Gefitinib (DB00317): A Comprehensive Monograph on its Pharmacology, Clinical Utility, and Evolving Role in Precision Oncology

Executive Summary

Gefitinib, marketed under the brand name Iressa®, is an orally active, small molecule therapeutic that represents a foundational achievement in the field of precision oncology.[1] As a first-generation inhibitor of the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, its development and clinical application have profoundly shaped the modern approach to treating non-small cell lung cancer (NSCLC).[1] The core mechanism of Gefitinib involves the reversible and competitive inhibition of the adenosine triphosphate (ATP) binding site within the EGFR's intracellular kinase domain. This action is particularly potent against tumors driven by specific "activating" mutations, namely exon 19 deletions and the L858R substitution in exon 21, for which Gefitinib demonstrates a significantly higher binding affinity compared to the wild-type receptor.[1]

The primary clinical application of Gefitinib is as a first-line monotherapy for patients with metastatic NSCLC whose tumors harbor these sensitizing EGFR mutations.[4] This targeted indication was definitively established by the landmark Iressa Pan-Asia Study (IPASS), which demonstrated superior progression-free survival (PFS) for Gefitinib over standard chemotherapy in the EGFR-mutated patient population, thereby cementing the role of EGFR mutation status as a critical predictive biomarker.[8] However, the initial efficacy of Gefitinib is invariably limited by the emergence of acquired resistance. The most common resistance mechanism is the development of a secondary "gatekeeper" mutation, T790M, which restores the kinase's affinity for ATP and renders the tumor insensitive to the drug.[1]