Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors. Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with an extracellular epidermal growth factor binding domain and an intracellular tyrosine kinase domain that regulates signaling pathways to control cellular proliferation. In particular, Olafertinib is a third-generation EGFR TKI, with GI50s of 5 nM (EGFR L858R/T790M), 10 nM (EGFR del19), and 689 nM (EGFR WT), respectively.

EGFR binding to its ligand results in autophosphorylation by intrinsic tyrosine/kinase activity, triggering several signal transduction cascades. Moreover, Mutations in the EGFR gene are the most common targetable genomic drivers of non-small cell lung cancer (NSCLC).

Mutations in EGF receptors have an association with some lung cancers. Lung adenocarcinomas with mutated epidermal growth factor receptors have significant responses to tyrosine kinase inhibitors. Both EGFR mutation and gene amplification status may be important in determining which tumors will respond to tyrosine kinase inhibitors.

In this review, researchers profiled many of the third-generation EGFR tyrosine kinase inhibitors in late-stage clinical development. The emergence of the acquired EGFR gatekeeper T790M mutation after first- or second-generation EGFR tyrosine kinase inhibitors in EGFR-mutant (EGFR+) NSCLC has necessitated the development of third-generation EGFR tyrosine kinase inhibitors to overcome this frequently acquired mutation. Abnormal activation of epidermal growth factor receptor (EGFR) associates with a variety of tumors, especially non-small cell lung cancer (NSCLC).

All in all, Olafertinib acts as a promising third-generation EGFR inhibitor. Olafertinib has the potential for NSCLC research.

Misako Nagasaka, et al. Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC. J Thorac Oncol. 2020 Dec 15;S1556-0864(20)31105-9.