CDK4/6-Inhibitoren beim Mammakarzinom

The cyclin-dependent kinase (CDK)4/6 inhibitors palbociclib, ribociclib, and abemaciclib have demonstrated significant improvements in progression-free survival in numerous clinical trials in metastasized hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Since palbociclib and ribociclib were approved in Germany, CDK4/6 inhibitors in combination with antihormonal therapy have been a standard treatment in first- and also in second-line therapy. Abemaciclib, the third CDK4/6, inhibitor will be approved in Germany this year. Side effects, particularly neutropenia, are well managed in daily routine by dose reductions and dose interruptions. The necessary intensive treatment monitoring has to be adhered to precisely, in order to administer treatment in the form of a well-tolerated maintenance therapy. Several clinical trials in the neo-/adjuvant setting are currently in progress, in order to transfer the survival advantage from the metastasized situation into early breast cancer. The aim of this article is to elucidate the mode of action, efficacy, and side effects of the CDK4/6 inhibitors, and to put them in a current clinical context.     

CDK4/6 inhibition in early and metastatic breast cancer: A review

Breast cancer (BC) is responsible for 14% of cancer-related deaths in women [1]. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of selective drugs, offering an effective and tolerable treatment. CDK4/6 inhibitors induce cell cycle arrest in the G1 phase, and may thereby prevent tumour progression. Three CDK4/6 inhibitors have been tested in clinical BC trials: palbociclib, ribociclib, and abemaciclib. The Food and Drug Administration (FDA) and European Commission (EMA) have approved palbociclib for the treatment of patients HR+ HER2- locally advanced or metastatic BC (aBC) in combination with an aromatase inhibitor as initial therapy in postmenopausal women or in combination with fulvestrant in women who have received prior endocrine therapy. Ribociclib has been approved by the FDA in combination with an aromatase inhibitor as initial therapy for postmenopausal women with HR+ HER2- aBC. Moreover, CDK4/6 inhibitors have shown promising results in the (neo)adjuvant setting. In this review, the principal completed and ongoing clinical trials in aBC are reviewed for both the metastatic as (neo)adjuvant setting. Tables will provide a complete overview of the ongoing clinical trials. At last, the future perspectives of these CDK4/6 inhibitors are discussed.     

Racial disparities in neutrophil counts among patients with metastatic breast cancer during treatment with CDK4/6 inhibitors

Breast Cancer Research and Treatment - The three CDK4/6 inhibitors (CDK4/6i) approved for use in HR-positive/HER2-negative metastatic breast cancer (MBC), palbociclib, ribociclib, and abemaciclib,...     

CDK4/6 Inhibition as a therapeutic strategy in breast cancer: palbociclib,ribociclib, and abemaciclib

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.     

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

BackgroundPalbociclib, 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.MethodsWe 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.Results8 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.ConclusionsPalbociclib, 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.     

Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

Deregulation of the cyclin D-CDK4/6-INK4-RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle-specific mechanisms and cell cycle-nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.     

Clinical development of CDK4/6 inhibitor for breast cancer

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.     

The Role of CDK4/6 Inhibition in Breast Cancer

Imbalance of the cyclin D and cyclin‐dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D‐dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan‐CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptor‐positive (ER+) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion. We describe the application of such therapy to other breast cancer settings, including HER2‐positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double‐strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improving the outcomes of patients with ER+ breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting.     

Mechanisms of therapeutic CDK4/6 inhibition in breast cancer

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.     

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

Use of cyclin-dependent kinase (CDK) 4/6 inhibitors for hormone receptor-positive,human epidermal growth factor receptor 2-negative,metastatic breast cancer: a roundtable discussion by The Breast Cancer Therapy Expert Group (BCTEG)

Purpose

To provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2?), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community.

Methods

A recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice.

Results

Level 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with HR+, HER2?, mBC. Currently, there are no biomarkers that reliably define patients who will, or will not, benefit from the addition of a CDK 4/6 inhibitor to their endocrine therapy. Additional research is needed to identify the optimal sequencing of CDK 4/6 inhibitors in relation to other therapies as well as the optimal duration of therapy; at present, evidence suggests that use in the upfront setting is better than waiting for a later line of therapy, or adding after endocrine therapy has started.

Conclusions

Thus far, three CDK 4/6 inhibitors—palbociclib, ribociclib, and more recently, abemaciclib—have been approved for use in the setting of HR+, HER2?, mBC.  The degrees to which these agents differ in terms of CDK4/6 affinity, side-effect profiles, dosing, degree of central nervous system (CNS) penetration, optimal use in combination with antiestrogen therapy, and across other subsets of breast cancer, remain an active area of investigation.

