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Meta-Analysis
. 2020 Nov 1;112(11):1089-1097.
doi: 10.1093/jnci/djaa071.

Overall Survival of CDK4/6-Inhibitor-Based Treatments in Clinically Relevant Subgroups of Metastatic Breast Cancer: Systematic Review and Meta-Analysis

Francesco Schettini  1   2   3 , Fabiola Giudici  4 , Mario Giuliano  1   5 , Massimo Cristofanilli  6 , Grazia Arpino  1 , Lucia Del Mastro  7   8 , Fabio Puglisi  9   10 , Sabino De Placido  1 , Ida Paris  11 , Pietro De Placido  1 , Sergio Venturini  12   13 , Michelino De Laurentis  14 , PierFranco Conte  15   16 , Dejan Juric  17 , Antonio Llombart-Cussac  3   18 , Lajos Pusztai  19 , Aleix Prat  2   3   20 , Guy Jerusalem  21 , Angelo Di Leo  22 , Daniele Generali  23   24
Affiliations
Meta-Analysis

Overall Survival of CDK4/6-Inhibitor-Based Treatments in Clinically Relevant Subgroups of Metastatic Breast Cancer: Systematic Review and Meta-Analysis

Francesco Schettini et al. J Natl Cancer Inst. .

Abstract

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors + endocrine therapy (ET) prolonged progression-free survival as first- or second-line therapy for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer prognosis. Given the recent publication of overall survival (OS) data for the 3 CDK4/6-inhibitors, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups.

Methods: We conducted a systematic literature search to select all available phase II or III randomized clinical trials of CDK4/6-inhibitors + ET reporting OS data in first- or second-line therapy of HR+/HER2-negative pre- or postmenopausal metastatic breast cancer. A random effect model was applied for the analyses. Heterogeneity was assessed with I2statistic. Subgroup analysis was performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP).

Results: Six studies were included in our analyses (3421 patients). A clear OS benefit was observed in patients without (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.54 to 0.85, I2 = 0.0%) and with visceral involvement (HR = 0.76, 95% CI = 0.65 to 0.89, I2 = 0.0%), with at least 3 metastatic sites (HR = 0.75, 95% CI = 0.60 to 0.94, I2 = 11.6%), in an endocrine-resistant (HR = 0.79, 95% CI = 0.67 to 0.93, I2 = 0.0%) and sensitive subset (HR = 0.73, 95% CI = 0.61 to 0.88, I2 = 0.0%), for younger than 65 years (HR = 0.80, 95% CI = 0.67 to 0.95, I2 = 0.0%) and 65 years or older (HR = 0.71, 95% CI = 0.53 to 0.95, I2 = 44.4%), in postmenopausal (HR = 0.76, 95% CI = 0.67 to 0.86, I2 = 0.0%) and pre- or perimenopausal setting (HR = 0.76, 95% CI = 0.60 to 0.96, I2 = 0.0%) as well as in chemotherapy-naïve patients (HR = 0.72, 95% CI = 0.55 to 0.93, I2 = 0.0%).

Conclusions: CDK4/6-inhibitors + ET combinations compared with ET alone improve OS independent of age, menopausal status, endocrine sensitiveness, and visceral involvement and should be preferred as upfront therapy instead of endocrine monotherapy.

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Figures

Figure 1.
Figure 1.
Pooled overall survival (OS) according to metastatic sites and tumor burden. Pooled OS in nonvisceral (A), visceral (B), no bone-only (C), or bone-only (D) disease and in case of less than 3 (E) and 3 or more metastatic sites (F). CI = confidence interval; HR = hazard ratio.
Figure 2.
Figure 2.
Pooled overall survival (OS) according to endocrine resistance status and previous chemotherapy (CT). Pooled OS in patients younger than 65 years (A), 65 years or older (B), postmenopause (C) and pre- or perimenopause (D). CI = confidence interval; HR = hazard ratio.
Figure 3.
Figure 3.
Pooled overall survival (OS)according to age and menopausal status. Pooled OS in patients younger than 65 years (A), 65 years or older (B), postmenopause (C) and pre- or perimenopause (D). CI = confidence interval; HR = hazard ratio.
See this image and copyright information in PMC

References

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