Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database

Abstract

IntroductionNon-small cell lung cancer (NSCLC) is often caused by molecular alterations that can be detected by predictive biomarkers including mutations or amplifications of several genes. Several tyrosine kinase inhibitors (TKIs) have been approved in Europe by the European Medicines Agency (EMA) for NSCLC. The aim of this study was to analyze the onset of adverse drug reactions (ADRs) related to TKIs in NSCLC through a spontaneous reporting system (SRS) database.MethodsAll ADR reports having as suspected drug afatinib (AFT), alectinib (ALEC), brigatinib (BRG), ceritinib (CER), crizotinib (CRIZ), erlotinib (ERL), gefitinib (GEF), lorlatinib (LORL), nintedanib (NTB), and osimertinib (OSI) recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2021 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by-case methodology was conducted paying particular attention to all serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, and comorbidities.ResultsOf the 3,048 Italian reports, most of ADRs were related to ERL (n = 1,448), followed by AFT (n = 435) and GEF (n = 366). ADR reports were slightly more frequent in females (52.2%) and in the age group >65 years (53.0%). A higher number of cases were related to skin disorders (n = 1,766; 57.9%), followed by gastrointestinal disorders (n = 1,024; 33.6%), general disorders and administration site conditions (n = 536; 17.6%), and infections (n = 483; 15.8%). The case-by-case assessment of Sicilian ADRs showed that 33 cases were serious (12.5%) and mainly involved ERL (n = 17; 51.5%), occurring in males with a higher onset of respiratory diseases (30.3%) such as respiratory failure, interstitial lung disease and dyspnea.DiscussionThe analysis of spontaneous ADR reports of TKIs confirmed, in general, well-known risks, which often include skin, gastrointestinal, general, liver, and respiratory diseases as well as infections. However, more attention should be paid to the occurrence of serious life-threatening ADRs including respiratory failure, interstitial lung disease, and cardiogenic shock, especially in young patients.

Renal Disorders with Oral Tyrosine Kinase Inhibitors in Metastatic Colorectal Cancer: An Analysis from the FDA Adverse Event Reporting System Database

“…One of the main advantages of using the SRS database is its ability to generate new potential safety signals for ADRs that may remain undetected during the pre-marketing phase [ 52 ]. Patients with cancer often experience a lower health-related QoL, which can be influenced by the use of chemotherapeutic agents, including second- and third-line therapies, as previously observed [ 53 , 54 ]. Notably, the increased use of TKIs as a second-line therapy in patients with mCRC following prior treatment with nephrotoxic chemotherapeutic agents may impact QoL [ 28 , 38 , 55 , 56 ].…”

A bibliometric analysis of research progress on pharmacovigilance and cancer from 2002 to 2021

“…With the widespread use of TKIs, drug-related adverse reactions are also receiving increasing attention. A study analyzing the safety of TKIs for the treatment of non-small cell lung cancer through the Italian Pharmacovigilance database:not only confirmed the well-known risks of TKIs, which usually include skin, gastrointestinal, general, liver and respiratory diseases and infections, but also found the occurrence of life-threatening severe ADRs with TKIs, including respiratory failure, interstitial lung disease and cardiogenic shock, especially in young patients ( 62 ). A pharmacovigilance analysis of ALK-TKI inhibitors conducted through the FDA Adverse Event Reporting System (FAERS) identified several important safety signals, including pulmonary arterial hypertension, rectal perforation, myasthenia gravis, and photosensitivity ( 63 ).…”

Neuropsychiatric Adverse Drug Reactions with Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors: An Analysis from the European Spontaneous Adverse Event Reporting System

“…Patients with GISTs have worse health-related quality of life than the general population, especially when TKIs are used as later treatment lines with more negative effects also influenced by the duration of the tumor course [ 62 ]. For this reason, avoiding the onset of ADRs that could further worsen health-related quality of life and providing information on neuropsychiatric ADRs could be useful for oncologists in patient management as shown in previous studies [ 63 , 64 ].…”