A comparison of the side effects associated with protein kinase inhibitors (PKIs) and other anticancer treatments was conducted using data from the FDA Adverse Events Reporting System (FAERS). The analysis encompassed 159 FDA-approved anticancer medications (71 PKIs and 88 non-PKIs) and examined 8216 distinct adverse event (AE) terms. PKIs exhibited reduced systemic toxicities overall, averaging 230.1 unique AEs per drug versus 537.7 for non-PKIs. Hematologic toxicities occurred less frequently with PKIs (e.g., febrile neutropenia: 1.93% versus 5.25%; thrombocytopenia: 2.18% versus 3.87%), along with decreased rates of infections (6.87% versus 14.2%) and immunosuppressive reactions. In contrast, gastrointestinal and dermatologic AEs were more prevalent among PKIs (such as diarrhea: 13.95% versus 8.36%). A greater share of AEs in the PKI category (14.57%) fell under the “Investigations” system organ class, compared with 9.87% in the non-PKI group. The occurrence of “Skin and subcutaneous tissue disorders” was approximately twice as high in the PKI group. Cluster analysis revealed that PKIs tended to form tighter, more uniform groups based on their AE patterns, whereas non-PKIs displayed greater diversity. Multi-kinase inhibitors targeting VEGFR were particularly associated with skin-related reactions, potentially linked to EGFR inhibition in basal keratinocytes. Although PKIs offer more precise mechanisms, drug resistance continues to pose difficulties, underscoring the importance of biomarker-guided approaches. Overall, these findings demonstrate the better tolerability of PKIs while highlighting the value of individualized treatment strategies to balance effectiveness and safety.
