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Cancers 2019, 11(3), 366; https://doi.org/10.3390/cancers11030366

Newer-Generation EGFR Inhibitors in Lung Cancer: How Are They Best Used?

1
and
1,2,3,*
1
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA
2
Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA
3
Division of Hematology-Oncology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA
*
Author to whom correspondence should be addressed.
Received: 15 January 2019 / Revised: 4 March 2019 / Accepted: 4 March 2019 / Published: 15 March 2019
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)
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Abstract

The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, double-blind trial of treatment-naïve patients with EGFR mutant NSCLC, osimertinib was compared to standard-of-care EGFR TKIs (i.e., erlotinib or gefinitib) in the first-line setting. Osimertinib demonstrated improvement in median progression-free survival (18.9 months vs. 10.2 months; hazard ratio 0.46; 95% CI, 0.37 to 0.57; p < 0.001) and a more favorable toxicity profile due to its lower affinity for wild-type EGFR. Furthermore, similar to later-generation anaplastic lymphoma kinase (ALK) inhibitors, osimertinib has improved efficacy against brain metastases. Despite this impressive effect, the optimal sequencing of osimertinib, whether in the first line or as subsequent therapy after the failure of earlier-generation EGFR TKIs, is not clear. Because up-front use of later-generation TKIs may result in the inability to use earlier-generation TKIs, this treatment paradigm must be evaluated carefully. For EGFR mutant NSCLC, considerations include the incidence of T790M resistance mutations, quality of life, whether there is a potential role for earlier-generation TKIs after osimertinib failure, and overall survival. This review explores these issues for EGFR inhibitors and other molecularly targeted therapies. View Full-Text
Keywords: epidermal growth factor receptor; lung cancer; osimertinib; resistance; personalized medicine; tyrosine kinase inhibitors epidermal growth factor receptor; lung cancer; osimertinib; resistance; personalized medicine; tyrosine kinase inhibitors
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Le, T.; Gerber, D.E. Newer-Generation EGFR Inhibitors in Lung Cancer: How Are They Best Used? Cancers 2019, 11, 366.

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