Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment.
PURPOSE
We assessed pulmonary toxicity of cyclin-dependent kinase (CDK)4/6 inhibitors by analyzing the publicly available FDA Adverse Event Reporting System (FAERS).


METHODS
Reports of interstitial lung disease (ILD) were characterized in terms of demographic information, including daily dose, latency, concomitant drugs known to be associated with ILD, and causality assessment (adapted WHO system). Disproportionality analyses were carried out by calculating reporting odds ratios (RORs) with 95% confidence interval (CI), accounting for major confounders, including notoriety and competition biases.


RESULTS
ILD reports (N = 161) represented 2.1% and 0.3% of all reports for abemaciclib and palbocilcib/ribociclib, respectively, with negligible proportion of concomitant pneumotoxic drugs. Increased reporting was found for CDK4/6 inhibitors when compared to other drugs (ROR = 1.50; 95%CI = 1.28-1.74), and abemaciclib vs other anticancer agents (4.70; 3.62-5.98). Sensitivity analyses confirmed a strong and consistent disproportionality for abemaciclib. Higher-than-expected reporting emerged for palbociclib (1.38; 1.07-1.77) and ribociclib (2.39; 1.34-3.92) only when removing Japan reports. ILD occurred at recommended daily doses, with median latency ranging from 50 (abemaciclib) to 253 (ribociclib) days. Causality was highly probable in 55% of abemaciclib cases, probable in 68% of palbociclib cases.


CONCLUSIONS
Increased reporting of ILD with CDK4/6 inhibitors calls for further comparative population-based studies to characterize and quantify the actual risk, taking into account drug- and patient-related risk factors. These findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals through FAERS and other real-world data, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of CDK4/6 inhibitors when diagnosing a lung injury.
['Raschi|Emanuel|E|https://orcid.org/0000-0003-0487-7996', 'Fusaroli|Michele|M|', 'Ardizzoni|Andrea|A|', 'Poluzzi|Elisabetta|E|', 'De Ponti|Fabrizio|F|']
D001943:Breast Neoplasms D051358:Cyclin-Dependent Kinase 4 D005260:Female D006801:Humans D007564:Japan D017563:Lung Diseases, Interstitial D060735:Pharmacovigilance D047428:Protein Kinase Inhibitors
Interstitial lung disease Pharmacovigilance FAERS Abemaciclib Signal Cyclin-dependent kinase (CDK) 4/6 inhibitors