Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?


Despite the efficacy of standard-of-care EGFR tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib and afatinib, in EGFR mutation-positive non-small-cell lung cancer, resistance develops, most commonly due to the T790M mutation. Osimertinib showed clinical activity in the treatment of T790M-positive disease following progression on a first-line TKI, and is approved in this setting. Recently, osimertinib improved efficacy versus first-generation TKIs (erlotinib and gefitinib) in the first-line setting. Multiple factors can influence first-line treatment decisions, including subsequent therapy options, presence of brain metastases and tolerability, all of which should be considered in the long-term treatment plan. Further research into treatment sequencing is also needed, to optimize outcomes in EGFR mutation-positive non-small-cell lung cancer.

Somatic mutations of the EGFR gene are found in up to 50% of Asian patients and 10–15% of Caucasian patients with lung adenocarcinoma [1]. Tumors with these mutations become dependent on EGFR signaling, enabling molecularly targeted inhibition of this pathway with tyrosine kinase inhibitors (TKIs) to be used as treatment [2]. Erlotinib and gefitinib were the first EGFR TKIs developed; they reversibly and competitively inhibit the tyrosine kinase domain of EGFR (Figure 1) [3]. Known as the first-generation EGFR TKIs, they rapidly became standard of care first-line treatment for EGFR mutation-positive non-small-cell lung cancer (NSCLC), and molecular testing for EGFR mutations in patients with lung adenocarcinoma is now recommended as part of baseline workup [4].

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