Real-world pharmacovigilance analysis unveils the toxicity profile of amivantamab targeting EGFR exon 20 insertion mutations in non-small cell lung cancer

Abstract

Background

While clinical trials have demonstrated enduring responses to amivantamab among advanced non-small cell lung cancer (NSCLC) patients bearing EGFR exon 20 insertion mutations, the associated toxicity profile in real-world scenarios remains elusive.

Methods

This pharmacovigilance study analyzed data from the FDA Adverse Event Reporting System (FAERS) to investigate adverse events associated with amivantamab over the period from September 2021 to December 2023. A comprehensive disproportionality analysis was performed, employing the reporting odds ratio (ROR), proportional reporting ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and the Bayesian confidence propagation neural network to calculate information components (ICs), to identify statistically significant adverse events.

Results

A significant proportion of adverse events (AEs) was attributable to injury, poisoning, and procedural complications, cutaneous disorders, respiratory ailments, infections, as well as vascular and lymphatic system disturbances. There were noteworthy incidences of AEs including infusion-related reactions, rash, dyspnea, pneumonitis, paronychia, pulmonary embolism, thrombocytopenia, nausea, acneiform dermatitis, deep vein thrombosis, febrile neutropenia, peripheral edema, hypokalemia, and neutropenia. Furthermore, the majority of AEs occurred within the first month following the initiation of amivantamab treatment, accounting for 51.74% of cases.

Conclusion

The reversibility of amivantamab-related toxicities suggests its promising utility in patients with EGFR exon 20 insertion mutations NSCLC.

Introduction

Mutations in the epidermal growth factor receptor (EGFR) represent a prevalent target in non-small cell lung cancer (NSCLC), with EGFR exon 20 insertion (ex20ins) mutations occurring in approximately 2–3% of cases [1]. These mutations, constituting the third most common EGFR mutation subtype following in-frame deletions in exon 19 and point mutations in exon 21, present a distinct challenge [1]. Unlike the preceding two prevalent sensitizing EGFR mutations, EGFR ex20ins mutations confer resistance to EGFR tyrosine kinase inhibitors (TKIs). Mechanistically, EGFR ex20ins mutations induce a structural alteration, forming a wedge at the end of the C-helix, which fosters an active kinase conformation but fails to enhance affinity for EGFR TKIs. This diminished drug binding capability may stem from steric hindrance, facilitated by a notable displacement of the C-helix and phosphate-binding loop of EGFR within the drug-binding pocket [2]. Consequently, NSCLC patients harboring EGFR ex20ins mutations face a less favorable prognosis [3], as chemotherapy remains their primary therapeutic recourse [1, 4].

Fortunately, several novel agents, such as amivantamab and mobocertinib, have exhibited promising outcomes in clinical trials and have received approval from the US Food and Drug Administration (FDA), offering a potential avenue for improved prognosis in cancer patients. Amivantamab, a fully human EGFR-MET bispecific antibody targeting EGFR and mesenchymal-epithelial transition (MET) receptors, has demonstrated remarkable clinical efficacy attributed to its concurrent blockade of relevant downstream signaling pathways and immunomodulatory effects [5]. Notably, the Phase I/II trial results, which prompted FDA accelerated approval for amivantamab monotherapy as second-line treatment following platinum-based chemotherapy in EGFR Ex20Ins patients, showcased superior response rates and overall survival compared to standard therapies [6]. Furthermore, findings from a phase III trial involving 308 patients, randomized to receive chemotherapy alone or in combination with amivantamab as first-line therapy, indicated a discernible trend towards enhanced survival in the combination arm [1]. Nevertheless, up to the present time, the effectiveness and safety profile of amivantamab have primarily been derived from clinical trials, given the expedited timeline to market. Despite its notable therapeutic benefits, the corresponding toxicity profile in real-world settings remains uncertain. Given the global voluntary withdrawal of mobocertinib following its phase III trial's failure to meet its primary endpoint, the objective of this real-world pharmacovigilance analysis is to scrutinize adverse event signals associated with amivantamab using FDA Adverse Event Reporting System (FAERS) mining data, thereby offering insights for its clinical utilization.

