First-in-Class CDK4/6 Inhibitor Palbociclib Could Usher in a New Wave of Combination Therapies for HR+, HER2- Breast Cancer.
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ABSTRACT:
SUBMITTER: McCain J
PROVIDER: S-EPMC4517534 | biostudies-literature | 2015 Aug
REPOSITORIES: biostudies-literature
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First-in-Class CDK4/6 Inhibitor Palbociclib Could Usher in a New Wave of Combination Therapies for HR+, HER2- Breast Cancer.
P & T : a peer-reviewed journal for formulary management 20150801 8
Women with hormone receptor-positive, human epidermal growth factor receptor 2- negative breast cancer-the most common subtype-have new options as palbociclib and similar drugs debut. This article outlines the rationale and evidence for their use. ...[more]
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Project description:BackgroundPalbociclib administered with endocrine therapy was tolerable when the overall incidence of toxicities was assessed separately for three PALOMA studies. This study analyzed pooled, longer-term PALOMA safety data longitudinally.MethodsData were pooled from three randomized phase II and III studies (ClinicalTrials.gov: NCT00721409, NCT01740427, NCT01942135) of hormone receptor-positive/human epidermal growth factor receptor 2‒negative advanced breast cancer patients. Front-line patients were randomly assigned to receive letrozole with/without palbociclib (PALOMA-1) or letrozole plus palbociclib/placebo (PALOMA-2). In PALOMA-3, patients with prior endocrine resistance received fulvestrant plus palbociclib/placebo. The cumulative event rates of adverse events (AEs), reporting up to 50 months of treatment, were assessed over time.ResultsPatients who received endocrine therapy (n = 1343) were included in this pooled analysis (872 were also treated with palbociclib, and 471 were not). The most common AEs with palbociclib plus endocrine therapy were neutropenia and infections (any grade, 80.6% and 54.7%, respectively), which were higher than in the endocrine monotherapy arm (any grade, 5.3% and 36.9%). The most common hematologic AEs (≥15.0% in the palbociclib arm) were more likely to be reported in the initial months of the study, after which time the cumulative event rate did not substantially increase. With palbociclib plus endocrine therapy, any grade AEs leading to permanent discontinuation over three years occurred in only 8.3% of patients.ConclusionsBased on these long-term safety analyses, there is no evidence of specific cumulative or delayed toxicities with palbociclib plus endocrine therapy, supporting the ongoing investigation of palbociclib plus endocrine therapy in early breast cancer (NCT02513394).
| S-EPMC6449170 | biostudies-literature
Project description:PurposeIn hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed.Experimental designWe performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2- MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor-positive (ER+)/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET.ResultsNon-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value = 0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models, we show that PLK1 inhibition reverses resistance to palbociclib+ET.ConclusionsWe confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.
| S-EPMC10102847 | biostudies-literature
Project description:Palbociclib was approved by the FDA for use in combination with letrozole for the treatment of postmenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. In addition, the combination of palbociclib with fulvestrant resulted in superior outcome than fulvestrant alone in those who had progressed during prior endocrine therapy. This research highlight summarized the current development of CDK4/CDK6 inhibitors and future directions in the treatment of advanced hormone-receptor-positive breast cancer.
| S-EPMC4534142 | biostudies-literature
Project description:IntroductionEndocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) are standard treatment options for hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). However, the efficacy of standard subsequent therapies after CDK4/6i-based treatment is unclear. This study aimed to examine physician practice patterns and treatment outcomes of subsequent therapies administered after progression on palbociclib therapy in clinical practice.MethodsThe study included 200 patients with HR+/HER2- MBC who underwent subsequent treatments after progressing on palbociclib-based regimens in five Chinese institutions between August 2017 and April 2020. The treatment pattern, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were reported.ResultsA total of 200 patients were included, of whom 147 (73.5%) and 53 (26.5%) received subsequent chemotherapy and endocrine therapy, respectively. The frequently used monochemotherapy regimens were taxane (n = 29), capecitabine (n = 21), and vinorelbine (n = 17), while the endocrine therapy regimens were chidamide plus exemestane (n = 16) and everolimus plus exemestane (n = 9). The overall median PFS (mPFS) was 5.5 months, with no significant difference in mPFS between the chemotherapy and endocrine therapy groups (p = 0.669). However, among patients not sensitive to prior palbociclib treatment, those administered chemotherapy had significantly longer PFS than those administered endocrine therapy (p = 0.006). The mPFS with endocrine therapy after first-, second-, and subsequent-line palbociclib was 13.4, 3.1, and 4.1 months, respectively (p = 0.233); in contrast, the mPFS with chemotherapy was 7.2, 6.5, and 4.9 months after first-, second-, and subsequent-line palbociclib, respectively (p = 0.364). The median OS was not achieved. The ORR was 10.6% among the 198 patients included in the analysis.ConclusionsPhysicians prefer chemotherapy over endocrine therapy for the treatment of patients with HR+/HER2- MBC who develop progression on palbociclib. Sensitivity to previous palbociclib treatment might be one of the indicators for predicting response to subsequent treatment.ClinicalTrials.gov identifier: NCT04517318.
