Adverse events reporting of XPO1 inhibitor - selinexor: a real-word analysis from FAERS database

As the world's first oral nuclear export inhibitor, selinexor is increasingly being used in clinical applications for malignant tumors. However, there is no extensive exploration on selinexor's adverse events (ADEs), necessitating a real-word assessment of its clinical medication safety. FAERS data (July 2019–June 2023) were searched for selinexor ADE reports across all indications. Use the system organ class (SOC) and preferred terms (PT) from the medical dictionary for regulatory activities (MedDRA) to describe, categorize, and statistic ADEs. Disproportionality analysis was employed through calculation of reporting odds ratio (ROR) and proportional reporting ratio (PRR). Based on total of 4392 selinexor related ADE reports as the primary suspect (PS), of which 2595 instances were severe outcomes. The predominant ADEs included gastrointestinal disorders, myelosuppression symptoms, and various nonspecific manifestations. 124 signals associated with selinexor ADE were detected, and 10 of these top 15 signals were not included into the instructions. Our study provides real-world evidence regarding the drug safety of selinexor, which is crucial for clinicians to safeguard patients’ health.


Data processing
In DEMO data, it documented 7,604,592 of ADE reports associated with selinexor.After excluding duplicates records (n = 1,587,493), the final DEMO was determined (n = 6,017,099).After filtering through the DRUG (n = 34,423), we identified these reports by considering selinexor as the primary suspect drug (PS), while excluding data of secondary suspect (SS) and concomitant (C) drug.Together with REAC (n = 17,894), a total of 4392 selinexor related ADE reports as the PS were ultimately confirmed.The system organ class (SOC) and preferred term (PT) based on the medical dictionary for regulatory activities (MedDRA) facilitated the description, code and classification of the ADEs.Subsequent analysis was conducted as shown in Fig. 1.

Statistical analysis
The reporting odds ratio (ROR) and proportional reporting ratio (PRR) methods were employed in this study, through a disproportional approach [26][27][28] .These two methods primarily rely on a four-cell table and calculate

Selinexor ADEs involved in SOC
Out of the submitted 4392 reports, a total of 17,483 ADE instances were identified based on different SOC categories.There were predominantly gastrointestinal reactions (n = 3811, 21.80%), followed by general disorders Table 1.Calculation formulas and corresponding thresholds for ROR and PRR methods.a, number of target event reports of target drugs; b, other event reports of the target drug; c, target event reports of other drugs; d, other event reports of other drugs; 95% CI, 95% confidence interval.and administration site conditions (n = 3208, 18.35%), investigations (n = 1744, 19.98%) meaning examination relevant abnormalities including various blood tests, biochemical analyses, imaging examinations, etc., as illustrated in Fig. 3.

