Abstract

Background:

With the increasing use of bispecific T cell engagers (BiTEs) in anti-tumor immunotherapy, the associated adverse reactions pose significant challenges to clinical application. Nervous system toxicity (NST) is one of the notable adverse events associated with this class of drugs. This study aims to provide a comprehensive analysis of BiTE-induced nervous system adverse events. Improving the diagnosis and monitoring of these adverse events is crucial for the early identification and treatment of NSTs.

Methods:

We utilized the FAERS database to analyze NSTs associated with BiTEs reported between January 2004 and September 2025. Positive safety signals of the drugs were assessed using four commonly applied disproportionality analysis methods. In addition, the time to onset of drug-induced adverse reactions was evaluated.

Results:

A total of 15,558 patients who developed NSTs during BiTE therapy were included in this study. The average age at NST onset was 51.12 ± 24.44 years. The incidence was 21.19% higher in men than in women (6,139 men vs. 5,065 women), with the United States reporting the highest proportion of cases (50.68%). Among the BiTEs analyzed, blinatumomab accounted for the highest number of reported cases (49.63%). The NSTs observed include immune effector cell-associated neurotoxicity syndrome and other forms of neurotoxicity. Tremor, seizures, and nervous system disorders were reported more frequently with blinatumomab. In the comparative analysis of drug induction time, glofitamab exhibited the longest induction time [82.00 days (range, 1∼1190)], whereas tarlatamab showed the shortest time [16.70 days (range, 1∼141)].

Conclusion:

BiTEs have the potential to induce significant adverse events within the central nervous system and may exacerbate pre-existing conditions. Given the increasing utilization of BiTEs, it is essential to integrate resources such as the FAERS database to effectively monitor adverse reactions associated with these novel therapeutic agents.

1 Introduction

Cancer treatment has advanced substantially over the last decade, particularly with the advent of immunomodulatory therapies that enhance host anti-tumor immunity. Unlike traditional radiotherapy and chemotherapy, immunotherapy aims to eliminate tumor cells by harnessing the body’s own immune system. This approach has led to the development of numerous immunotherapeutic agents that are now available on the market. Among these, bispecific T cell engagers (BiTEs) have gained considerable attention and demonstrated great promise. BiTEs represent a transformative immunotherapy modality by effectively bridging the gap between T cell cytotoxicity and tumor antigen specificity. These engineered molecules simultaneously bind CD3 on T cells and tumor-associated antigens (TAAs) on cancer cells, thereby facilitating targeted immune activation and tumor cell lysis (Iwahori et al., 2015). Owing to their specificity and efficacy, BiTEs have become an attractive strategy for cancer treatment. Consequently, BiTEs targeting multiple tumor-associated antigens have been developed and achieved remarkable outcomes in clinical trials.

As of May 2025, the food and drug administration (FDA) has approved nine BiTE drugs, seven of which are indicated for treating hematological malignancies—blinatumomab, elranatamab, epcoritamab, glofitamab, mosunetuzumab, talquetamab, and teclistamab; the remaining two—tarlatamab and tebentafusp—are indicated for the treatment of solid tumors. Notably, blinatumomab has garnered significant attention as it was the first FDA-approved BiTE for clinical use in treating hematological malignancies. It targets CD19 and CD3, and is currently approved for the treatment of relapsed, refractory, and minimal residual disease (MRD)-positive B-cell acute lymphoblastic leukemia (BCP-ALL) in both adults and children. A Phase III clinical trial demonstrated that, compared to chemotherapy alone, the addition of blinatumomab to consolidation chemotherapy significantly improved overall survival in adult patients with MRD-negative remission from BCP-ALL (Litzow et al., 2024), with similar results observed in pediatric patients as well (Gupta et al., 2025). Tarlatamab is the first FDA-approved BiTE drug for the treatment of solid tumors (Ahn et al., 2023). This bispecific T-cell engager targets delta-like ligand 3 and has demonstrated durable anticancer activity with a manageable safety profile in previously treated patients with small cell lung cancer (SCLC), as evidenced in the DeLLphi-300 Phase I and DeLLphi-301 Phase II trials (Ahn et al., 2023; Paz-Ares et al., 2023). Furthermore, a Phase III trial reported that treatment with tarlatamab improved overall survival compared with chemotherapy in patients with SCLC whose disease progressed during or after platinum-based chemotherapy (Mountzios et al., 2025). Collectively, these findings underscore the considerable advantages of BiTEs in tumor treatment.

