CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials

Messina, Carlo; Cattrini, Carlo; Buzzatti, Giulia; Cerbone, Luigi; Zanardi, Elisa; Messina, Marco; Boccardo, Francesco

doi:10.1007/s10549-018-4901-0

Cited by 57 publications

(59 citation statements)

References 33 publications

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“…This behavior relies on the diffused perception, among both oncologists and patients, that chemotherapy is a more potent treatment, yielding on average a higher ORR than ET-based treatments. In contrast, our meta-analysis, as well as the previous ones [56][57][58][59] confirms that the combination of CDK4/6 inhibitors and ET yields a very high rate of tumour regression, which is on average as high as 55% for patients with measurable disease, with no heterogeneity among different compounds. To the best of our knowledge, this ORR is higher than we would expect with mono-chemotherapy and comparable (but still lower) to what we would expect with an aggressive polychemotherapy in HR+ patient populations.…”

Section: Discussionsupporting

confidence: 74%

Progression-Free Survival and Overall Survival of CDK 4/6 Inhibitors Plus Endocrine Therapy in Metastatic Breast Cancer: A Systematic Review and Meta-Analysis

Piezzo

Chiodini

Riemma

et al. 2020

IJMS

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The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR) positive, HER2-negative metastatic breast cancer over the last few years. This meta-analysis of randomized controlled trials (RCTs) is aimed to better characterize the efficacy of CDK4/6 inhibitors in some relevant subgroups and to test heterogeneity between different compounds with a particular focus on their ability to improve overall survival (OS). Pooled estimates of hazard ratios (HRs) were computed for progression-free survival (PFS), OS, and objective response rate (ORR) analysis in predefined subgroups to better understand treatment effect concerning specific patients’ characteristics. To estimate the absolute benefit in terms of PFS, pooled survival curves were generated by pooling the data of all trials. A total of eight RCTs were included. Adding a CDK4/6 inhibitor to ET is beneficial in terms of PFS, irrespective of the presence or not of visceral metastases, the number of metastatic sites, and the length of the treatment-free interval (TFI). The addition of CDK4/6 inhibitors produces a significant OS improvement, both in aromatase inhibitor (AI)-sensitive (HR 0.75, 95% CI) and AI-resistant patients (HR 0.77, 95% CI [0.67–0.89]). Pooled data from each single drug show that palbociclib remains the only class member not showing a statistically significant HR for OS (HR 0.83, 95% CI [0.68–1.02]).

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Section: Discussionsupporting

confidence: 74%

Progression-Free Survival and Overall Survival of CDK 4/6 Inhibitors Plus Endocrine Therapy in Metastatic Breast Cancer: A Systematic Review and Meta-Analysis

Piezzo

Chiodini

Riemma

et al. 2020

IJMS

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“…Several other previously published meta-analyses and pooled analyses of PFS concluded that the use of CDK4/6 inhibitors plus ET was associated with significantly extended PFS. 2,3,13,19 The survival data, references, and subgroup analyses included in the present meta-analysis are more comprehensive, complete, and contain a larger sample size compared with those previously published meta-analyses. Thus, the present meta-analysis has several strengths over previous analyses.…”

Section: Discussionmentioning

confidence: 99%

“…The addition of CDK4/6 inhibitors to treatment regimens was associated with a high risk of increased rates of neutropenia, leukopenia, and diarrhea, 3 grade 3/4 AEs that should be considered when treatment periods are long. 2 Neutropenia, leukopenia, and diarrhea were the most common symptoms observed among patients who received CDK4/6 inhibitors plus ET treatment of metastatic breast cancer, with diarrhea being the most frequent nonhematologic grade 3/4 AE. 36,39 However, those grade 3/4 AEs may be controlled through experience, medication, or dose Downloaded From: https://jamanetwork.com/ on 10/31/2020 adjustment.…”

Section: Discussionmentioning

confidence: 99%

“…The inclusion criteria were (1) phase 2 or 3 randomized clinical trials of HR-positive, ERBB2-negative metastatic breast cancer (2) with patients randomly assigned to receive CDK4/6 inhibitors plus ET or ET alone, (3) having OS or PFS outcomes. The exclusion criteria were (1) phase 1 trials, (2) retrospective studies, or (3) studies without survival outcomes.…”

