metastasis; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone

Molecularly targeted therapies aim to obstruct cell autonomous programs required for tumor growth. We show that mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 4/6 inhibitors act in combination to suppress the proliferation of KRAS-mutant lung cancer cells while simultaneously provoking a natural killer (NK) cell surveillance program leading to tumor cell death. The drug combination, but neither agent alone, promotes retinoblastoma (RB) protein-mediated cellular senescence and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). SASP components tumor necrosis factor-α and intercellular adhesion molecule-1 are required for NK cell surveillance of drug-treated tumor cells, which contributes to tumor regressions and prolonged survival in a KRAS-mutant lung cancer mouse model. Therefore, molecularly targeted agents capable of inducing senescence can produce tumor control through non-cell autonomous mechanisms involving NK cell surveillance.

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Cellular Senescence; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cytostatic Agents; Cytotoxicity, Immunologic; Humans; Immunologic Surveillance; Intercellular Adhesion Molecule-1; Killer Cells, Natural; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Purines; Pyridines; Pyridones; Pyrimidinones; Retinoblastoma Protein; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 CDK inhibitors are less potent than the INKs at displacing CDK4 and CDK6 from Cdc37. However, they cooperate with the D-type cyclins to generate CDK4/6-containing ternary complexes that are resistant to cyclin D displacement by Cdc37, suggesting a molecular mechanism to explain the assembly factor activity ascribed to CIP/KIP family members. Overall, our data reveal multiple mechanisms whereby the Hsp90 system may control formation of CDK4- and CDK6-cyclin complexes under different cellular conditions.

Topics: Adenosine Triphosphate; Aminopyridines; Benzimidazoles; Cell Cycle Proteins; Chaperonins; Cyclin D; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p27; Fluorescence Resonance Energy Transfer; HSP90 Heat-Shock Proteins; Humans; Inhibitory Concentration 50; Kinetics; Piperazines; Protein Binding; Purines; Pyridines; Surface Plasmon Resonance

The discovery of ATP competitive CDK4 inhibitors is an on-going challenging task in cancer therapy. Here, an attempt has been made to develop new leads targeting ATP binding site of CDK4 by applying 3D-QSAR pharmacophore mapping and molecular docking methods The outcome of 6 leads offers a significant contribution for selective CDK4 inhibition, since they show potential binding interactions with Val

Topics: Adenosine Triphosphate; Aminopyridines; Benzimidazoles; Binding Sites; Cyclin-Dependent Kinase 4; Drug Discovery; Humans; Molecular Docking Simulation; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Quantitative Structure-Activity Relationship

Dysregulation of cellular cycle is a key component of carcinogenesis and its targeting represents an interesting approach. Recently, the development of selective inhibitors of the cycle targeting the cyclin-dependent kinases (CDK) 4 and 6 revived interest in this therapeutic class after the failure of pan-inhibitors. Palbociclib, ribociclib, and abemaciclib are the 3 drugs with the most advanced development. They demonstrated preclinical activity in luminal breast cancer models and are under clinical evaluation. The first available studies demonstrate the value of these compounds with an improved prognosis of metastatic patients in combination with endocrine therapy (palbociclib, ribociclib) or in monotherapy (abemaciclib). The results of ongoing studies will clarify the role of these agents in our new strategies and the individualisation of biomarkers will help to define patients who benefit most from this approach.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cell Cycle; Cell Cycle Checkpoints; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Neoplasms, Hormone-Dependent; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Clinical Trials, Phase II as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; Receptors, Estrogen; Research; Treatment Outcome

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cell Cycle; Clinical Trials, Phase I as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Purines; Pyridines; Randomized Controlled Trials as Topic; ras Proteins; Receptors, Estrogen