Overall Treatment Strategy for Patients With Metastatic NSCLC With Activating EGFR Mutations

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR-activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21_L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G, and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed.

Keywords: EGFR–tyrosine kinase inhibitor (EGFR-TKI); Non–small-cell lung cancer; disease control rate (DCR); epidermal growth factor receptor; epidermal growth factor receptor (EGFR); exon 19 deletion mutation (ex19del); exon 21 L858R mutation (L858R); first line (1L); median overall survival (mOS); median progression-free survival (mPFS); mutation subtype. Abbreviations: first generation (1G); non–small cell lung cancer (NSCLC); objective response rate (ORR); overall survival (OS); progression-free survival (PFS); second generation (2G); second line (2L); third generation (3G); treatment plan; tyrosine kinase inhibitor; tyrosine kinase inhibitor (TKI); vascular endothelial growth factor (VEGF).