Postmarketing safety of loratinib: An analysis of the FDA Adverse Event Reporting System (FAERS).

Abstract

e24103 Background: Mesenchymal lymphoma kinase (ALK) gene mutation inhibitors are highly effective treatments for ALK-positive lung cancer. We performed a pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: A total of 22 quarterly FAERS files from Q4 2018 to Q1 2024 were used. Reports of lorlatinib were screened. A total of 8,193,675 background patients were included in the analysis (2,425,1106 adverse event occurrences), applying the current MedDRA 27.0 analysis.Adverse events were searched by preferred term (PT) level based on case reports in the literature. After filtering duplicate reports, disambiguation analyses detected safety signals by calculating proportionality ratios of reports (prr), ratios of dominance of reports (RORs), empirical Bayesian geometric means, and information components. Results: The number of patients with lorlatinib was 3,146.Of these, 64 (2.03%) were life-threatening adverse events, 716 (22.76%) were hospitalised due to adverse events, 49 (1.56%) were disabled, and 1021 (32.45%) died. Four methods, ROR, PRR, BCPNN, and MGPS, were used in combination to detect signals, and thresholds were set as follows: a ≥ 3, lower limit of the 95% confidence interval of the ROR > 1PRR ≥ 2, chi-square value ≥ 4, IC-2SD > 0, and EBGM05 > 2. A total of 124 positive PT signals were detected, and the top 5 preferred phrases (PTs) in terms of the frequency of lorlatinib risk signals were ranked:Death ROR (95% CI) 5.81 (5.39-6.27), PRR (Chi-Square) 5.44 (2634.70), IC (IC-2SD) 2.44 (2.32), EBGM (EBGM05) 5.43 (5.03); progressive tumours ROR (95% CI) 72.80 (66.60-79.58), PRR(Chi-Square) 68.74(34238.5), IC(IC-2SD) 6.07(5.76), EBGM(EBGM05) 67.00(61.29); blood cholesterol elevation, ROR(95% CI) 26.24(22.15-31.08), PRR(Chi-Square) 25.86 (3244.42), IC (IC-2SD) 4.68 (4.19), EBGM (EBGM05) 25.62 (21.63).Top 3 preferred terms (PT) for lorlatinib-positive signal intensity: very low-density lipoprotein elevation ROR (95% CI) 274.80 (132.58-569.55),PRR (Chi-Square274.56 (1972.86),IC (IC-2SD) 7.96 (2.11),EBGM (EBGM05)248.51 (119.90); Hypercholesterolaemia ROR (95% CI) 113.27 (92.53-138.66),PRR (Chi-Square) 112.08 (10450.5),IC (IC-2SD) 6.75 (5.41),EBGM (EBGM05) 107.50 (87.82);Lipid abnormalities ROR (95% CI) 126.88 (71.06-226.56), PRR (Chi-Square) 126.72 (1427.41), IC (IC-2SD) 6.92 (2.74), EBGM (EBGM05) 120.90 (67.71). Conclusions: The overall adverse effects of lorlatinib are manageable, but the risk of hyperlipidaemia, particularly very low-density lipoprotein elevation, is strong, in addition to adverse effects including death, progressive tumours, impaired consciousness and psychiatric disorders. These signals require further regulatory investigation to determine their significance.