     

Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes

In the cell cycle, the G₁/S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6 dysregulates G₁/S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G₁ phase in cancer cell lines, including A549 human non–small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell‐death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell‐death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar‐type ATPase (V‐ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live‐cell imaging revealed that the abemaciclib‐induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes.     

Palbociclib or Ribociclib in First-Line Treatment in Patients With Hormone Receptor–Positive/Human Epidermal Receptor 2–Negative Advanced or Metastatic Breast Cancer? A Perspective Based on Pharmacologic Costs

PurposeTo assess the pharmacologic costs of CDK4/6 inhibitors (palbociclib and ribociclib) in hormone receptor–positive (HR⁺)/human epidermal receptor 2–negative (HER2^?) advanced or metastatic breast cancer (BC). Pivotal phase 3 randomized controlled trials (RCTs) were considered.DiscussionTwo phase 3 RCTs including 1334 patients were considered. European Society for Medical Oncology Magnitude of Clinical Benefit Scale reached grade 3 for the PALOMA-2 and MONALEESA-2 trials. Pharmacologic costs of palbociclib and ribociclib at full dose were similar, at €3864 and €4002 per month of progression-free survival (PFS) gained, respectively. The reduction of dose of ribociclib (36.1% in the pivotal RCT vs. 36.0% of palbociclib in pivotal RCT) resulted in €2718 and €1348 per month of PFS gained at 400 and 200 mg daily, respectively.ConclusionWhen pharmacologic costs of drugs are combined with the measure of efficacy represented by PFS, both palbociclib and ribociclib are cost-effective first-line treatments in postmenopausal women with HR⁺/HER2^? advanced or metastatic BC, with a lower cost in favor of ribociclib in patients with dose reduction.     

Cyclin‐dependent kinase 4/6 inhibitors suppress tumor growth in extramammary Paget’s disease

Extramammary Paget’s disease (EMPD) is a rare adnexal neoplasm commonly seen in the genital areas among the senior population. The prognosis of advanced EMPD is not favorable; thus, the development of potential treatments has long been sought. Cyclin‐dependent kinase (CDK) 4/6 inhibitors such as abemaciclib and palbociclib have been proven effective against metastatic breast cancer; however, no studies have addressed CDK4/6 inhibitors as an EMPD treatment. We herein examine the efficacy of CDK4/6 inhibitors against an EMPD patient‐derived xenograft (PDX) model. Abemaciclib (50 mg/kg/day) or palbociclib (120 mg/kg/day) was given orally to tumor‐bearing NOD/Scid mice over a 3‐week period. We also investigated the protein expression levels of CDK4/6 and cyclin D1 through immunohistochemical staining using EMPD clinical samples. Treatment with abemaciclib or palbociclib as a single agent was found to significantly suppress tumor growth in EMPD‐PDX. The Ki‐67‐positive ratio of the treated EMPD‐PDX tumors was significantly lower than that of the nontreated tumors. Clinically, the expression levels of CDK4 and cyclin D1 were significantly higher in the EMPD tumor cells than in the normal epidermis. Our results suggest that CDK4/6 inhibitors could be novel and potent therapeutics for the treatment of EMPD.     

Cyclin-dependent kinase 4/6 inhibitors as first-line treatment for post-menopausal metastatic hormone receptor-positive breast cancer patients: a systematic review and meta-analysis of phase III randomized clinical trials

Background

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.

Materials and methods

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 I² statistics.

Results

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.

Conclusion

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.

     

Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer

BackgroundWhile deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+ breast cancer, and targeted CDK 4/6 inhibitors that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known.Patients and methodsWe identified patients who had pre- and post-genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors. Genotyping was carried out in tumor tissue or blood collected before start of CDK 4/6 inhibitor and after disease progression on CDK 4/6 inhibitor, covering more than 90% of the coding region in RB1.ResultsWe identified detectable acquired RB1 mutations in circulating tumor DNA (ctDNA) after exposure to CDK4/6 inhibitor (palbociclib, palbociclib, ribociclib) for 5, 8, and 13 months, respectively, in three patients. The RB1 mutations included substitution in donor splicing site of exon 8 of the RB1 gene in patient #1; substitution in donor splicing site of exon 22 of RB1 gene, exon 19 deletion, exon 3 insertion in patient #2; and RB1 exon 16 H483Y mutation in patient #3. None of these RB1 mutations were present in the pre-CDK 4/6 specimen highlighting these molecular alterations, which lead to functional loss of Rb1, likely emerged under selective pressure from the CDK4/6 inhibitor potentially confering therapeutic resistance.ConclusionThis is the first clinical report to describe the emergence of somatic RB1 mutations after exposure to palbociclib or ribociclib, in patients with metastatic breast cancer. Further research is needed to validate these findings, identify how these mutations temporally emerge under selective pressure of CDK 4/6 inhibitor, and develop rational therapeutic strategies.     

