Using the FDA Adverse Event Reporting System to Find Links Between Interstitial Lung Disease and CDK4/6 Inhibitors

As noted in the pneumotox.com database, respiratory impairment has been attributed to more than 1300 medications, procedures, or substances; remarkably, pulmonary liability is often noted after approval of medications and often related in postmarketing reports. A challenging aspect of applying “interstitial lung disease” (ILD) as a clinical diagnosis is that the term itself refers to a spectrum of disorders that are heterogeneous and have widely divergent histories, etiology, pathophysiology, and prognoses. For example, connective tissue disease, idiopathic pulmonary fibrosis, and sarcoidosis have all been associated with ILD. Anticancer medications, antirheumatic agents, amiodarone, and antibiotics are the most common causes of drug-induced ILD, the incidence rates of which range between 4.1 million and 12.4 million cases a year.¹

The class of medications called cyclin-dependent kinase (CDK)4/6 inhibitors are generally well-tolerated with similar safety profiles; within the class, clinical decisions about medication selection may be specifically influenced by some differences in toxicity frequency. For several anticancer drugs, reports of pulmonary toxicity have been observed. While pulmonary toxicity data are scarce with CDK4/6 inhibitors, case reports of pneumonitis have been described recently, including 3 fatal cases due to pneumonitis: 1 death in the MONARCH 3 trial and 2 deaths in the MONARCH 2 trial.² In addition, there were 2 deaths secondary to acute respiratory failure in patients who received letrozole combined with ribociclib in the MONALEESA-2 trial.³

Researchers analyzed the US Food and Drug Administration Adverse Event Reporting System, the largest publicly available pharmacovigilance database, to assess pulmonary toxicity associated with CDK4/6 inhibitors. Rare adverse events, which may escape detection and reporting from randomized controlled trials, make this a particularly suitable approach for analysis. The investigators identified cases of ILD and assessed them on the basis of demographic information, daily-dose medication regimen, latency, known drug combinations linked with ILD, and causality.

A total of 161 ILD reports were included in the analysis, constituting approximately 2.1% and 0.3% of all reports for abemaciclib and palbociclib/ribociclib, respectively, with an insignificant percentage of concomitant pneumotoxic medications. For CDK4/6 inhibitors, there were increased reports when compared with other medications (reporting odds ratio [ROR], 1.50; 95% confidence interval [CI], 1.28-1.74) and abemaciclib compared with other anticancer agents (ROR, 4.70; CI, 3.62-5.98). A strong and consistent disproportionality for abemaciclib was confirmed through sensitivity analyses. For palbociclib and ribociclib, higher-than-expected reporting emerged only after eliminating reports from Japan, in which case it should be noted that 14 patients developed pulmonary toxicity likely caused by abemaciclib exposure and the Japanese Ministry of Health released a warning. At recommended daily doses, ILD occurred with median latency times ranging from 50 days for abemaciclib to 253 days for ribociclib. In 55% of abemaciclib cases, causality was highly probable, and in 68% of palbociclib cases causality was probable.

The investigators concluded that reports of ILD potentially associated with CDK4/6 inhibitors warrants further analysis. This study suggests that appropriately timed pharmacovigilance efforts focused on assisting clinicians in accurately assessing the potential responsibility of CDK4/6 inhibitors when diagnosing a lung injury are critical. Evaluating postmarketing data and real-world reports will ultimately help with the early clinical assessment of adverse events taken on a case-by-case basis.

Source:

Raschi E, Fusaroli M, Ardizzoni A, et al. Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment. Breast Cancer Res Treat. 2021;186:219-227.

References

1. Skeoch S, Weatherley N, Swift AJ, et al. Drug-induced interstitial lung disease: a systematic review. J Clin Med. 2018;7:356.
2. Rugo HS, Huober J, García-Sáenz JA, et al. Management of abemaciclib-associated adverse events in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: safety analysis of MONARCH 2 and MONARCH 3 [published correction appears in Oncologist. 2021 Mar;26:e522]. Oncologist. 2021;26:e53-e65
3. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2019;30:1842.