Discussion
This study utilized the FAERS database to rigorously evaluate ADEs associated with selinexor's clinical use.Notably, we observed an elevated occurrence of events leading to severe outcomes that could not be ignored.This requires the focus of patient health, regulatory authorities as well as pharmaceutical companies.Based on PT description, major ADEs identified included myelosuppression, gastrointestinal disorders, and non-specific general reactions in our study.Regarding as ADEs involved in SOC, given that the administration manner of oral drugs, the top ADEs were generally refer to be gastrointestinal tract (GI), aligning with the premarketing evaluations.However, some inconsistent and unreported ADE signals emerged compared to previous reports, which deserve more attention.Hypercreatinemia, typically defined as elevated blood creatine level, is usually associated with issues of musculoskeletal, connective tissue, and metabolism.It has not been explicitly reported in public studies on selinexor, indicating that such an ADE should be closely monitored in following clinical practice.Similar with hypercreatininemia, which is a sign of renal function abnormality, both of them reflect an imbalance of substances related to body metabolism.Yet, the causes for themselves are generally diverse.In FAERS analysis, hypercreatinemia and hypercreatininemia are categorized under varied SOC classes, thus the captured ADE signals differed.Regarding as issue of renal dysfunction, it was notably evidenced by 19 instances of abnormal renal function and 9 instances of hypercreatininemia in our results.It's well-known that injury of renal may be caused by various factors including disease progression, infections, and the use of other certain medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs) 29 , statins/fibrates lipid-lowering drugs 30 , certain antibiotics (aminoglycosides) 31 , antifungal agents (amphotericin B) 32 , and antipsychotics (olanzapine) 33 , etc. Nevertheless, our study focused on statistical analysis of ADEs which were primarily suspected to be related to selinexor, there was no  www.nature.com/scientificreports/need to consider of concomitant medication.We attempted to explore whether the use of selinexor is associated with renal impairment or not, and found there were only minority of studies elucidated previously 34 .A clinical trial on RR-DLBCL patients found that selinexor's safety and efficacy to be independent of renal function.The post-hoc analysis of the SADAL study indicates that selinexor remained safe and effective even in patients with impaired renal function 35 .In assessments of MM, Bader's study suggested the use of selinexor cannot aggravate the side effects on renal injuries 34 , regardless of the patient's prior renal function.Furthermore, descriptions of renal function impairment in ADE signals involve many abnormal indicators, including electrolyte level abnormalities.For instance, hyponatremia occurrences were reported frequently in previous studies, with an incidence rate about 30% 36 .In our study, we did not find specific signals linked selinexor ADEs to electrolyte imbalance.Taken together, the direct association of selinexor with renal function abnormality appears insufficient in clinical applications.We're not sure if it is caused by other concomitant medications, and look forward to further studies in the future.
Regarding issues on tumor signals following the clinical application of selinexor, we could not conclude a definite causal relationship.As shown in the results, our study showed that several ADE signals with tumors were involved, such as neurofibrosarcoma, refractory DLBCL, sarcoma, and bone tumors, etc.Because our analysis did not set a specific application scope, it suggests that patients for potential indications might have experienced progression of their own diseases, due to selinexor is currently under clinical trials for numerous hematologic malignancies and solid tumors.For example, Gounder's et al. 37 study assessed the pharmacokinetics, pharmacodynamics, safety, and efficacy of selinexor in patients with advanced soft tissue or bone sarcomas.Another study evaluated the safety of selinexor in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), including subtypes of NHL such as diffuse large B-cell lymphoma, Richter transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia 38 .Additionally, Lewin's study explored the safety and efficacy of selinexor in combination with doxorubicin in treating advanced soft tissue sarcomas (STS), compassing malignant peripheral nerve sheath tumors (n = 3) and other types of sarcomas (n = 16) 39 .According to these results, selinexor has shown certain effectiveness in treating various solid tumors as a potential indication.Nevertheless, even if selinexor is highly associated with specific tumor signals, it is difficult to conclude that the drug directly caused the event.
Moreover, selinexor may cause a variety of non-specific side effects as a novel targeting anti-tumor drug.Nagham et al. 40 retrospectively analyzed the medical records of 174 patients who received at least one dose of selinexor in combination with chemotherapy or immunotherapy drugs.This cohort monitored the occurrence of the ocular ADEs, with blurred vision (12.64%), followed by dry eye syndrome (12.1%), and progression of cataracts (4.0%).However, there were no discontinuations due to ocular ADEs, leading to the conclusion that selinexor-related ocular ADEs are mild.In our study, meibomian gland dysfunction and iridesma were reported for the first time, suggesting that we can offer distinct insights into selinexor related ADE signals.Another related ADE of taste reduction, the possible physiological mechanisms behind this side effect include the drug's direct toxic effect on taste cells or indirect impacts on the oral environment.Nevertheless, this non-specific ADE of selinexor is rarely reported in clinical, possibly because it is temporary which did not cause enough attention.
The discovery of these potential ADEs underscores the need for a deeper investigation into selinexor's safety profile.Firstly, the identification of these unreported ADEs highlights the importance of continuous drug monitoring post-marketing.Secondly, these findings remind us that with the expanding indications and broaden applications in real-world of selinexor, unexpected ADEs might emerge.Although clinical trials provide crucial data on safety and efficacy, they are usually employed in a strictly controlled environment with limited sample However, the FAERS analysis also has its certain limitations.Self-reporting bias, the lack of controlled studies, and the complexity of determining causal relationships are inherent flaws in FAERS analysis 41 .As a spontaneous reporting system, it means the reports come from numerous sources, and over-or under-reporting of specific information may lead to reporting bias.Therefore, the quality, completeness and accuracy of the reports may be limited.For instance, "N/A" in the chart of our study signifies missing data from the up-loader.This lack of basic information may compromise data integrity, but the generation of ADE signals would not be affected due to the massive real-word data.Besides, ADE reports in FAERS could not establish a causal relationship between drug use and ADEs.In FAERS report, there was no control group to compare ADEs between drug users and non-users.Without a control group, it is difficult to determine whether ADEs caused by specific drug or other factors.Therefore, ADE reports in the FAERS should be interpreted cautiously.Although spontaneous report system provides an inadequate level of evidence hierarchy, it serves as a tool for timely and early assessment of safety issues, especially in new compounds.It's well-known that clinical trials are considered the best source of evidence, but they are often limited by stringent criteria and limited sample sizes.Conversely, the analysis of spontaneous reports reflects these conditions where patients experience primary outcomes within a complex real-world context.
In conclusion, our study offers the first real-world insights into oncological ADEs of selinexor, supplementing its post-marketing safety research and providing reference for its clinical use.

Figure 1 .
Figure 1.Flow chart of the study.

Table 2 .
Clinical characteristics of reports with selinexor ADEs.N/A not recorded information.

Table 3 .
The distribution of selinexor severe outcomes.

Table 5 .
Top 15 disproportional signals for ADEs associated with selinexor.a Indicates the ADEs which were not included in the instruction manual.b Indicates that selinexor has undergoing clinical trials for this disease, meaning a potential indication.