Association of skin cancer with Bruton tyrosine kinase inhibitors: A FAERS analysis.

Abstract

e21551 Background: Bruton tyrosine kinase inhibitors (BTKis)—including Ibrutinib, Acalabrutinib, Zanubrutinib, and Pirtobrutinib—have revolutionized treatment of B-cell malignancies (e.g., CLL, MCL). However, secondary skin cancers have been increasingly reported in patients receiving BTKis. Preclinical and clinical evidence suggests BTKis (especially ibrutinib) may predispose patients to non-melanoma and melanoma skin cancers. We conducted a FAERS analysis to evaluate the association between BTKis and skin cancer risk. Methods: All reports in the FDA Adverse Event Reporting System (FAERS) from Q4 2013 through Q2 2025 listing a BTKi as a suspect drug were identified (N = 88,792). Skin cancer events were defined using relevant MedDRA preferred terms, including squamous cell carcinoma, basal cell carcinoma, and melanoma. The frequency and proportion of skin cancer reports were summarized for each BTKi and descriptively compared across agents. Results: Among 88,792 BTKi-associated reports, 413 skin cancer cases were identified (0.46%). Ibrutinib accounted for the majority of cases (n = 359), followed by Acalabrutinib (n = 42) and Zanubrutinib (n = 12); no skin cancer reports were identified with Pirtorutinib. Skin cancer reports predominantly occurred in older patients (≥65 years) and were more common in males. Across BTK inhibitors, skin cancer reports represented approximately 0.39–0.47% of total reported adverse events. Conclusions: Post-marketing surveillance data demonstrate a consistent signal of reported skin cancers among patients receiving BTK inhibitors, with the highest number of reports observed for Ibrutinib. While causality cannot be inferred from FAERS data, these findings highlight a potential class-associated safety concern and support the importance of routine dermatologic surveillance in patients treated with BTK inhibitors. Further prospective and real-world studies are warranted to better define absolute risk and underlying mechanisms. Skin cancer reports by BTK inhibitors. Drug Skin Ca cases (n) Skin Ca cases as % of BTKi AEs Ibrutinib 359 0.47% Acalabrutinib 42 0.39% Zanubrutinib 12 0.39% Pirtobrutinib 0 0% Total 413 0.46%