CDK 4/6 inhibitors plus endocrine therapy in ER positive metastatic breast cancer (MBC): Systematic review and meta-analysis of randomized clinical trials

Abstract

Background: CDK 4/6 inhibitors (palbociclib, ribociclib, abemaciclib) have been rencently introduced in the clinical management of ER positive metastatic breast cancer (MBC) patients, based on significant improvements in terms of progression free survival (PFS); however, no improvent in overall survival (OS) has been demonstrated in individual trials so far. The purpose of this analysis was to assess, across trials, the effect on progression free (PFS) and overall survival (OS) of the combination of endocrine therapy and CDK 4/6 inhibitors. Method(s): We searched literature databases to identify randomized controlled trials that compared endocrine therapy (ET) with ET plus CDK4/6 inhibitors in ER positive MBC. The main outcome measures for this analysis were OS and PFS. Log hazard ratios (HRs) for OS and PFS were pooled across the studies by inverse variance weighting. Primary analyses were done with a fixed effects model, since no heterogeneity was found among studies. Result(s): We found 7 randomised clinical trials including 3854 patients. Of these, 4 included only first line therapy and 3 allowed prior treatments for MBC. Overall, the addition of CDK4/6 inhibitors to ET was associated with a significant improvement in PFS (HR=0.54, 95% CI, 0.49 to 0.59; P 0.001), without any remarkable heterogeneity (I2= 0). In trials of first line therapy, the HR was 0.56 (95% CI, 0.49 to 0.63, P<0.001); in trials including pretreated MBC the HR was 0.52 (95% CI 0.46 to 0.60, P<0.001). OS data were reported by 3 out of 7studies (1354 patients); a statistically significant improvement in OS was detected (HR 0.79; 95% CI, 0.66 to 0.96; P 0.015). There were no differences in effects on PFS among subgroups defined by age, metastatic site and Disease Free Interval. Conclusion(s): The addition of CDK 4/6 inhibitors to endocrine therapy in ER positive MBC was consistently associated with a 50% reduction in the rate of progression both in first and subsequent lines of treatment and this effect appears to be independent of age, site of metastasis and DFI. Overall survival data are available in 3 studies, showing that the PFS advantage translates into a clinically meaningful and statistically significant survival advantage.