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

Abstract

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. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00865-8.

Measuring Safety and Outcomes for the Use of Compassionate and Off-Label Therapies for Children, Adolescents, and Young Adults With Cancer in the SACHA-France Study

“…This includes, for example, a secondary malignant neoplasm in a patient younger than 5 years with ATRT and a long-lasting response to tazemetostat, which is the second case reported to our knowledge. 21 Interestingly, some of the reported unexpected SADRs are well-known toxic effects already reported to a specific drug or drug class but not included in the summary of product characteristics (eg, alectinib and psychiatric ADRs 22 ; regorafenib and pneumothorax 23 ), further stressing the importance of adequate reporting of these toxic effects.…”

Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database

“… 17 The actual clinical and epidemiological impact of these relatively rare adverse events (e.g., psychiatric disorders) can be better assessed in real world data (e.g., the FAERS database) than in registration trials. 18 …”

Lorlatinib in Frontline Therapy for ALK+ Advanced Non–Small-Cell Lung Cancer: Still a Matter of Debate?

“…In the CROWN trial, CNS AEs affected 35% of patients receiving lorlatinib, without clear evidence of a correlation with the presence or the location of brain metastases at baseline or prior brain radiotherapy. 18 Their mechanism remains speculative, possibly related to ALK blockade as CNS AEs have also been described with other ALK inhibitors 19 or to interference with tropomyosin-related kinase B signaling on the basis of its high ATP binding site sequence homology to ALK 20 and the impact of its downregulation on memory, cognition, and eating disorders. 21,22 Thirty-nine percent of these CNS AEs were grade 2 or 3 events, representing 13% of the population receiving lorlatinib 18 ; many grade 2 CNS AEs already imply interference with work performance and limitation in instrumental activities of daily living.…”