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Meta-Analysis
. 2020 Sep 3;21(17):6400.
doi: 10.3390/ijms21176400.

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

Michela Piezzo  1 , Paolo Chiodini  2 , Maria Riemma  1 , Stefania Cocco  1 , Roberta Caputo  1 , Daniela Cianniello  1 , Germira Di Gioia  1 , Vincenzo Di Lauro  1 , Francesca Di Rella  1 , Giuseppina Fusco  1 , Giovanni Iodice  1 , Francesco Nuzzo  1 , Carmen Pacilio  1 , Matilde Pensabene  1 , Michelino De Laurentiis  1
Affiliations
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

Michela Piezzo et al. Int J Mol Sci. .

Abstract

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]).

Keywords: CDK4/6 inhibitors; cancer; epidemiology; hormone receptors; hormone therapy; metastatic breast cancer; overall survival; subgroup analysis; therapies.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pooled comparison of PFS according endocrine sensitivity (de novo disease, AI sensitive, AI resistant) and treatment-free interval (TFI <= 24 months, TFI > 24 months, TFI <= 36 months, TFI > 36 months). Abbreviations: PFS: progression free survival; N exp: number of patients randomized in experimental arm; N control: number of patients randomized in control arm; HR: hazard ratio; CI: confidence interval; AI: aromatase inhibitors; TFI: treatment free interval).
Figure 2
Figure 2
Pooled comparison of PFS according to site of metastasis (visceral disease, bone-only disease and no bone-only disease) and number of organs involved (1, 2, 3+). Abbreviations: PFS: progression free survival; N exp: number of patients randomized in experimental arm; N control: number of patients randomized in control arm; HR: hazard ratio; CI: confidence interval).
Figure 3
Figure 3
Bar plot of pooled ORR in all randomly assigned patients and in patients with measurable disease according to ET sensitivity status. Abbreviations: ORR: objective response rate; OT: hormonal therapy; CDK: cyclin dependent kinase).
Figure 4
Figure 4
Meta-analysis of overall survival grouped by AI sensitivity (AI sensitive versus AI resistant) and CDK 4/6 inhibitor (Ribociclib, Abemaciclib, Palbociclib). Abbreviations: OS: overall survival; N exp: number of patients randomized in experimental arm; N control: number of patients randomized in control arm; HR: hazard ratio; CI: confidence interval; AI: aromatase inhibitors).
Figure 5
Figure 5
Meta-curves of PFS for AI-sensitive and AI-resistant patients: PFS is significantly longer in patients treated with CDK4/6 inhibitor than patients treated with ET alone (dashed lines), in both AI sensitive (red line and violet dashed line) and AI resistant (blue line and azure dashed line) group. Abbreviations: PFS: progression free survival; AI: aromatase inhibitor; ET: endocrine therapy.
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