As with other anticancer drugs, adverse reactions associated with BiTEs can often lead to treatment interruption due to poor tolerability. Previous studies have reported that BiTEs may induce cytokine release syndrome (CRS), cardiovascular adverse reactions, anemia, infections, and diarrhea, among other side effects (Litzow et al., 2024; Labanca et al., 2025; Thieblemont et al., 2024). Furthermore, analyses of the FDA Adverse Event Reporting System (FAERS) database have revealed hepatobiliary toxicities associated with BiTE drugs, including conditions not documented in product labeling, such as ascites, hepatobiliary diseases, graft-versus-host disease after liver transplant, and veno-occlusive liver disease (Hu et al., 2025). Multiple clinical trials have also reported nervous system toxicity (NST) during BiTE treatment. Research indicates that BiTEs may lead to immune effector cell-associated neurotoxicity syndrome (ICANS) and other neurotoxic effects, with blinatumomab in particular being associated with epilepsy-related adverse reactions and cerebellar disorders (Bargou et al., 2008; Topp et al., 2011). The adverse reactions of these drugs can also vary depending on factors such as race, age, and dosage (Mocquot et al., 2022).

Given the inherent limitations of clinical trials—such as insufficient sample sizes and racial differences—the association between BiTEs and NSTs remains incompletely understood. Consequently, pharmacovigilance serves as a crucial method for uncovering post-marketing drug–adverse event (AE) relationships. FAERS constitutes the database for FDA’s post-marketing monitoring program for drugs and therapeutic biologics, collecting reports of AEs and medication errors. Therefore, utilizing FAERS data is essential for identifying pharmacovigilance signals during the clinical trial phase. To date, no systematic analysis has been performed on NSTs associated with BiTE drugs. Therefore, this study employed the FAERS database to analyze neurological AEs related to BiTE therapy reported in recent years, thereby establishing a theoretical foundation for understanding potential NSTs in patients receiving BiTE drugs.

2 Data and methods2.1 Data source

FAERS is a crucial pharmacovigilance database utilized by the U.S. FDA to monitor post-marketing safety signals associated with drugs and medical products. Established as a repository for spontaneous AE reports, FAERS collects and compiles data from healthcare professionals, consumers, manufacturers, and legal representatives through the FDA MedWatch program. The FAERS database comprises seven core tables: DEMO (demographics), DRUG (drug/biologic information), REAC (adverse events), OUTC (patient outcomes), RPSR (report sources), THER (therapy dates), and INDI (indications). These tables are interconnected by unique identifiers to facilitate integrated analyses. This study analyzed all nervous system adverse reactions associated with BiTE drugs reported between January 2004 and September 2025. Adverse reactions in FAERS are coded using “Preferred Terms” (PT) codes from the Medical Dictionary for Regulatory Activities (MedDRA) to ensure standardized and accurate event classification and analysis. Integration with MedDRA and standardizing AE coding through both PTs and System Organ Classes (SOCs) enables granular signal detection via disproportionality analyses—such as the reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN)—which quantify associations between drugs and specific AEs.

2.2 Statistical analysis

Detection of AE signals in FAERS is typically performed using the disproportionality analysis method, which identifies safety signals by comparing the occurrence proportion of AEs between a specified drug and all other drugs. In this study, the ROR and proportional reporting ratio (PRR) were applied. Additionally, BCPNN and the multi-item gamma Poisson shrinker (MGPS) were employed to detect AE signals associated with BiTE drugs, as detailed in Tables 1, 2. The combined application of these methods improves the robustness of the results through cross-validation. The ROR value evaluates the risk level of a target drug–AE combination in comparison to other drug–AE combinations; a higher ROR value indicates a stronger signal, reflecting a stronger correlation between the drug and AE. The PRR identifies signals by calculating proportional differences in AE reports between the target drug and all other drugs. Both BCPNN and MGPS are Bayesian statistical approaches that evaluate the strength of associations using the information component and empirically adjusted geometric means. All statistical analysis and data mining were performed using R software (version 4.5.1).