Section: Inclusion and Exclusion Criteriamentioning

confidence: 99%

“…1 The most frequent subtype of breast cancer is hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative breast cancer, which accounts for approximately 65% of all breast cancers. 2,3 Nearly two-thirds of patients with metastatic breast cancer are HR-positive, and it is estimated that about 25% of patients with breast cancer will experience recurrence after surgery. 4,5 Endocrine therapy (ET) is an important method of treatment for women with HR-positive, ERBB2-negative metastatic breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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Association of Cyclin-Dependent Kinases 4 and 6 Inhibitors With Survival in Patients With Hormone Receptor–Positive Metastatic Breast Cancer

Huo

Zhao

et al. 2020

JAMA Netw Open

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IMPORTANCE One of the most recent treatment regimens used for hormone receptor (HR)positive, ERBB2 (formerly HER2)-negative metastatic breast cancer is treatment with the cyclindependent kinases 4 and 6 (CDK4/6) inhibitors and endocrine therapy (ET). OBJECTIVE To assess overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events, especially grades 3 and 4 adverse events, among patients with HR-positive, ERBB2-negative metastatic breast cancer who were treated with CDK4/6 inhibitors plus ET vs ET alone. DATA SOURCES A systematic search of PubMed, Embase, the main oncology conference of the European Society of Medical Oncology, and the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium databases for randomized clinical trials of CDK4/6 inhibitors plus ET vs ET for HR-positive, ERBB2-negative metastatic breast cancer. Searches were performed up to March 30, 2020. STUDY SELECTION A total of 472 records were assessed in PubMed and Embase by 2 authors, including studies, international meeting reports, and reviews. Inclusion criteria were Englishlanguage phase 2 or 3 randomized clinical trials of HR-positive, ERBB2-negative metastatic breast cancer, with patients randomly assigned to receive CDK4/6 inhibitors plus ET or ET alone, and having OS or PFS outcomes. The exclusion criteria were phase 1 trials, retrospective studies, or studies without survival outcomes. Excluding the references, 16 articles were relevant. After excluding studies based on exclusion criteria, 9 studies were considered eligible for this meta-analysis. DATA EXTRACTION AND SYNTHESIS Two researchers independently extracted data and assessed potential bias. Data assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. The results were pooled using a fixed-effect model. MAIN OUTCOMES AND MEASURES Study heterogeneity was assessed using the I 2 statistic. Hazard ratios (HRs) and 95% CIs were used to evaluate PFS, OS, and subgroup analyses. Overall response and 95% CIs were used to evaluate the objective response rate and grade 3 or 4 adverse events. The primary outcome was OS. RESULTS In total, 9 studies that included a total of 5043 patients with metastatic breast cancer were assessed in this meta-analysis.

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In Support of CDK4/6 Inhibitors—A Meta-analysis of Available Randomized Data

Martin

Goldstein

2020

JAMA Netw Open

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The recent development of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) is arguably one of the most clinically important discoveries for patients living with hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative metastatic breast cancer. Currently, there are 3 available CDK4/6 inhibitors: palbociclib, ribociclib, and abemaciclib. These CDK4/6 inhibitors induce cell cycle arrest by preventing the G1 to S phase transition, and they are often administered in combination with endocrine therapy (ET). Li et al 1 performed a meta-analysis of the 9 published randomized clinical trials that compared ET plus either a CDK4/6 inhibitor or placebo. Eight phase 3 clinical trials were included as well as 1 randomized phase 2 study. Phase 1 trials, retrospective studies, and those without overall survival (OS) outcomes were not included in their analysis.

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CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials

Abstract: Emerging data provide a new standard treatment for advanced HR+/HER2- breast cancer, regardless of menopausal status, prior hormonal/chemotherapy treatments delivered, sites of metastasis. However, benefits should be balanced with longer treatment duration, toxicities, and costs.

Cited by 57 publications

References 33 publications

Progression-Free Survival and Overall Survival of CDK 4/6 Inhibitors Plus Endocrine Therapy in Metastatic Breast Cancer: A Systematic Review and Meta-Analysis

Progression-Free Survival and Overall Survival of CDK 4/6 Inhibitors Plus Endocrine Therapy in Metastatic Breast Cancer: A Systematic Review and Meta-Analysis

Association of Cyclin-Dependent Kinases 4 and 6 Inhibitors With Survival in Patients With Hormone Receptor–Positive Metastatic Breast Cancer

In Support of CDK4/6 Inhibitors—A Meta-analysis of Available Randomized Data

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