Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment

Breast Cancer Research and Treatment https://doi.org/10.1007/s10549-020-06001-w EPIDEMIOLOGY Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment Emanuel Raschi1 · Michele Fusaroli1 · Andrea Ardizzoni2 · Elisabetta Poluzzi1 · Fabrizio De Ponti1 Received: 30 July 2020 / Accepted: 26 October 2020 © The Author(s) 2020 Abstract 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. Keywords Cyclin-dependent kinase (CDK) 4/6 inhibitors · Abemaciclib · Interstitial lung disease · Pharmacovigilance · FAERS · Signal Introduction The cyclin-dependent kinase (CDK)4/6 inhibitors – palbociclib, abemaciclib, and ribociclib – are now approved both in the United States and Europe for women with hormone * Emanuel Raschi 1 Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy 2 Medical Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Policlinico S. Orsola‑Malpighi, Alma Mater Studiorum - University of Bologna, Bologna, Italy receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, based on positive results of several large pivotal phase III randomized controlled trials [1–3]. From a safety standpoint, CDK4/6 inhibitors are welltolerated agents, with similar safety profile, although some differences exist in the pattern and frequency of toxicities, which might influence the choice of a given medication. The most common side effect for palbociclib and ribociclib is neutropenia, whereas gastrointestinal toxicity is associated especially with abemaciclib (showing less selectivity for CDK4, which plays a critical role in hematopoietic stem cell differentiation) [4]. Among rare adverse events, higher frequency of QT prolongation emerged for ribociclib, whereas transaminases increase was recorded 13 Vol.:(0123456789) Breast Cancer Research and Treatment with ribociclib and abemaciclib resulting in regulatory warnings [5]. Pulmonary toxicity was reported for several anticancer drugs, and over 1300 medications, procedures, or substances are considered to cause respiratory impairment (www.pneumotox.com), although the pulmonary liability is often recognized after marketing approval. The term “interstitial lung diseases” (ILDs) poses a challenging clinical diagnosis as it refers to heterogeneous disorders with remarkably different clinical pathophysiology, histories, and prognoses, such as idiopathic pulmonary fibrosis, sarcoidosis, connective tissue disease associated with ILDs, and hypersensitivity pneumonitis. Drug-induced ILD incidence rates vary between 4.1 and 12.4 cases/million/year, with anticancer agents, anti-rheumatic drugs, amiodarone, and antibiotics being the most common causes [6]. Although data on pulmonary toxicity with CDK4/6 inhibitors are scant, recent case reports have described the potential occurrence of pneumonitis, including fatal cases [7]. Moreover, in the Food and Drug Administration (FDA) label for abemaciclib, it is reported that there was 1 death due to pneumonitis in the MONARCH 3 trial, and 2 deaths due to pneumonitis in the MONARCH 2 trial. In the MONALEESA-2 trial, there were two deaths secondary to acute respiratory failure in patients receiving ribociclib plus letrozole. In May 2019, the Japanese Ministry of Health released a warning as 14 patients in Japan developed pulmonary toxicity likely due to abemaciclib exposure (nearly 2000 exposed), and three of them died. Recently, on September 13th, 2019, the FDA issued a warning about rare but severe lung inflammation with CDK4/6 inhibitors, based on cases of ILD and pneumonitis identified in the manufacturers’ completed and ongoing clinical trials and the postmarketing safety databases. Although rare (1–3% of patients had ILD/pneumonitis of any grade), there were serious cases (less than 1% had fatal outcome), and some patients had at least one risk factor (https://www.fda.gov/drugs/drug-safet y-and-availability/fda-warns-about-rare-severe-lung-infla mmation-ibrance-kisqali-and-verzenio-breast-cancer). Post-marketing monitoring is therefore crucial to timely characterize ILD and to target preventive strategies for diagnosis and management [8]. In this context, international spontaneous reporting systems, through collection of millions of worldwide reports, represent a primary source of data for safety assessment of recently marketed drugs receiving fast track designation and priority review, which deserve rigorous post-marketing monitoring [9, 10]. In particular, the FDA Adverse Event Reporting System (FAERS) is the largest publicly available pharmacovigilance database particularly suitable to detect rare adverse events, which may escape detection and/or reporting from randomized controlled trials. 13 On these grounds, the aim of this real-world post-marketing study is to comprehensively characterize spontaneous reports of ILD with CDK4/6 inhibitors submitted to FAERS and investigate whether pulmonary toxicity actually occurs with all CDK4/6 inhibi (...truncated)