ItemTarget adverse eventsAll other adverse eventsTotalTarget drugsaba + bAll other drugscdc + dTotala + cb + da+b + c + d

Four-grid table of disproportionality analysis method.

A contingency table for the calculation formula of the proportion imbalance analysis.

MethodsCalculation formulaInclusion standard of positive signalRORa ≥ 3 and 95%CI > 1PRRa ≥ 3 and 95%CI > 1BCPNN1) No signal (-): IC025 ≤ 0
2) Low signal (+):0<IC025 ≤ 1.5
3) Medium signal (++):1.5<IC025 ≤ 3
4) High signal (+++): IC025 > 3Where α1 = β1 = 1; α = β = 2; MGPSEBGM05 > 2 and a>0

Principle of disproportionality analysis and standard of signal detection.

Abbreviation: ROR, reporting odds ratio; PRR, proportional reported ratio; BCPNN, bayesian confidence propagation neural network; MGPS, multi-item gamma Poisson shrinker; CI, confidence interval; IC, information component.

3 Results3.1 Descriptive analysis

A total of 23,607,454 reports from the FAERS database between January 2004 and September 2025 were analyzed. After deduplication, 19,682,792 reports remained, including 7,724 cases of blinatumomab, 907 cases of elranatamab, 1,304 cases of epcoritamab, 893 cases of glofitamab, 503 cases of mosunetuzumab, 999 cases of talquetamab, 677 cases of tarlatamab, 387 cases of tebentafusp, and 2,166 cases of teclistamab (Figure 1). The demographic and clinical characteristics of adverse drug events (ADEs) reported in the FAERS database, including age, weight, sex, reporting country, and outcomes, are summarized in Table 3; Figure 2. The results indicated that the average age at onset of adverse neurological reactions was 51.12 ± 24.44 years, with the highest incidence observed in individuals aged ≥45 years. The number of male patients was higher than that of female patients (6,139 males vs. 5,065 females), representing a 21.19% higher incidence in males. Reports were predominantly submitted by physicians, followed by other health professionals. Since 2022, the number of reported AEs has increased annually, with 3,021 cases reported in 2025. Among the reporting countries, the United States accounted for the highest number of reports (7,885 cases), followed by Japan (2,017 cases). Regarding outcome indicators, a total of 3,192 deaths were recorded, of which 1,398 cases (43.80%) were associated with blinatumomab. Additionally, 3,363 cases involved hospitalization due to initial or prolonged illness, with 1,367 cases (40.65%) linked to blinatumomab. Furthermore, a total of 5,072 cases were classified as other serious medical events, among which 2,686 cases (52.96%) were associated with blinatumomab.

The FAERS database’s pipeline flowchart for screening BiTEs-related NSTs.