Method

FAERS data sources and mining

Between September 2021 and December 2023, adverse events (AEs) related to amivantamab were retrieved from the FDA Adverse Event Reporting System (FAERS; https://fis.fda.gov). Each AE entry was systematically curated to include comprehensive clinical information, such as drug names, pharmacological classification, therapeutic indication, case identification, patient gender, and age group. Adverse events attributed specifically to amivantamab were designated as primary outcomes, classified using preferred terms (PTs) within system-organ classes (SOCs), as defined by the Medical Dictionary for Regulatory Activities (MedDRA, Version 26.1; https://www.meddra.org). In cases where multiple suspect drugs were reported for a single AE, we prioritized AEs in which amivantamab was explicitly listed as the primary suspect drug in the FAERS database. This field is designed to identify the drug most likely responsible for the reported AE, as assessed by the reporters (e.g., healthcare professional). To minimize confounding from combination therapies, we limited our analysis to cases where amivantamab was a suspect drug and excluded reports where it was solely listed as a concomitant or interacting drug. This approach helps to focus on AEs most directly attributed to amivantamab.

Signal mining and statistical analysis

All data processing and statistical analyses were rigorously performed using R software (https://www.r-project.org/, version 4.2.1). Central to our evaluation was the use of disproportionality analysis, integrating multiple approaches to ensure comprehensive signal detection. Four distinct methodologies were employed to assess disproportionality, including reporting odds ratio (ROR), Empirical Bayes Geometric Mean (EBGM), proportional reporting ratio (PRR), and the Bayesian confidence propagation neural network-derived information components (ICs) [7,8,9]. The ROR, calculated using a two-by-two contingency table, compares the frequency of a specific adverse event (AE) associated with a drug to its frequency across all other drugs [7,8,9]. The PRR was utilized to assess the frequency of a specific AE associated with a particular medication in relation to its overall occurrence in the entire database. The EBGM is a statistical measure used in disproportionality analysis to detect signals in large datasets, such as adverse event reporting systems. It adjusts for data sparsity and variability by borrowing strength from the entire dataset, thereby providing more stable estimates compared to raw reporting ratios [7,8,9]. Bayesian confidence propagation neural network-derived IC is a machine learning approach that applies Bayesian inference principles within a neural network framework to model and predict relationships in complex datasets. It is commonly used in pharmacovigilance to assess associations between drugs and adverse events with confidence intervals that account for uncertainty [7,8,9]. To identify significant safety signals, stringent criteria were employed. A signal was considered significant if the lower bounds of the 95% confidence intervals for the ROR, PRR, EBGM (EBGM025), and IC (IC025) exceeded predefined thresholds: 1 for ROR and PRR, and 0 for EBGM and IC, in at least three out of the four methodologies. The threshold of ROR > 1 is supported by evidence from the Health Sciences Authority, Singapore, which demonstrated its efficacy as a screening tool for detecting significant drug–AE pairs in spontaneous reporting systems [10]. The study also highlighted that ROR provides high sensitivity and robust performance when compared to other methodologies, such as Gamma Poisson Shrinker [10]. Moreover, ROR and PRR are algorithms used by the Pharmaceuticals and Medical Devices Agency in Japan and the Pharmacovigilance Center in the Netherlands [11]. For EBGM and IC, a lower bound of 0, is commonly used to indicate a statistically significant signal. This threshold is derived from the Bayesian framework underpinning these methods, where a value of 0 indicates that the observed association is stronger than what would be expected by chance. These criteria are frequently employed in studies using Bayesian disproportionality analyses, as supported by published research [12]. Eventually, the time to onset of AEs was determined by calculating the difference between the treatment initiation date and the reported date of AE onset. The results were summarized using the median and interquartile range (IQR) to characterize the distribution of time to onset of AEs. We present this article in accordance with the STROBE reporting checklist (Additional files).

Results

A comprehensive collection of 5,361,420 AE reports was sourced from the FAERS database. Following the exclusion of duplicate entries,1644 AE reports associated with amivantamab from 798 NSCLC patients were incorporated (Fig. 1; Table 1). Notably, there was a prevalence of female patients (46.0%, n = 367) compared to male patients (28.2%, n = 225). The majority of reports came from healthcare professionals, accounting for 91.3% (728 cases), with only 8.6% (69 cases) from consumers. Geographically, 48.4% (386 cases) originated from the United States, 9.6% (77 cases) from China, 3.9% (31 cases) from France, and 3.1% (25 cases) from Japan, while 32% (256 cases) were from other countries.