Aspects biologiques,précliniques et cliniques de l’association de radiothérapie et d’inhibiteur de CDK 4/6

Several clinical studies have shown that CDK4/6 inhibitors (CDK4/6i) improve survival in patients with metastatic or locally advanced HR-positive, HER-2-negative breast cancer (BC). The aim of this review was to synthesize the biological, preclinical and clinical aspects of the treatment of BC with CDK4/6i, with a focus on the combination of CDK4/6i and radiotherapy. The DNA damage induced after exposure of cells to ionizing radiation activates control pathways that inhibit cell progression in the G1 and G2 phases and induce a transient delay in progression in the S phase. These checkpoints are in particular mediated by cyclin-dependent kinases (CDK) 4/6 activated by cyclin D1. Several preclinical studies have shown that CDK4/6i could be used as radiosensitizers in non-small cell lung cancer, medulloblastoma, brainstem glioma and breast cancer. CDK4/6 inhibition also protected against radiation-induced intestinal toxicities by inducing redistribution of quiescent intestinal progenitor cells, making them less radiosensitive. Clinical data on the combination of CDK inhibitors and radiotherapy for both locoregional and metastatic irradiation are based on retrospective data. Nevertheless, the most optimal therapeutic sequence would be radiotherapy followed by palbociclib. Pending prospective clinical trials, the concomitant combination of the two treatments should be done under close supervision.     

Cyclin-Dependent Kinase 4/6 Inhibitors Combined With Radiotherapy for Patients With Metastatic Breast Cancer

BackgroundThe 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.Patients and MethodsWe 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.ResultsThirty 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.ConclusionWe 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.     

Ribociclib for the treatment of hormone receptor-positive,human epidermal growth factor receptor 2-negative advanced breast cancer

Introduction: The emergence of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors marked a significant advancement in the treatment of advanced breast cancer. Ribociclib is an orally bioavailable, highly selective inhibitor of CDK4/6. In combination with various endocrine therapies, ribociclib has demonstrated clinical activity as a first-line therapy for patients with HR+, HER2? advanced breast cancer, without compromising the favorable toxicity profile associated with endocrine therapy. Thus, ribociclib is now considered a new standard of care for HR+, HER2? advanced breast cancer.

Areas covered: This review provides a concise overview of the preclinical and clinical development of ribociclib, including evidence of its clinical activity and safety profile when combined with endocrine therapy in HR+, HER2? advanced breast cancer.

Expert commentary: CDK4/6 inhibition represents a promising treatment option for patients with HR+ metastatic breast cancer. Ribociclib significantly improved progression-free survival in patients receiving first-line endocrine therapy for HR+, HER2? advanced breast cancer. Planned and ongoing trials investigating ribociclib in combination with other endocrine therapies and in various clinical settings will help to determine the optimal treatment sequence for different patient populations.     

Current challenges in the management of breast cancer brain metastases

Approximately 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC) ultimately develop breast cancer brain metastases (BCBM), which are associated with significant morbidity and mortality. The advent of HER2-directed therapy resulted in greatly improved survival outcomes, but unfortunately at the price of an increased cumulative incidence of BCBM. We review challenges in the management of BCBM, and potential treatment strategies, including novel agents such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287). The utility of human epidermal growth factor 2 (HER2)-directed therapies—lapatinib, ado-trastuzumab emtansine (T-DM1), neratinib and tucatinib—is also being studied in this setting. We address the need for improved imaging techniques and innovation in clinical trial design. For example, the current practice is to initially administer whole-brain radiotherapy (WBRT) as treatment for patients with multiple BCBM. However, in selected circumstances, first-line systemic treatment may be more appropriate in order to avoid neurocognitive toxicities, and potential options should be evaluated in window of opportunity trials. Other strategies that may aid development of more effective clinical trials and expedite the development of promising agents include the use of different clinical endpoints and different imaging tools.