Cyclin-dependent kinase 4/6 inhibitors for the management of advanced or metastatic breast cancer in women.

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.

Cersosimo RJ 《-》

Role of cyclin-dependent kinase 4/6 inhibitors in the current and future eras of cancer treatment.

Parylo S ，Vennepureddy A ，Dhar V ，Patibandla P ，Sokoloff A ... -  《-》

Clinical Management of Potential Toxicities and Drug Interactions Related to Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Practical Considerations and Recommendations.

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.

Spring LM ，Zangardi ML ，Moy B ，Bardia A ... -  《-》

Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: A network meta-analysis.

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.

Desnoyers A ，Nadler MB ，Kumar V ，Saleh R ，Amir E ... -  《-》

Differences of cyclin-dependent kinase 4/6 inhibitor, palbociclib and abemaciclib, in breast cancer.

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.

Tamura K 《-》