CDK4/6 inhibitors for the treatment of advanced hormone receptor positive breast cancer and beyond: 2016 update

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.     

Ribociclib for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer

Introduction: The introduction of CDK4/6 inhibitors, such as ribociclib, has changed the treatment landscape for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer. As first-line treatment of HR+/HER2- MBC, the addition of a CDK4/6 inhibitor to an aromatase inhibitor improves progression-free survival compared to an aromatase inhibitor alone.

Areas covered: In this drug profile, we review the current market for HR+/HER2- MBC, as well as the characteristics, mechanism, pharmacology, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, toxicities, monitoring, and dosing modification of the CDK4/6 inhibitor ribociclib.

Expert commentary: CDK4/6 inhibitors, such as ribociclib, improve outcomes in post-menopausal women with HR+/HER2- MBC. The most common toxicity of ribociclib is neutropenia, which is generally not complicated and can be managed with dose modification and/or supportive care measures. Additional research will help better define the optimal clinical use of ribociclib.     

PI3K inhibition to overcome endocrine resistance in breast cancer

Introduction: Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway.

Areas covered: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker.

Expert opinion: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.     

CDK4/6 blockade in breast cancer: current experience and future perspectives

Introduction: 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.     

Benefits versus risk profile of buparlisib for the treatment of breast cancer

Introduction: Activation of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways occurs in 70% of breast cancer, including PIK3CA activating mutations, PTEN loss and AKT mutation. It is associated with poor prognosis and resistance to anti-HER2 and endocrine therapy. PI3K inhibitors are promising anticancer targets that can reverse resistance to these therapies. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different solid tumors as monotherapy or in combination.

Areas covered: This article reviews preclinical data, clinical studies that have evaluated the efficacy and safety profiles of buparlisib as a monotherapy or in combination with targeted therapy (including endocrine and anti-HER2 therapy) or cytotoxics. The authors cover completed and ongoing studies to evaluate the benefit vs risk profile of buparlisib.

Expert opinion: Targeting PI3K showed efficacy in BC. Buparlisib, a pan PI3K inhibitor, presents manageable but not negligible toxicity with an activity/toxicity ratio in favor of the use of emerging second generation, α–selective PI3K inhibitors for ongoing and future trials.     

Palbociclib for the treatment of postmenopausal breast cancer – an update

Introduction

Breast cancer is a heterogeneous disease comprising different biological subtypes. In two thirds of tumours, expression of steroid-receptors is present, allowing for targeted treatment with endocrine therapy. In metastatic breast cancer, sequential administration of different non-cross resistant drugs offers a chance to delay cytotoxic chemotherapy. Activity of endocrine therapy, however, decreases with time as indicated by a shorter progression-free survival interval with every further treatment line, suggesting onset of resistance. Current research therefore focuses on prevention or delay of resistance by combining endocrine therapy with other targeted treatment approaches such as small-molecule pathway-inhibitors. Indeed, combining the steroidal aromatase-inhibitor exemestane with the mTor-inhibitor everolimus doubles activity of endocrine therapy in a pretreated population albeit at the price of increased toxicity.

Data from several clinical trials suggest that inhibitors of the cycline-dependent kinases (CDK) 4 and 6 are able to delay or reverse resistance to endocrine therapy as well, while tolerability may be superior.

Areas Covered

This review provides a summary of clinical data on CDK 4/6 inhibitors, summarizes the biological rational for their use and provides an outlook to future developments in this field. A systematic literature search was performed in order to identify publications concerning the use of CDK 4/6 inhibitors in breast cancer. The search included original research articles, abstracts from major conferences and reviews published from 2005 to 2015 and was limited to English-language publications.

Expert opinion

Based upon available data regarding activity and tolerability, it is believed that CDK 4/6 inhibitors will evolve to become a valuable addition to the therapeutic options in metastatic breast cancer.     

Pharmacokinetic drug evaluation of ribociclib for the treatment of metastatic,hormone-positive breast cancer

Introduction: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). Ribociclib is an orally bioavailable, highly selective small molecule inhibitor of CDK4/6 that induces G1 arrest at sub-micromolar concentrations in a variety of pRb-positive cancer cells in vitro. Ribociclib is a new standard of care for metastatic HR+/HER2 negative metastatic breast cancer.

Area covered: In this article, we review the preclinical and clinical development of ribociclib as well as discussing the role for novel applications of these agents outside the arena of HR-positive, HER2-negative advanced breast cancer.

Expert opinion: Results of pivotal phase II and III trials investigating ribociclib in patients with advanced-stage (HR)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a safe toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge and 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. The use of combination therapies to optimize CDK4/6 targeting is under development.     