Fig. 1

Flow diagram of our study. These components comprise DEMO, which encompasses essential demographic and administrative information, DRUG, which pertains to intricate drug-related data, REAC, serving as the preferred terminology for adverse events, and PS, which denotes the primary suspect drug under investigation

Table 1 Characterstics of included cases

A substantial portion of these reports emanated from both the United States and China. Among 23 SOCs investigated, injury, poisoning and procedural complications (n = 253, ROR: 1.33, 95%CI: 1.16–1.53), skin and subcutaneous tissue disorders (n = 195, ROR: 2.18, 95%CI:1.87–2.53), respiratory, thoracic and mediastinal disorders (n = 178, ROR: 2.56, 95%CI: 2.19–3.00), infections and infestations (n = 156, ROR: 1.77, 95%CI: 1.50–2.09), vascular disorders (n = 77, ROR: 2.57, 95%CI: 2.05–3.23), and blood and lymphatic system disorders (n = 70, ROR: 2.58, 95%CI: 2.04–3.29) emerged as the most significant and prevalent SOCs (Table 2).

Table 2 Disproportionality analysis at SOC level

Additionally, notable occurrences of AEs were observed in infusion related reaction (n = 175, ROR: 93.68, 95%CI: 80.06–109.63), rash (n = 85, ROR: 7.45, 95%CI: 5.99–9.27), dyspnoea (n = 44, ROR: 3.20, 95%CI: 2.37–4.32), pneumonitis (n = 30, ROR: 39.69, 95%CI: 27.65–56.99), paronychia (n = 27, ROR: 243.39, 95%CI: 165.86–357.16), pulmonary embolism (n = 24, ROR: 13.69, 95%CI: 9.14–20.48), oxygen saturation decreased (n = 22, ROR: 13.04, 95%CI: 8.56–19.87), thrombocytopenia (n = 22, ROR: 8.01, 95%CI: 5.26–12.20), nausea (n = 21, ROR:1.13, 95%CI: 0.73–1.73), dermatitis acneiform (n = 17, ROR: 120.17, 95%CI: 74.37–194.18), pneumonia (n = 16, ROR: 1.90, 95%CI: 1.17–3.12), deep vein thrombosis (n = 15, ROR: 14.43, 95%CI: 8.68–24.00), febrile neutropenia (n = 14, ROR: 7.71, 95%CI: 4.56–13.05), chills (n = 13, ROR: 4.53, 95%CI: 2.62–7.81), flushing (n = 13, ROR: 6.88, 95%CI: 3.98–11.87), oedema peripheral (n = 12, ROR: 5.77, 95%CI: 3.27–10.18), hypokalaemia (n = 12, ROR: 10.71, 95%CI: 6.07–18.90), neutropenia (n = 12, ROR: 2.85, 95%CI: 1.61–5.02), hypotension (n = 11, ROR: 2.22, 95%CI: 1.23–4.03), hypersensitivity (n = 10, ROR: 1.96, 95%CI: 1.05–3.65), stomatitis (n = 10, ROR: 6.07, 95%CI: 3.25–11.30), and pyrexia (n = 10, ROR: 1.15, 95%CI: 0.62–2.13) (Fig. 2A, B; Table 3). The majority of AEs occurred within the first 30 days of treatment, comprising 267 cases (45% of the total events). A smaller proportion of events occurred between 31–60 days, representing 76 cases (9.5%). The subsequent intervals show a steady decline in case numbers, with 37 cases (4.6%) reported between 61–90 days, 54 cases (6.8%) between 91–180 days, 55 cases (6.9%) between 181–360 days, and only 27 cases (3.4%) reported after more than 360 days (Fig. 2C). Figure 2D depicts the overall spectrum of AEs induced by amivantamab.

Fig. 2

A Statistical data regarding the incidence of amivantamab-related adverse events within the hierarchical framework of system organ classes. B The reporting odds ratio of amivantamab-related adverse events. C Onset time of adverse events. D Overall AEs elicited by amivantamab

Table 3 Disproportionality analysis at PT level (n > 3)

Discussion

To the best of our knowledge, this represents the inaugural pharmacovigilance investigation conducted within a real-world context, elucidating the toxicity profile of amivantamab targeting EGFR ex20ins mutations in patients with NSCLC. Based on the disproportionality analysis, the most prevalent and clinically significant signals at the SOC level included injury, poisoning, and procedural complications, dermatologic disorders, respiratory conditions, infections, as well as vascular and lymphatic system dysfunctions. Associated AEs encompassed infusion-related reactions, rash, dyspnea, pneumonitis, paronychia, pulmonary embolism, thrombocytopenia, nausea, acneiform dermatitis, deep vein thrombosis, febrile neutropenia, peripheral edema, hypokalemia, and neutropenia. Consistent with prior clinical investigations [6, 13], the predominant amivantamab-associated AEs were rash, nausea, infusion-related reactions, and paronychia, with grade 3–4 events frequently involving hypokalemia, pulmonary embolism, diarrhea, and neutropenia. The majority were of AEs and did not necessitate dosage adjustments or discontinuations [13]. Overall, our real-world findings not only corroborate and reinforce the safety profile established in clinical trials, including hematologic, EGFR-related, and infusion-related AEs, but also extend the breadth of their outcomes.

