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. 2022 Nov 23:12:1005626.
doi: 10.3389/fonc.2022.1005626. eCollection 2022.

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

Maria Antonietta Barbieri  1 , Emanuela Elisa Sorbara  1 , Giuseppe Cicala  1 , Vincenza Santoro  1 , Paola Maria Cutroneo  2 , Tindara Franchina  3 , Mariacarmela Santarpia  3 , Nicola Silvestris  3 , Edoardo Spina  1
Affiliations

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

Maria Antonietta Barbieri et al. Front Oncol. .

Abstract

Introduction: Non-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.

Methods: All 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.

Results: Of 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.

Discussion: The 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.

Keywords: adverse drug reactions; anaplastic lymphoma kinase; epidermal growth factor receptor; non-small cell lung cancer; pharmacovigilance; tyrosine kinase inhibitors.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Italian (A) and Sicilian (B) trend of ADR reports related to TKIs approved for NSCLC over the years. ADR, adverse drug reaction; NSCLC, non-small cell lung cancer; TKIs, tyrosine kinase inhibitors.
Figure 2
Figure 2
Time to onset of Sicilian ADRs related to TKIs approved for NSCLC. ADR, adverse drug reaction; AFT, afatinib; ALEC, alectinib; ALKi, anaplastic lymphoma kinase inhibitors; BRG, brigatinib; CER, ceritinib; CRIZ, crizotinib; EGFRi, epidermal growth factor receptor inhibitors; ERL, erlotinib; GEF, gefitinib; LORL, lorlatinib; NSCLC, non-small cell lung cancer; NTB, nintedanib; OSI, osimertinib; TKIs, tyrosine kinase inhibitors.
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