| S-EPMC8202336 | biostudies-literature
Project description:PurposeThe aim of this study was to evaluate the cost-effectiveness of ribociclib compared to palbociclib, both in combination with letrozole, in the first-line treatment of postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC) from the perspective of the Spanish National Health System (NHS).Patients and methodsDisease progression was simulated with a partitioned survival model developed from the parameterization and extrapolation of survival curves of postmenopausal women with HR+/HER2- ABC from clinical trials with ribociclib or palbociclib, both in combination with letrozole. The model was structured on the basis of three health states (progression-free, progressed disease, and death), with a 1-month cycle length and inclusion of subsequent treatments administered for disease progression, over a time horizon of 15 years. Clinical, economic, and quality of life parameters were drawn from clinical trials and the literature. The use of resources and clinical practice in the Spanish setting was validated by a panel of experts. The Spanish NHS perspective was adopted, taking into account exclusively direct health costs from 2017 expressed in Euros. Drug prices used were the reported ex-factory prices. Uncertainty of the parameters and robustness of the results were evaluated using deterministic and probabilistic sensitivity analyses (2,000 iterations).ResultsThis cost-effectiveness analysis showed a greater benefit (0.437 and 0.285 life-years gained [LYGs] and quality-adjusted life years [QALYs] gained, respectively) and a slightly higher cost (€439.86) for ribociclib+letrozole compared to palbociclib+letrozole. The resulting incremental cost-effectiveness and cost-utility ratios were €1,007.69 per LYG and €1,543.62 per QALY gained, respectively. The results of the multiple sensitivity analyses showed limited dispersion of the outcomes, thus corroborating their robustness.ConclusionFrom the NHS perspective, considering the most commonly established willingness-to-pay thresholds in the Spanish setting, ribociclib+letrozole would represent a cost-effective therapeutic option compared to palbociclib+letrozole in the first-line treatment of HR+/HER2- ABC in postmenopausal women.
| S-EPMC6241542 | biostudies-literature
Project description:BackgroundFindings from randomized clinical trials may have limited generalizability to patients treated in routine clinical practice. This study examined the effectiveness of first-line palbociclib plus letrozole versus letrozole alone on survival outcomes in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (MBC) treated in routine clinical practice in the USA.Patients and methodsThis was a retrospective observational analysis of electronic health records within the Flatiron Health Analytic Database. A total of 1430 patients with ≥ 3 months of follow-up received palbociclib plus letrozole or letrozole alone in the first-line setting between February 3, 2015, and February 28, 2019. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics. Real-world progression-free survival (rwPFS) and overall survival (OS) were analyzed.ResultsAfter sIPTW adjustment, median follow-up was 24.2 months (interquartile range [IQR], 14.2-34.9) in the palbociclib group and 23.3 months (IQR, 12.7-34.3) in those taking letrozole alone. Palbociclib combination treatment was associated with significantly longer median rwPFS compared to letrozole alone (20.0 vs 11.9 months; hazard ratio [HR], 0.58; 95% CI, 0.49-0.69; P < 0.0001). Median OS was not reached in the palbociclib group and was 43.1 months with letrozole alone (HR, 0.66; 95% CI, 0.53-0.82; P = 0.0002). The 2-year OS rate was 78.3% in the palbociclib group and 68.0% with letrozole alone. A propensity score matching analysis showed similar results.ConclusionsIn this "real-world" population of patients with HR+/HER2- MBC, palbociclib in combination with endocrine therapy was associated with improved survival outcomes compared with patients treated with letrozole alone in the first-line setting.Trial registrationClinicaltrials.gov; NCT04176354.
| S-EPMC7989035 | biostudies-literature
Project description:Although early breast cancer (BC) is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and is associated with significantly worse prognosis. Among the new targeted agents, anticancer drugs exploiting the cell-cycle machinery have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell-cycle arrest, reduced cell viability and tumor shrinking. As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies represents a rational approach to elicit synergic antitumor activity in hormone receptor-positive BC. The results of clinical trials have indeed confirmed the superiority of the combination of CDK4/6 inhibitors plus endocrine therapies over endocrine therapy alone. Currently approved are three compounds that exhibit similar structural characteristics as well as biological and clinical activities. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration (FDA) in view of the results of the MONARCH 1 and 2 trials. Further trials are ongoing as other important questions await response. In this review, we focus on abemaciclib to examine preclinical and clinical results, describing current therapeutic indications, open questions and ongoing clinical trials.
| S-EPMC5818877 | biostudies-literature
Project description:BackgroundPalbociclib is indicated for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC), in combination with endocrine therapy. Emerging real-life data suggest that the efficacy of a palbociclib-based therapy is highly conserved. We report the Institut Curie hospital experience.Patients and methodsWe retrospectively reviewed all patients with HR + HER2- ABC treated with a palbociclib-based therapy as first or second line for ABC, with an initial prescription from November 2016 to December 2018. Clinical, laboratory and imaging data were retrieved from electronic records. Data lock was December 31st, 2019. Descriptive analyses, univariate and multivariate Cox regression analyses were performed.ResultsWe included 310 consecutive patients. Median age was 61.8 years old. Palbociclib was prescribed in first line in 225 patients (72.6%). Before palbociclib-based therapy initiation, 122 patients (39.3%) were endocrine naive, 96 (31.0%) endocrine sensitive and 92 (29.7%) endocrine resistant. Median follow-up was 20.7 months. Median progression free survival (PFS) was 23.4 months (95%CI: 21.6-NR) in endocrine naive patients, 22.7 months (95%CI: 14.7-NR) in endocrine sensitive, and 13.4 months (95%CI: 10.7-20.8) in endocrine resistant. At 12 months from the initiation of palbociclib, 94.5% of patients were alive. By multivariate analysis, poor prognosis factors for PFS were identified in the endocrine naive/sensitive population: initial ECOG status 2, previous endocrine therapy for ABC, 3 metastatic sites or more. Toxicity profile was similar to previously published data.ConclusionIn a non-selected population of patients with HR + HER2- ABC, the efficacy and safety data are strikingly similar to those previously reported.
| S-EPMC7695984 | biostudies-literature
Project description: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.
| S-EPMC5652078 | biostudies-literature
Project description: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 ESR1 and PIK3CA testing for select patients. Where possible, engage a multidisciplinary care team to apply evidence in a patient-centric manner.
| S-EPMC10297170 | biostudies-literature