EGFR expression is a critical driver of the pathogenesis and progression of NSCLC. Aberrant EGFR expression, resulting from overexpression or activating mutations, contributes to tumor growth, angiogenesis, and resistance to apoptosis. These changes are directly linked to increased tumor aggressiveness, enhanced metastatic potential, and reduced overall survival in affected patients. Studies have shown that elevated EGFR expression correlates with poorer prognosis and increased risk of disease progression in NSCLC [14]. Furthermore, EGFR expression levels are also predictive of treatment response, with higher expression often associated with greater sensitivity to EGFR-targeted therapies such as TKIs [15]. Common EGFR mutations in NSCLC include exon 19 deletions and the L858R substitution in exon 21, which together account for approximately 85–90% of all activating EGFR mutations [16, 17]. These mutations lead to constitutive activation of the EGFR tyrosine kinase domain, driving uncontrolled cell proliferation, enhanced tumor invasiveness, and increased metastatic potential. In contrast, exon 20 insertions, which are less common but clinically significant, account for 4–10% of EGFR mutations and are often associated with resistance to first- and second-generation TKIs [18, 19]. The presence of these mutations not only accelerates cancer progression but also contributes to acquired drug resistance and chemoresistance, ultimately impacting patient outcomes. For example, secondary mutations such as T790M have been identified as a major mechanism of resistance to first-line TKIs and are associated with disease relapse and reduced survival [20]. Mechanistically, EGFR mutations aberrantly activate downstream signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which collectively promote cell survival, proliferation, and resistance to apoptosis [21, 22]. Additionally, EGFR-driven activation of epithelial-to-mesenchymal transition (EMT) facilitates metastatic spread by promoting cancer cell migration and invasion while decreasing cell adhesion [23]. Acquired resistance to TKIs poses a significant therapeutic challenge in EGFR-mutated NSCLC. Beyond secondary mutations such as T790M, bypass signaling pathways including MET amplification, allow tumor cells to circumvent EGFR inhibition [20, 24]. Additionally, chemoresistance is mediated by enhanced DNA repair mechanisms and apoptotic inhibition via sustained activation of the PI3K/Akt signaling cascade [25].

One of the key findings of our study is the observation of amivantamab-related cardiovascular toxicities, including tachycardia, bradycardia, and pericardial effusion, in patients with NSCLC. This aligns with previous research indicating that the cardiovascular toxicity associated with the dual-targeted antibody amivantamab may exceed that of TKIs [11]. Notably, the median onset time for cardiovascular AEs, such as heart failure, stroke, arrhythmias, and venous thromboembolic disorders, was found to occur within the first month of drug administration [26]. Amivantamab may indirectly activate pathways or mechanisms that contribute to cardiovascular toxicity. For instance, our study, along with previous clinical research [6], identified a link between hypokalemia and cardiovascular toxicity. It is well established that low potassium levels can disrupt the heart’s electrical activity, leading to complications such as arrhythmias, which may present as tachycardia or bradycardia [27]. Furthermore, hypokalemia can impair the contractile and relaxation functions of myocardial cells, potentially contributing to the development of heart failure. Electrocardiographic changes associated with hypokalemia, such as flattened T waves and prominent U waves, may predispose patients to life-threatening arrhythmias like ventricular fibrillation. Given that the median onset of cardiovascular AEs associated with amivantamab occurs within the first month of treatment, it is critical to closely monitor patients for signs of hypokalemia and cardiovascular toxicity during this period. Early identification and management of hypokalemia could reduce the risk of subsequent cardiovascular events, highlighting the need for vigilant monitoring and timely intervention in clinical practice.

In this study, dermatological toxicities were common among patients receiving amivantamab, with rash, acneiform dermatitis, paronychia, pruritus, skin ulcers, and fissures being the most frequently reported adverse events. These skin manifestations are likely a result of disrupted EGFR signaling, a well-documented mechanism of skin toxicity observed with other EGFR inhibitors [28]. EGFR plays a critical role in maintaining skin barrier integrity and regulating the proliferation and differentiation of epidermal cells [15]. This disruption can give rise to dermatological conditions such as acneiform dermatitis, rashes, and skin fissures. The effectiveness of preemptive management for dermatologic adverse events in patients treated with amivantamab remains uncertain, particularly given the unique dual-targeting mechanism of the drug. Nevertheless, a previous trial demonstrated that preemptive treatment with moisturizers, sunscreen, topical corticosteroids, and oral tetracyclines led to a more than 50% reduction in grade 2 or higher dermatologic adverse events in patients receiving EGFR-TKIs [29]. Therefore, the incorporation of preemptive management strategies, such as sun protection and the use of topical corticosteroids, warrants consideration before initiating amivantamab therapy. These approaches may help mitigate the severity of dermatological toxicities and improve overall patient outcomes.

