PMID- 35025076 OWN - NLM STAT- MEDLINE DCOM- 20220412 LR - 20220520 IS - 1776-260X (Electronic) IS - 1776-2596 (Print) IS - 1776-2596 (Linking) VI - 17 IP - 1 DP - 2022 Jan TI - Psychiatric Adverse Reactions to Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer: Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System. PG - 43-51 LID - 10.1007/s11523-021-00865-8 [doi] AB - BACKGROUND: The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC). The adverse events (AEs) related to ALK inhibitors are fairly well known; notably, about 20% of patients receiving lorlatinib experienced cognitive effects and behavioral alterations in pivotal trials. Therefore, psychiatric disorders could represent AEs of special interest for all ALK TKIs, deserving careful assessment in the post-marketing setting. OBJECTIVE: We conducted a real-world pharmacovigilance study on psychiatric AEs with marketed ALK inhibitors in subjects with advanced NSCLC. PATIENTS AND METHODS: We performed an observational, retrospective analysis of spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS, as of December 2020), selecting psychiatric AEs to ALK TKIs approved in NSCLC (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib). These AEs were independently scrutinized by three oncologists applying predefined exclusion criteria, described in terms of clinical/demographic features and assessed for drug-related causality according to an adaptation of the WHO-UMC system, a standardized probabilistic algorithm. RESULTS: Among 584 reported psychiatric AEs, 95 cases were selected as potentially treatment related, with higher reporting frequency for lorlatinib (26, 2.8%), followed by brigatinib (10, 1.2%), alectinib (18, 0.7%), ceritinib (12, 0.6%), and crizotinib (29, 0.3%). Reported psychiatric symptoms were mood disorders (39), psychotic disorders (24), and anxiety, agitation, and irritability (25). In the majority (74%) of cases, psychiatric AEs were serious and required hospitalization in about 32% of patients; 15.8% of retained cases were considered as highly probable and 69.5% as probable. Drug discontinuation was recorded in 31.6% of the reported cases, with the highest proportion for lorlatinib (65.4%). CONCLUSION: Notwithstanding limitations, our study found a higher proportion of psychiatric AEs with lorlatinib, but also raised the hypothesis of psychiatric reactions as a class effect of ALK TKIs. CI - (c) 2022. The Author(s). FAU - Sisi, Monia AU - Sisi M AUID- ORCID: 0000-0002-0395-6038 AD - Department of Experimental, Diagnostic and Specialty Medicine, Policlinico S. Orsola-Malpighi, Alma Mater Studiorum-University of Bologna, Bologna, Italy. monia.sisi@studio.unibo.it. FAU - Fusaroli, Michele AU - Fusaroli M AD - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy. FAU - De Giglio, Andrea AU - De Giglio A AD - Department of Experimental, Diagnostic and Specialty Medicine, Policlinico S. Orsola-Malpighi, Alma Mater Studiorum-University of Bologna, Bologna, Italy. AD - Divisione di Oncologia Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. FAU - Facchinetti, Francesco AU - Facchinetti F AD - Institut Gustave Roussy, Inserm, Biomarqueurs Predictifs et Nouvelles Strategies Therapeutiques en Oncologie, Universite Paris-Saclay, Villejuif, France. FAU - Ardizzoni, Andrea AU - Ardizzoni A AD - Department of Experimental, Diagnostic and Specialty Medicine, Policlinico S. Orsola-Malpighi, Alma Mater Studiorum-University of Bologna, Bologna, Italy. AD - Divisione di Oncologia Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. FAU - Raschi, Emanuel AU - Raschi E AD - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy. FAU - Gelsomino, Francesco AU - Gelsomino F AD - Department of Experimental, Diagnostic and Specialty Medicine, Policlinico S. Orsola-Malpighi, Alma Mater Studiorum-University of Bologna, Bologna, Italy. AD - Divisione di Oncologia Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220113 PL - France TA - Target Oncol JT - Targeted oncology JID - 101270595 RN - 0 (Protein Kinase Inhibitors) RN - 53AH36668S (Crizotinib) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) SB - IM MH - Anaplastic Lymphoma Kinase MH - *Carcinoma, Non-Small-Cell Lung/pathology MH - Crizotinib/therapeutic use MH - Humans MH - *Lung Neoplasms/pathology MH - Protein Kinase Inhibitors/adverse effects MH - Retrospective Studies MH - United States MH - United States Food and Drug Administration PMC - PMC8783913 COIS- Dr. F. Facchinetti reports personal fees from BMS and ROCHE, outside the submitted work. Prof. A. Ardizzoni reports grants and personal fees from BMS, personal fees from Eli-Lilly, Pfizer, MSD and Boehringer; grants from Celgene, outside the submitted work. Dr. F. Gelsomino reports personal fees from AstraZeneca and Eli-Lilly, outside the submitted work. Prof E. Raschi reports personal fees from Novartis, outside the submitted work. Dr. M. Sisi, Dr. M. Fusaroli, Dr. A. De Giglio declare that they have no conflicts of interest that might be relevant to the contents of this article. EDAT- 2022/01/14 06:00 MHDA- 2022/04/13 06:00 PMCR- 2022/01/13 CRDT- 2022/01/13 12:58 PHST- 2021/12/16 00:00 [accepted] PHST- 2022/01/14 06:00 [pubmed] PHST- 2022/04/13 06:00 [medline] PHST- 2022/01/13 12:58 [entrez] PHST- 2022/01/13 00:00 [pmc-release] AID - 10.1007/s11523-021-00865-8 [pii] AID - 865 [pii] AID - 10.1007/s11523-021-00865-8 [doi] PST - ppublish SO - Target Oncol. 2022 Jan;17(1):43-51. doi: 10.1007/s11523-021-00865-8. Epub 2022 Jan 13.