VariableTotalBlinatumomabElranatamabEpcoritamabGlofitamabMosunetuzumabTalquetamabTarlatamabTebentafuspTeclistamab(N = 15,558)(N = 7722)(N = 907)(N = 1304)(N = 893)(N = 503)(N = 999)(N = 677)(N = 387)(N = 2166)Age51.12 ± 24.4438.59 ± 23.2365.24 ± 15.9560.25 ± 25.6062.98 ± 14.4565.69 ± 13.6562.27 ± 17.1354.09 ± 26.4768.38 ± 10.4665.58 ± 14.85Weight69.14 ± 22.1964.24 ± 27.1565.40 ± 17.1664.39 ± 17.9574.44 ± 20.5077.64 ± 19.6474.73 ± 20.7367.73 ± 21.8286.23 ± 28.0572.05 ± 18.25SexFemale5065(32.56)2528(32.74)359(39.58)460(35.28)304(34.04)191(37.97)226(22.62)203(29.99)100(25.84)694(32.04)Male6139(39.46)2947(38.16)408(44.98)706(54.14)469(52.52)244(48.51)303(30.33)238(35.16)101(26.10)723(33.38)Unknown4354(27.99)2247(29.10)140(15.44)138(10.58)120(13.44)68(13.52)470(47.05)236(34.86)186(48.06)749(34.58)ReporterConsumer1480(9.51)530(6.86)63(6.95)71(5.44)230(25.76)22(4.37)203(20.32)80(11.82)84(21.71)197(9.10)Health professional2896(18.61)1551(20.09)117(12.90)134(10.28)71(7.95)35(6.96)224(22.42)188(27.77)83(21.45)493(22.76)Other health-professional750(4.82)750(9.71)​​​​​​​​Pharmacist2265(14.56)1261(16.33)118(13.01)132(10.12)60(6.72)40(7.95)127(12.71)130(19.20)59(15.25)338(15.60)Physician8119(52.19)3624(46.93)607(66.92)963(73.85)529(59.24)404(80.32)437(43.74)278(41.06)160(41.34)1117(51.57)Unknown48(0.31)6(0.08)2(0.22)4(0.31)3(0.34)2(0.40)8(0.80)1(0.15)1(0.26)21(0.97)CountryBrazil434(2.79)239(3.10)17(1.87)41(3.14)0(0)20(3.98)54(5.41)1(0.15)0(0)62(2.86)China698(4.49)323(4.18)22(2.43)2(0.15)258(28.89)17(3.38)15(1.50)0(0)0(0)61(2.82)France785(5.05)171(2.21)103(11.36)29(2.22)86(9.63)23(4.57)10(1.00)0(0)26(6.72)337(15.56)Italy363(2.33)205(2.65)21(2.32)53(4.06)31(3.47)11(2.19)8(0.80)1(0.15)6(1.55)27(1.25)Japan2017(12.96)1017(13.17)254(28.00)653(50.08)0(0)13(2.58)0(0)68(10.04)0(0)12(0.55)Other countries2824(18.15)1284(16.63)215(23.70)236(18.10)315(35.27)146(29.03)119(11.91)62(9.16)96(24.81)351(16.20)Spain281(1.81)99(1.28)11(1.21)17(1.30)34(3.81)28(5.57)44(4.40)0(0)1(0.26)47(2.17)United Kingdom271(1.74)75(0.97)48(5.29)40(3.07)51(5.71)10(1.99)11(1.10)2(0.30)6(1.55)28(1.29)United state7885(50.68)4309(55.80)216(23.81)233(17.87)118(13.21)235(46.72)738(73.87)543(80.21)252(65.12)1241(57.29)OutcomeDeath3192(20.52)1398(18.10)227(25.03)472(36.20)284(31.80)67(13.32)79(7.91)111(16.40)66(17.05)488(22.53)Disability42(0.27)24(0.31)2(0.22)0(0)1(0.11)1(0.20)5(0.50)0(0)1(0.26)8(0.37)Hospitalization - initial or prolonged3363(21.62)1367(17.70)294(32.41)260(19.94)255(28.56)260(51.69)185(18.52)114(16.84)101(26.10)527(24.33)Life-threatening597(3.84)319(4.13)29(3.20)48(3.68)39(4.37)16(3.18)29(2.90)39(5.76)8(2.07)70(3.23)Other serious (important medical event)5072(32.60)2686(34.78)242(26.68)461(35.35)172(19.26)69(13.72)342(34.23)275(40.62)98(25.32)727(33.56)Required intervention to prevent permanent impairment/Damage21(0.13)3(0.04)0(0)0(0)1(0.11)0(0)4(0.40)1(0.15)1(0.26)11(0.51)Unknown3271(21.02)1925(24.93)113(12.46)63(4.83)141(15.79)90(17.89)355(35.54)137(20.24)112(28.94)335(15.47)Year2015 Year403(2.59)403(5.22)0(0)0(0)0(0)0(0)0(0)0(0)0(0)0(0)2016 Year637(4.09)637(8.25)0(0)0(0)0(0)0(0)0(0)0(0)0(0)0(0)2017 Year690(4.44)690(8.94)0(0)0(0)0(0)0(0)0(0)0(0)0(0)0(0)2018 Year649(4.17)649(8.40)0(0)0(0)0(0)0(0)0(0)0(0)0(0)0(0)2019 Year638(4.10)636(8.24)0(0)0(0)2(0.22)0(0)0(0)0(0)0(0)0(0)2020 Year676(4.35)645(8.35)0(0)0(0)19(2.13)12(2.39)0(0)0(0)0(0)0(0)2021 Year890(5.72)845(10.94)0(0)1(0.08)18(2.02)24(4.77)0(0)0(0)0(0)2(0.09)2022 Year1033(6.64)772(10.00)0(0)0(0)77(8.62)26(5.17)0(0)0(0)95(24.55)63 2.91)2023 Year2907(18.68)885(11.46)167(18.41)184(14.11)177(19.82)322(64.02)163(16.32)0(0)99(25.58)910(42.01)2024 Year4014(25.80)1049(13.58)262(28.89)613(47.01)370(41.43)82(16.30)454(45.45)307(45.35)132(34.11)745(34.40)2025 Year3021(19.42)511(6.62)478(52.70)506(38.80)230(25.76)37(7.36)382(38.24)370(54.65)61(15.76)446(20.59)

