Understanding Toxicities of Targeted Agents: Implications for Anti-tumor Activity and Management.

Targeted treatments have distinctive side effects: dermatologic problems (rash, hand-food skin reaction, skin/hair whitening), endocrine dysfunction (hyperglycemia, hypothyroidism, dyslipidemia), as well as hypertension, diarrhea, liver problems, ocular toxicity and proteinuria. Toxicities can be classified as: (1) on-target, mechanism-driven toxicities that are either related or unrelated to response; and (2) off-target side effects. Off-target toxicities may be specific to the class of agent, eg, small molecule tyrosine kinase inhibitor versus antibody versus cytotoxic; alternatively, they may also be mediated by metabolites or immune reactions. Both on- and off-target toxicities can be amplified or attenuated by drug concentrations or end-organ sensitivity, which in turn can be attributable to genetic polymorphisms regulating metabolism or tissue responsiveness. On-target side effects are important to identify as some are associated with response and, therefore, controlling these side effects is preferable to dose reduction or treatment discontinuation. Side effects caused by relevant target impact may be recognized when different types of agents, eg, small molecule inhibitors and antibodies, with the same target have the same side effect. These on-target effects may also correlate with better outcomes. We discuss toxicity of targeted agents in the context of understanding target impact, drug-drug interactions, and implications for optimized management.