Gastrointestinal toxicity of targeted cancer therapies in the United States: Clinicopathologic patterns, FDA safety frameworks, and implications for national patient protection

Background: As precision oncology advances, non-immune checkpoint targeted therapies such as tyrosine kinase inhibitors (TKIs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cell (CAR-T) therapies are increasingly used across gastrointestinal (GI) and non-GI malignancies. While these agents have transformed cancer treatment, they are also associated with a broad spectrum of GI toxicities that remain underrecognized in both clinical practice and pathology.

Objective: This review comprehensively examines the mechanisms, clinicopathological features, and management strategies of GI toxicity induced by TKIs, ADCs, and CAR-T therapies, emphasizing the diagnostic role of pathologists in identifying treatment-related injury patterns.

Methods: We synthesized data from pivotal clinical trials, FDA drug labeling, post-marketing surveillance (FAERS), and real-world histopathologic descriptions of GI adverse events. SEER data on GI malignancies treated with targeted therapies were also reviewed to highlight epidemiologic context.

Results: TKIs may induce mucosal ischemia, apoptosis, or colitis-like inflammation due to angiogenesis inhibition and off-target effects. ADCs contribute to epithelial injury through cytotoxic payloads, while CAR-T therapy is associated with cytokine-mediated GI inflammation. Histological findings range from apoptotic enteropathy to ulcerative colitis and mimic infections, GVHD, or autoimmune disease. Misdiagnosis can lead to treatment delays or unnecessary dose reductions.

Conclusions: The landscape of GI toxicity from targeted cancer therapies is expanding rapidly. Accurate recognition of characteristic pathology patterns and integration with clinical history are crucial for safe and effective management. Enhanced pharmacovigilance, pathology-oncology collaboration, and incorporation of national surveillance data (FAERS, SEER) are essential to advancing precision medicine and patient safety.