HER2-targeted tyrosine kinase inhibitors in breast cancer: Real-world analysis of gastrointestinal and musculoskeletal toxicities using the FAERS database.

1058 Background: Human Epidermal Growth Factor Receptor 2 (HER2)-targeted tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib are approved for HER2-positive breast cancer but have distinct adverse event (AE) profiles. We analyzed the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to characterize gastrointestinal (GI) and musculoskeletal (MSK) toxicities associated with these agents. Methods: We conducted a retrospective FAERS data review to assess GI and MSK AEs associated with the three TKIs from 2020-2025. The chi-square test was used to compare categorical variables across drugs and age groups (<65 vs ≥65 years). Results: Among 9,045 total cases (lapatinib n=1,897; neratinib n=1,113; tucatinib n=6,035), neratinib demonstrated the highest GI toxicity rate at 64.2%, compared to 40.4% for tucatinib and 31.3% for lapatinib (χ²=319.3, p<0.001). Diarrhea was the predominant GI AE across all agents, affecting 82.1% of neratinib-treated patients, 64.8% of tucatinib-treated patients, and 55.6% of lapatinib-treated patients. Other common GI AEs included nausea (33.2 neratinib, 34.6 tucatinib, 23.1 lapatinib) and vomiting (21.1% neratinib, 19.5% tucatinib, 23.9 lapatinib). MSK AE rates were comparable across all three agents (lapatinib 10.5%, neratinib 11.3%, tucatinib 10.5%; χ²=0.72, p=0.70). The most frequent MSK AEs were pain in extremities (23% overall), arthralgia (18% overall), back pain (17.8% overall), and muscle spasms (17.6% overall). Age-stratified analysis revealed significant differences in GI toxicity. In patients <65 years, neratinib showed the highest GI AE rate at 63.1%, versus 34.8% for tucatinib and 28.1% for lapatinib (χ²=74.0, p<0.001). In patients ≥65 years, this pattern persisted with neratinib at 73.7%, tucatinib at 36.9%, and lapatinib at 40.1% (χ²=49.4, p<0.001). Moreover, older patients (≥65 years) experienced significantly higher rates of both GI and MSK AEs with lapatinib (GI: 40.1% vs 28.1%, p<0.001; MSK: 19.3% vs 9.6%, p<0.001) and neratinib (MSK: 25.3% vs 6.3%, p<0.001). Tucatinib showed no significant age-related differences in AE rates. Conclusions: The findings in this study highlight trends for selected AEs with various TKIs in order to help guide shared decision-making and tailored management strategies for patients with HER2-positive breast cancer.