The resistance mechanisms and treatment strategies for EGFR-mutant advanced non-small-cell lung cancer.

Wen-Zhao Zhong,Qing Zhou,Yi-Long Wu

doi:10.18632/oncotarget.20311

Abstract

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been established as the standard therapy for EGFR-sensitizing mutant advanced non-small-cell lung cancer (NSCLC). However, patients ultimately develop resistance to these drugs. There are several mechanisms of both primary and secondary resistance to EGFR-TKIs. The primary resistance mechanisms include point mutations in exon 18, deletions or insertions in exon 19, insertions, duplications and point mutations in exon 20 and point mutation in exon 21 of EGFR gene. Secondary resistance to EGFR-TKIs is due to emergence of T790M mutation, activation of alternative signaling pathways, bypassing downstream signaling pathways and histological transformation. Strategies to overcome these intrinsic and acquired resistance mechanisms are complex. With the development of the precision medicine for advanced NSCLC, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account resistance mechanism. Though combination therapy is emerging as the standard of to overcome resistance mechanisms. Personalized treatment modalities based on molecular diagnosis and monitoring is essential for disease management. Emerging data from the ongoing clinical trials on combination therapy of third generation TKIs and antibodies in EGFR mutant NSCLC are promising for better survival outcomes.

Highlights

The development of epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKI) has led to significant advances in patients with tumors harboring EGFR mutations (EGFRm)
With the development of the precision medicine for advanced nonsmall-cell lung cancer (NSCLC), available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account resistance mechanism
In patients with sensitizing mutations of EGFR, firstline TKI treatment has good response rates of 50 to 80% compared to conventional chemotherapy that has response rate of 30%.Despite the demonstrated benefits of EGFRtargeting therapies, not all patients respond to treatment, patients who respond to EGFR-TKIs develop resistance to these drugs with the median progression-free survival around 9 to 13 months [2, 3]

Summary

Introduction

The development of epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKI) has led to significant advances in patients with tumors harboring EGFR mutations (EGFRm). 50% of Asian patients with NSCLC have EGFR mutations [1]. In patients with sensitizing mutations of EGFR, firstline TKI treatment has good response rates of 50 to 80% compared to conventional chemotherapy that has response rate of 30%.Despite the demonstrated benefits of EGFRtargeting therapies, not all patients respond to treatment, patients who respond to EGFR-TKIs develop resistance to these drugs with the median progression-free survival (mPFS) around 9 to 13 months [2, 3]. 50% of patients who respond well initially to TKIs develop resistance due to the occurrence of secondary mutation T790M, This is the most common mechanism of acquired resistance to EGFRTKIs [6, 7].

Objectives

Findings

Conclusion