Impact of palbociclib plus letrozole on pain severity and pain interference with daily activities in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer as first-line treatment

Background Palbociclib is a recently approved drug for use in combination with letrozole as initial endocrine-based therapy for the treatment of postmenopausal women with advanced estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. This report assesses the impact of palbociclib in combination with letrozole versus letrozole alone on patient-reported outcomes of pain.

Methods Palbociclib was evaluated in an open-label, randomized, phase II study (PALOMA-1/TRIO-18) among postmenopausal women with advanced ER+/HER2- breast cancer who had not received prior systemic treatment for their advanced disease. Patients received continuous oral letrozole 2.5?mg daily alone or the same letrozole dose and schedule plus oral palbociclib 125?mg, given once daily for 3 weeks followed by 1 week off over repeated 28-day cycles. The primary study endpoint was investigator-assessed progression-free survival in the intent-to-treat population, and these results have recently been published (Finn et al., Lancet Oncol 2015;16:25-35). One of the key secondary endpoints was the evaluation of pain, as measured using the Brief Pain Inventory (BPI) patient-reported outcome tool. The BPI was administered at baseline and on day 1 of every cycle thereafter until disease progression and/or treatment discontinuation.

Clinical trial registration This study is registered with ClinicalTrials.gov (NCT00721409).

Results There were no statistically significant differences in Pain Severity or Pain Interference scores of the BPI between the two treatment groups for the overall population or among those with any bone disease at baseline. A limitation of the study is that results were not adjusted for the concomitant use of opioids or other medications used to control pain.

Conclusions The addition of palbociclib to letrozole was associated with increased efficacy without negatively impacting pain severity or pain interference with daily activities.     

A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer

Background: 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.

Scope: 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.

Findings: 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.

Conclusion: 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.     

Palbociclib and beyond for the treatment of HR + HER2- metastatic breast cancer: an Asian-Pacific perspective and practical management guide on the use of CDK4/6 inhibitors

Abstract

Breast cancer is the most frequent cancer amongst women worldwide including in Asia where the incidence rate is rapidly increasing. Even with treatment, around 30% of patients with early breast cancer progress to metastatic disease, with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer the most common phenotype. First-line endocrine therapy targeting the estrogen receptor signaling pathway provides a median progression-free survival or time to progression of 6–15?months in HR?+?HER2- metastatic breast cancer. Recently, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, combined with endocrine therapy, have achieved more than two years median progression-free survival in HR?+?HER2- metastatic breast cancer. However, the characteristics of the Asian breast cancer population differ from those of Western populations and need to be considered when selecting a suitable treatment. Breast cancer is diagnosed at a younger age in Asian populations and late stage at presentation is generally more common in low-/middle-income countries than high-income countries. Consequently, the proportion of premenopausal women with metastatic breast cancer is higher in Asian compared with Western populations. While CDK4/6 inhibitors have been approved in the USA (FDA) since 2015, experience with them in Asia is more limited. We review the experience with the CDK4/6 inhibitor palbociclib in Asian patients with HR?+?HER2- metastatic breast cancer and provide guidance on the use of palbociclib in these patients.     

Pharmacokinetic drug evaluation of palbociclib for the treatment of breast cancer

Introduction: Cyclin-dependent kinases (CDKs) 4 and 6 regulate the transition from G0/G1-phase to S-phase of the cell cycle and have been identified as key drivers of proliferation in hormone receptor (HR)-positive breast cancer. The CDK4/6 inhibitor palbociclib in combination with endocrine therapy has been approved for treatment of HR-positive/HER2-negative breast cancer patients.

Areas covered: In this article, we provide an update of the data on pharmacodynamics, pharmacokinetics, preclinical, and clinical studies of palbociclib in breast cancer. We performed a search of data on palbociclib in the PubMed and the clinicaltrials.gov databases, in the FDA website and in the ASCO and AACR proceedings.

Expert opinion: In order to optimize the clinical outcome of HR-positive breast cancer patients treated with palbociclib, predictive biomarkers allowing patient selection are urgently needed. A recent study suggested that early dynamics of PIK3CA mutations in circulating tumor DNA might be a potential predictive biomarker for CDK4/6 inhibitors. Several clinical trials are ongoing with the aim to explore the activity of combinations of palbociclib with targeted agents and/or immunotherapy in the different subtypes of breast cancer in both metastatic and early phases of the disease. These combinations might allow improving the sensitivity and overcoming mechanisms of resistance.     

