# Development of EGFR TKIs and Options to Manage Resistance of Third-Generation EGFR TKI Osimertinib: Conventional Ways and Immune Checkpoint Inhibitors

## TL;DR

This paper reviews the development of EGFR TKIs, focusing on osimertinib and strategies to manage resistance, including immune checkpoint inhibitors.

## Contribution

The paper provides a comprehensive review of resistance mechanisms to third-generation EGFR TKIs and explores potential solutions including immune checkpoint inhibitors.

## Key findings

- Osimertinib is effective in treating EGFR-mutant NSCLC but resistance still occurs.
- Multiple mechanisms of resistance to third-generation EGFR TKIs have been identified.
- Immune checkpoint inhibitors show potential in managing resistance in EGFR-mutant NSCLC.

## Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been first-line therapy in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Progression inevitably happens after 10–14 months of first- or second-generation EGFR TKIs treatment for acquired resistance. Owing to the successful identification of EGFR T790M, third-generation EGFR TKIs such as osimertinib were developed to target such resistance mutation. Nowadays, osimertinib has shown its efficacy both in first-line and second-line after resistance to previous generations of TKI treatment of EGFR-mutant NSCLC. However, drug resistance also emerges on third-generation EGFR TKIs. Multiple mechanisms of acquired resistance have been identified, and some novel strategies were reported to overcome third-generation TKI resistance. Immune checkpoint inhibitors (ICIs) have dramatically changed the prognosis of selected patients. For patients with EGFR-addicted metastatic NSCLC, ICIs have also revealed a potential role. In this review, we will take stock of mechanisms of acquired resistance to third-generation TKIs and discuss current challenges and future perspectives in clinical practice.