Demographic and clinical characteristics of BiTEs-related NST reports.

The characteristics of age, sex, reporter, year and country in BiTEs-related NSTs (a) the number of people of all ages who reported adverse neurological reactions; (b) the number of men and women reporting adverse neurological reactions; (c) the number of people reporting adverse neurological reactions; (d) the annual number of reported adverse reactions of the nervous system; (e) the number of reported cases of adverse neurological reactions in various countries.

3.2 Signal spectrum of NSTs associated with BiTEs

We employed four disproportionality methods in this study: ROR, PRR, EBGM05, and IC025. If all four algorithms yielded positive signals, the outcome was classified as positive. The signal values for NSTs associated with BiTEs are illustrated in Figure 3; Table 4. The results indicate that several drugs exhibited a high proportion of ICANS, with notably strong positive signals. The highest ROR was observed for tarlatamab (ROR: 1161.09; 95% CI: 959.87–1404.5), followed by teclistamab (ROR: 586.28; 95% CI: 508.98–675.33). The ROR value for epcoritamab was 398.57 (95% CI: 326.9–485.96), talquetamab was 322.36 (95% CI: 253.85–409.37), elranatamab was 288.05 (95% CI: 215.44–385.15), and glofitamab was 233.37 (95% CI: 166.05–327.99). Furthermore, NSTs were observed in several drugs. Among the BiTE drugs analyzed, blinatumomab accounted for the highest number of reported neurological adverse reactions. The five most frequently reported NSTs (exceeding 100 cases each) were: neurotoxicity (433 cases), tremor (215 cases), seizure (182 cases), nervous system disorder (119 cases), and ICANS (107 cases). For teclistamab, the most frequently reported NST was ICANS, followed by neurotoxicity. Tarlatamab was mainly associated with ICANS and dysgeusia, while talquetamab was associated with ageusia and dysgeusia. For epcoritamab, the most reported NST was ICANS, followed by neurotoxicity. Both elranatamab and glofitamab were predominantly associated with ICANS, whereas mosunetuzumab was associated with relatively fewer cases of neurotoxicity (three cases each of encephalopathy and ICANS). The positive signal results of the disproportionality analysis for neurological adverse reactions at the PT level are detailed in Table 4.

ROR, PRR, EBGM05, IC025 values and the number of reports of signal PTs for BiTEs-related NSTs. ROR, reporting odds ratio; 95% CI, 95% confidence interval; PRR, proportional reporting ratio; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of 95% CI of EBGM; IC, information component; IC025, the lower limit of 95% CI of IC.

DrugPTROR (95%CI)PRR (95%CI)MGPS (95%CI)BCPNN (95%CI)PRR (X2)BlinatumomabAgnosia38.23(12.23–119.46)38.22(37.08–39.36)37.72(14.54–97.86)5.24(3.56–6.91)38.22(107.28)BlinatumomabSeizure3.17(2.74–3.67)3.15(3.01–3.3)3.15(2.79–3.56)1.65(-0.01–3.32)3.15(267.6)BlinatumomabAtaxia5.97(4–8.91)5.96(5.56–6.36)5.95(4.26–8.32)2.57(0.91–4.24)5.96(98.9)BlinatumomabApraxia24.44(13.84–43.14)24.42(23.85–24.99)24.22(15.05–38.97)4.6(2.93–6.27)24.42(267.23)BlinatumomabAphasia10.01(8.24–12.15)9.96(9.77–10.16)9.93(8.44–11.68)3.31(1.65–4.98)9.96(828.17)