Cost-effectiveness of Ribociclib in HER2- negative breast cancer: A synthesis of current evidence

BackgroundThe main aim of this study was to investigate the cost-effectiveness of Ribociclib in the treatment of patients with breast cancer by assessing the published evidence.MethodA systematic review of the published literature was conducted to identify the economic evaluations/cost-effectiveness study of Ribociclib. In this study, several databases were inspected, including PubMed, NHS Economic Evaluation, Cochran, and Scopus. Studies were eligible if they assessed the cost-effectiveness of Ribociclib and reported incremental cost-effectiveness ratio (ICER). The study was performed and conducted following the PRISMA reporting guidelines.ResultsOf 70 studies identified, 8 articles meet our inclusion criteria. The cost-effectiveness threshold varied from $24,144.18 in Spain to $198,000/QALY in the USA. Moreover, the result demonstrated that the mean ICER varied across different countries $1,863.47/QALY in Spain and $813,132/QALY in the USA.ConclusionAmong all CDK4/6 inhibitors medications, current evidence indicated that the use of Ribociclib for HER2- negative breast cancer management was beneficial and considered to be cost-effective. Future research is needed to investigate the role of Ribociclib in long-term treatment.     

Abemaciclib for the treatment of breast cancer

Introduction: There have been numerous clinical trials of CDK4/6 inhibitors performed on various carcinomas including breast cancer. One such inhibitor tested and which has ongoing clinical trials for breast cancer is abemaciclib. Abemaciclib is a molecular-targeted agent that targets basic cell cycle regulatory mechanisms.

Areas covered: This review discusses the available clinical data and ongoing clinical trials of abemaciclib in breast cancer.

Expert opinion: Abemaciclib has demonstrated a clear anti-tumour effect and manageable toxicity against HR-positive, HER2-negative breast cancer in many clinical trials and is expected to be an important standard therapy. However, currently, besides oestrogen receptor expression, there is a definite lack of predictive biomarkers for response and/or tolerance to abemaciclib, which is important for patient selection. Another problem is that its contribution to overall survival (OS) has not been shown. And while two large the phase 3 study highlighted the anti-tumour effect of abemaciclib, the OS results are awaited. Furthermore, the effect on brain metastases is expected to be unique to abemaciclib as the response of brain metastasis in HR-positive breast cancer patients has been confirmed in a few cases with case collection still ongoing.     

Predictors of systemic therapy sequences following a CDK 4/6 inhibitor-based regimen in post-menopausal women with hormone receptor positive,HEGFR-2 negative metastatic breast cancer

Objective: To identify systemic treatment in the real-world following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDKi) among post-menopausal women with hormone receptor positive, human epidermal growth factor receptor 2 Negative (HR+/HER2–) metastatic breast cancer (mBC).

Methods: Post-menopausal women with HR+/HER2– mBC were identified from MarketScan claims databases between January 1, 2012 and October 31, 2017. Eligible mBC patients who received a CDKi-based line of therapy following metastasis diagnosis were selected. A line of therapy ended at the earlier of systemic therapy discontinuation, switch to new treatment, or censoring.

Results: In total, 525 patients that received systemic therapy after a CDKi-based line were included (39.6% transitioned from use of a CDKi-based regimen in first line following metastasis diagnosis to any second line, and 60.4% shifted from a CDKi-based [second, third, or fourth line] to a subsequent line). Of post-CDKi second line regimens (n?=?208), 38.0% were endocrine only, 35.6% were chemotherapy-based, 14.4% were everolimus-based, 9.6% were also CDKi-based line, and 2.4% were others. After adjusting for demographic and clinical characteristics, patients transitioning from a CDKi-based line to chemotherapy (vs others) had a trend of being more likely to have recurrent rapidly progressing disease, and were significantly less likely to have the prior CDKi-based line in combination with an AI (both p?<?.05).

Conclusions: This population-based study suggests that rapidly progressing disease, metastatic site location, age, and endocrine therapy partner may be predictive of subsequent systemic therapy regimen selection after progression on a CDKi-based line therapy in patients with HR+/HER2– mBC.     

Clinical efficacy of ribociclib as a first-line therapy for HR-positive,advanced breast cancer

Introduction: Breast cancer (BC) remains the most frequently diagnosed cancer and the most common cause of cancer death among women of all races worldwide. Over 80% of BC cases are hormone receptor (HR)-positive, comprised of luminal A and luminal B per molecular subtypes, imposing an urgent need to fully understand the mechanisms behind progression. Ribociclib is a selective cycline-dependent kinase 4 and 6 inhibitor. A phase 1 and a phase 3 trial have established a definitive role of ribociclib as frontline in the treatment of endocrine-sensitive advanced BC.

Areas covered: Herein, the authors provide an overview of the data on ribociclib covering all aspects of the drug from its pharmacokinetics to efficacy and safety. The authors also provide their perspectives for the future.

Expert opinion: Ribociclib is offering an opportunity to explore a new compound at the crossroads of different molecular activity and cell targets, which focus on endocrine-resistance reversal in multiple settings including early BC. Moreover, its activity against different subtypes of BC is being studied as is its immune-modulating effect. One cautionary note is that, in a market of concomitant similar competitors, a financial discussion will be mandatory.     

Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer

Introduction: Endometrial cancer (EC) is the most common neoplasm of the female genital tract in developed countries. Despite the progress in early detection and treatment, a significant number of cases of advanced ECs are still diagnosed. These patients have few treatment options and a poor prognosis. Our understanding of EC pathogenesis and progression has been enhanced by recent genomic studies. Among the relevant biological pathways, phosphatidylinositol 3-kinase/AKT (PIK3/AKT)-mammalian target of rapamycin (mTOR) signaling is frequently upregulated in this cancer.

Areas covered: This review covers investigational EC therapeutics acting on the PI3K/AKT/mTOR pathway. The authors review the results of clinical studies and highlight ongoing trials.

Expert opinion: Several new agents are under evaluation for treating patients with metastatic, recurrent, and persistent EC. Clinical trials investigating PI3K/AKT/mTOR inhibitors have yielded controversial results. In the near future, new studies with dual inhibitors or multi-pathways inhibitors as mono or combination therapies with conventional chemotherapy (CT) or other targeted drugs may provide more promising data. Moreover, the evaluation of new serum and histological biomarkers is an attractive strategy for patient selection.     

Emerging protein kinase inhibitors for treating pancreatic cancer

Introduction: Pancreatic cancer, the incidence and mortality of which are increasing around the world, has the most dismal prognosis among the commonly encountered cancers. Systemic chemotherapy plays an important role in the treatment of patients with pancreatic cancer, and development of more effective chemotherapies is being sought.

Areas covered: This review article provides a summary about protein kinase inhibitors that have been investigated for the treatment of pancreatic cancer, not only existing agents targeting RAS, EGFR, VEGFR, MEK, etc., but also various compounds targeting, including the MAPK, PI3 K/Akt/mTOR, and JAK/STAT signaling pathways, trials of which are currently ongoing. To date, none has shown sufficient efficacy as to merit becoming established as a standard treatment agent for pancreatic cancer.

Expert opinion: As the toxicities of protein kinase inhibitors usually differ from those of cytotoxic agents, it could be of value to use these agents in combination with gemcitabine plus nab-paclitaxel. It may be reasonable to identify a suitable disease and/or predictive markers for new compounds in proof of concept trials. It is an urgent need to conduct phase III trials, on the basis of the results obtained, in subpopulations with biomarkers to predict the efficacy of these drugs.     

Epidemiological characteristics of and risk factors for breast cancer in the world

通过动物实验研究疏肝健脾解毒方对乳腺癌癌前病变的作用机制。

取SD大鼠,分为6组(每组10只)：空白组、乳腺癌癌前病变模型组、他莫昔芬组和疏肝健脾解毒方低、中、高剂量组。采用二甲基苯蒽造模法对乳腺癌癌前病变大鼠模型造模。采用HE染色观察各组乳腺组织病理变化,流式细胞仪检测CD4⁺、CD8⁺含量;ELISA检测IL-2、IL-4、IL-6、IL-10、IL-12、E2、P含量。Western blotting检测ER、PI3K、p-Akt及mTOR的蛋白表达。

HE染色显示大鼠乳腺组织发生改变,提示造模成功。与空白组比较,模型组外周血中CD4⁺含量降低,CD8⁺含量升高,差异有统计学意义(P<0.01);与模型组比较,疏肝健脾解毒方低、中、高剂量组和他莫昔芬组CD4⁺含量增加,CD8⁺含量下降,差异均有统计学意义(P<0.01)。与空白组比较,模型组IL-2、IL-4、IL-10浓度显著降低(P<0.01),IL-12、IL-6显著升高(P<0.01);与模型组比较,疏肝健脾解毒方低、中、高剂量组和他莫昔芬组IL-2、IL-4、IL-10浓度均显著升高(P<0.01),IL-12、IL-6显著下降(P<0.05或P<0.01)。与空白组比较,模型组E2和P含量显著升高(P<0.01);与模型组比较,疏肝健脾解毒方低、中、高剂量组和他莫昔芬组E2和P含量均显著降低(P<0.01)。Western blotting检测结果表明,与空白组比较,模型组ER、PI3K、p-Akt及mTOR的表达显著升高(P<0.01);与模型组比较,疏肝健脾解毒方低、中、高剂量组和他莫昔芬组ER、PI3K、p-Akt及mTOR的表达均显著下降(P<0.01)。

疏肝健脾解毒方可能是通过使ER的表达下降,从而抑制PI3K/Akt/mTOR信号通路的表达,同时影响机体免疫应答来逆转大鼠乳腺癌变进程。