Several AEs associated with amivantamab, such as pulmonary embolism, deep vein thrombosis, febrile neutropenia, thrombocytopenia, and hypokalemia, carry significant life-threatening risks and warrant immediate medical intervention. The potential mechanisms underlying these AEs may be linked to the targeted inhibition of both EGFR and MET signaling pathways. EGFR and MET play essential roles in cell proliferation, survival, and vascular homeostasis [24]. Inhibition of MET, for example, can disrupt normal angiogenesis and endothelial function [30], potentially leading to thromboembolic events such as deep vein thrombosis and pulmonary embolism. These conditions are exacerbated by the hypercoagulable state often observed in cancer patients [31], which amivantamab may amplify through its biological actions. Besides, febrile neutropenia and thrombocytopenia could result from amivantamab’s impact on bone marrow function. Both EGFR and MET are implicated in hematopoiesis [32], and their inhibition could impair the production of white blood cells and platelets, leading to increased vulnerability to infections and bleeding complications. The reduced neutrophil count, combined with the immunosuppressive nature of cancer itself, may predispose patients to febrile neutropenia. Collectively, these findings highlight the importance of early detection and intervention for severe AEs, ensuring timely management to reduce morbidity and mortality in patients treated with amivantamab.

Targeted therapies have transformed the treatment landscape for NSCLC, particularly for patients with actionable driver mutations. While the present study focuses on the safety and efficacy of amivantamab for EGFR exon 20 insertion mutations, similar efforts have been made to address other uncommon EGFR mutations. For instance, Priantti et al. [33] conducted a systematic review and meta-analysis evaluating the safety and efficacy of osimertinib for patients with rare EGFR mutations. This pooled analysis demonstrated a robust objective response rate of 51.3% and a disease control rate of 90.1%, with median progression-free survival and overall survival reaching 9.71 months and 16.79 months, respectively [33]. The intracranial response rate of 45.96% further underscores osimertinib's efficacy in addressing central nervous system involvement. Their findings underscore the importance of tailored therapeutic approaches to improve outcomes in this underserved patient population, further reinforcing the relevance of precision medicine in NSCLC. The incorporation of amivantamab into this framework highlights the growing therapeutic arsenal available for rare molecular subtypes, paving the way for improved treatment strategies. While our study provides novel insights, several limitations must be considered when interpreting the findings. First, the FAERS database operates as a voluntary, passive reporting system, which is non-mandatory. This introduces inherent challenges such as incomplete, inaccurate, inconsistent, and delayed reporting of AEs [34]. Additionally, the database lacks detailed patient characteristics, precise drug exposure information, and comprehensive outcome data, including dosage, duration of amivantamab therapy, and concurrent treatments. These missing data elements can influence the observed associations, potentially resulting in biased or incomplete conclusions. Second, the attribution of AEs in spontaneous reporting databases, such as FAERS, is subject to potential confounding from concomitant therapies, especially in the context of combination regimens. While steps were taken to minimize this bias by prioritizing cases where amivantamab was identified as the primary suspect drug, causality cannot be definitively established. Future studies leveraging prospective data or mechanistic approaches may further clarify the safety profile of amivantamab in combination therapies. Moreover, FAERS data are subject to reporting biases, as severe or unusual events are more likely to be reported than common or expected side effects, which may lead to an overestimation of risks associated with the drugs studied [35]. Finally, the study exclusively utilized data from the FAERS database, which primarily contains reports from regions such as the United States and East Asia. This geographic concentration may limit the generalizability of the findings to other populations and healthcare settings. As a result, caution is needed when interpreting these findings, and further prospective clinical studies and post-marketing surveillance are essential to validate these results and provide a more comprehensive understanding of the safety profile of amivantamab across diverse patient populations.

Conclusion

This study provides a groundbreaking characterization of amivantamab-related AEs reported to FAERS. Overall, the majority of AEs were deemed preventable and mitigated in severity, thereby potentially obviating the need for treatment discontinuations. The current analysis offers valuable insights into AE prevention and paves the way for additional in-depth investigations.