Biochemical affinity is an incomplete descriptor of anticancer drug action when drug concentrations, target availability, and signaling states change over time. This critical review examines the conditions under which association and dissociation kinetics improve the interpretation of sustained pharmacological responses and the circumstances in which other processes can produce a similar phenotype. Evidence from biochemical measurements, living-cell engagement assays, covalent-inhibitor studies, oncology models, and pharmacokinetic–pharmacodynamic analyses is evaluated according to the level of response directly measured. In a simple reversible binding model, residence time describes complex persistence; it does not incorporate free-drug exposure, target synthesis, cellular rebinding, or pathway compensation. Covalent modification introduces a distinct dependence on chemical inactivation and protein renewal. Washout experiments are especially informative when residual intracellular drug and assay-specific recovery are independently assessed. Examples from kinase inhibition and KRAS G12C-directed pharmacology show that molecular engagement and tumor-cell response may separate because of state-dependent accessibility and adaptive signaling. A temporal interpretation is therefore most defensible when kinetic parameters are connected to cellular occupancy, target abundance, and downstream recovery through orthogonal experiments. The resulting synthesis outlines how apparently durable inhibition can be attributed without assuming that prolonged binding necessarily predicts clinical efficacy.
