QTc prolongation across CDK4/6 inhibitors: a systematic review and meta-analysis of randomized controlled trials

• Published in: JNCI cancer spectrum Vol. 8; no. 5
• Main Authors: Murad, Bruno, Reis, Pedro C A, Deberaldini Marinho, Alice, Marin Comini, Ana Carolina, Pinheiro Xavier, Débora, Mella Soares Pessoa, Beatriz, Raheem, Farah, Ernst, Brenda, Mina, Lida A, Batalini, Felipe
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 02.09.2024
• Subjects: Aminopyridines - administration & dosage; Aminopyridines - adverse effects; Aminopyridines - therapeutic use; Benzimidazoles; Breast Neoplasms - drug therapy; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Female; Humans; Long QT Syndrome - chemically induced; Meta-Analysis; Piperazines - adverse effects; Piperazines - therapeutic use; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - therapeutic use; Purines - administration & dosage; Purines - adverse effects; Purines - therapeutic use; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - therapeutic use; Randomized Controlled Trials as Topic; Roscovitine - adverse effects
• ISSN: 2515-5091; 2515-5091
• DOI: 10.1093/jncics/pkae078

Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2- breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. We included 14 RCTs comprising 16 196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P < .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.