Anaplastic lymphoma kinase (ALK) inhibitors represent an important treatment option in ALK-positive non-small cell lung cancer. Crizotinib is the first-generation of ALK-tyrosine kinase inhibitors (TKI), while ceritinib, alectinib, and brigatinib are second-generation, and lorlatinib the third-generation. Clinical trial results have demonstrated that these drugs differ in their safety profile.
To examine the safety profiles of ALK-TKIs by analysing the frequency of selected suspected adverse events, we obtained reports of suspected adverse events (AEs) for all five investigated drugs from the EudraVigilance database, reported within the European Economic Area between 2012 and 2023. The data were exported to computer program Excel, and AEs terms were categorized per Medical Dictionary for Regulatory Activities (MedDRA). Our analysis focused on AEs listed in section 4.4 Special Warnings and Precautions for Use, of the SmPC for the investigated drugs. Disproportionality analyses were conducted to detect safety signals by calculating reporting odds ratios (RORs).
During 2012-2023, 3377 reports and 8415 suspected AEs were submitted in the EudraVigilance database, including 1365 reports for crizotinib, 1069 for alectinib, 470 for lorlatinib, 246 for ceritinib, and 227 for brigatinib. Significant safety signs were found among some common class AEs. Diarrhoea, nausea and vomiting (ROR 4,81) and lipase or amylase elevations (ROR 5,19) were significantly associated with ceritinib, urinary tract disorders (ROR 2,42), neutropenia and leukopenia (ROR 11,64), bradycardia (ROR 2,36), QT interval prolongation (ROR 6,40) and cardiac failure (ROR 2,99) with crizotinib, whereas muscle disorders (ROR 3,38), pneumonitis (ROR 2,08), haemolytic anaemia (ROR 8,06) and atrioventricular block (ROR 8,69) were significantly associated with alectinib. As expected, eye disorders were significantly associated with crizotinib (ROR 3,19), hyperglycaemia with ceritinib (ROR 4,04), hypertension with brigatinib (ROR 16,87), while hyperlipidaemia and psychiatric disorders with lorlatinib (ROR 79,05, and ROR 3,11, respectively). Photosensitivity was associated both with alectinib (ROR 2,29) and brigatinib (ROR 8,16). We did not find statistically significant differences between investigated ALK-TKIs regarding gastrointestinal perforation and hepatotoxicity.
The analysis revealed significant safety signals and confirmed differences between the safety profiles of the investigated medicines, which can contribute to the selection of the most appropriate ALK-TKI in clinical practice and confirms the importance of post-authorization monitoring and reporting suspected AEs.
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