Postmarketing Cases of Erdafitinib‐Associated Skeletal Growth Toxicity Events in Pediatric Patients

Erdafitinib is a fibroblast growth factor receptor (FGFR) inhibitor that received accelerated approval for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma by the Food and Drug Administration (FDA) in 2019 [1]. During routine surveillance, the Division of Pharmacovigilance at the FDA's Center for Drug Evaluation and Research identified postmarketing cases of skeletal growth toxicity, including slipped capital femoral epiphysis (SCFE), associated with erdafitinib use in pediatric patients from the FDA Adverse Event Reporting System (FAERS) and the literature. To investigate a potential association between erdafitinib and these events, we reviewed postmarketing data and report our findings. We searched the FAERS, PubMed, and Embase databases through December 2, 2024, to identify cases of skeletal growth toxicity and related terms with erdafitinib. We searched the FAERS database using the Medical Dictionary for Regulatory Affairs (MedDRA) dictionary's High Level Terms of Bone disorders not elsewhere classifed, Cartilage disorders, Epiphyseal disorders, Limb fractures, Pelvic fractures, the MedDRA Preferred Term of Growth accelerated, and erdafitinib. We reviewed all reports retrieved and included those with objective diagnostic findings of skeletal growth toxicity (e.g., growth rates or curves, imaging). We applied a modified version of the World Health Organization–Uppsala Monitoring Centre causality criteria to include cases of interest with a plausible drug-event association—that is, cases with a reasonable time relationship to erdafitinib exposure and unlikely to be attributed to another factor [2]. We excluded reports that were duplicates, and those that were unassessable or unlikely associated with erdafitinib. Descriptive statistics were used to summarize quantitative variables. Under statutory authority pursuant to public health, approval from institutional review boards or informed consent was not required. In the context of limited pediatric exposure and off-label use in this population, we identified five postmarketing cases of skeletal growth toxicity events with erdafitinib, all of which were derived from the literature, with three of these also reported to the FDA via FAERS (Table 1). All cases described single-agent erdafitinib use for the treatment of central nervous system malignancies in pediatric patients. At the time of the event, the median age was 13 (range: 10–15) years, and most cases were reported in males (n = 4). The median time to onset was 137 (range: 84–274) days from the start of erdafitinib. The most common presenting symptoms were pain in the lower extremities (n = 3) and difficulty with ambulation (n = 2). In three cases, relevant confounding factors included obesity (n = 2) and concomitant growth hormone use (n = 1). Erdafitinib was permanently discontinued in all cases, and three cases required surgical correction for the event. Our case series was not age-restricted, making the existence of an entirely pediatric case series supportive of an age-related adverse drug reaction. The relevance of FGFR signaling in regulating bone homeostasis, including chondrogenesis and osteogenesis, is well described [8-10]. Completed toxicology studies involving erdafitinib note chondroid or cartilage dysplasia in young animal species, and an overview of these nonclinical findings is described in the labeling of FGFR inhibitors marketed in the United States, including erdafitinib [1]. Although some cases in our series described coexisting risk factors for skeletal growth toxicities, we considered erdafitinib the likely cause of these events based on the temporal association, underlying mechanism of FGFR inhibitors, and the relevance of FGFR signaling in endochondral bone growth. The United States Prescribing Information (USPI) for erdafitinib does not currently include a treatment indication for the pediatric population; however, clinical trials are ongoing, and there is real-world use of erdafitinib for the treatment of pediatric cancers with FGFR rearrangements [11, 12]. Following FDA's postmarket evaluation, the USPI for erdafitinib was revised to include bone growth abnormalities, including SCFE and accelerated growth, under the Use in Specific Populations: Pediatric Use subsection [1]. This revision, and we hope this communication, will increase clinician awareness of this risk and minimize long-term complications by improving the likelihood of early detection and intervention. The detection of skeletal growth toxicity underscores the importance of FDA's postmarket surveillance program, which is designed to detect rare but serious events that are unlikely to manifest in a clinical development program, especially for underrepresented populations (i.e., pediatric patients). The authors have nothing to disclose. There was no non-US governmental funding for the work reported in the manuscript. The authors had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors have nothing to disclose.