(227) Risk of Cardiovascular Events with Cyclin-Dependent Kinases 4 and 6 (CDK 4/6) Inhibitors among Patients with Metastatic Breast Cancer: A Systematic Review and Network Meta-Analysis
PhD Candidate The University of Texas at Austin, United States
Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have shown promising survival outcomes with additional treatments to the traditional endocrine therapy (ET) in patients with hormone receptor-positive, and HER2-negative advanced breast cancer (aBC). However, the head-to-head cardiovascular safety profile of these three agents (palbociclib, ribociclib, and abemaciclib) remains unclear.
Objectives: We aimed to qualitatively synthesize the incidence of major adverse cardiovascular events (MACE) associated with the use of CDK4/6 inhibitors and to investigate the comparative MACE risks of the three agents through randomized clinical trials (RCTs).
Methods: A systematic search through PubMed and Cochrane Library was performed to identify phase III RCTs reporting cardiovascular safety data of CDK4/6 inhibitors in patients with aBC. The outcome of interest was an occurrence of MACE within on-treatment or placebo-controlled duration. A Bayesian NMA with fixed-effects models was performed using NetMetaXL which is a worksheet linked to WinBUGS 1.4.3. Effect sizes were pooled using the Markov Chain Monte Carlo approach with 10,000 iterations, and pair-wise comparisons between treatment options were presented by odds ratios (OR) and 95% credible intervals (CIs). The probability of each treatment arm’s relative ranking was reported using surface under the cumulative ranking curve (SUCRA) scores. A sensitivity analysis was conducted using the Mantel–Haenszel (MH) method in R.
Results: Nine RCTs with four unique treatment arms and event(s) in at least one arm were included in the NMA. A total of 5,218 patients were analyzed for MACE outcomes. The overall incidence of MACE in the CDK4/6 inhibitors plus endocrine therapy group was 0.8%, while the endocrine therapy alone group was 0.4%. Abemaciclib+ET ranked the best in reducing the risk of MACE (SUCRA=0.90) as compared to ET alone (SUCRA=0.67, OR 0.45, 95% Cl 0.07 to 2.82), palbociclib+ET (SUCRA=0.25, OR 0.09, 95% Cl 0.00 to 2.39), and ribociclib+ET (SUCRA=0.17, OR 0.08, 95% Cl 0.00 to 1.18). However, no statistically significant differences were observed among different intervention arms. The findings were similar in the NMA based on the MH method. However, abemaciclib+ET (OR 0.11; 95% Cl 0.02 to 0.81) had a significantly lower risk of MACE than ribociclib+ET in the MH network. No statistically significant differences in hypertension were shown among all treatment comparisons.
Conclusions: Abemaciclib+ET may have a lower risk of MACE for the treatment of aBC while palbociclib+ET may reduce the risk of hypertension in this population. Further research on direct comparisons is needed in guiding treatment choice.
