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Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor
Chee-Seng Tan1, Byoung-Chul Cho2, Ross A Soo3
1Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
Abstract:
Since the discovery of sensitizing EGFR mutations as a predictive marker of sensitivity to EGFR tyrosine kinase inhibitors (TKIs), the field of targeted therapy in non-small cell lung cancer (NSCLC) has been revolutionized. Patients harbouring these sensitizing mutations treated with EGFR TKI have derived significant clinical outcome when compared with standard platinum based chemotherapy doublets. However disease progression invariably occurs at a median of about 9-13 months from initiation treatment, if acquired resistance commonly due to the development of EGFR T790M mutation. A novel class of "third generation" EGFR TKIs have been developed that is sensitising and T790M mutant-specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Early phase clinical data suggest the third generation EGFR TKIs such as osimertinib, rociletinib, and HM61713 are highly efficacious and well tolerated. Another promising class of EGFR TKI such as AZD3759 has been designed to penetrate blood brain barrier to treat brain metastases and leptomeningeal disease and has showed promising responses in patients with brain metastases. Acquired resistance to third generation EGFR TKIs has been reported including EGFR C797S. Given its non-invasive nature, plasma ctDNA is being explored as a possible approach to detect T790M mutation and to also inform on novel molecular mechansims of tertiary resistance to third generation EGFR TKIs. An understanding of the mechanisms of acquired resistance to the third-generation EGFR TKIs will greatly aid in the development of the next generation of EGFR TKIs.
Insights
Third-generation EGFR TKIs offer a breakthrough for non-small cell lung cancer (NSCLC) patients with acquired resistance, showing high efficacy. Understanding resistance mechanisms is key to developing future targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal Growth Factor Receptor (EGFR) mutations revolutionized non-small cell lung cancer (NSCLC) targeted therapy.
- EGFR Tyrosine Kinase Inhibitors (TKIs) significantly improve outcomes but acquired resistance, often via EGFR T790M mutation, limits durability.
- Standard chemotherapy doublets are less effective than EGFR TKIs in patients with sensitizing EGFR mutations.
Purpose of the Study:
- To review the development and clinical data of third-generation EGFR TKIs for NSCLC.
- To discuss novel EGFR TKIs designed for brain metastases and leptomeningeal disease.
- To explore emerging resistance mechanisms and the role of plasma ctDNA in monitoring treatment response and resistance.
Main Methods:
- Review of early-phase clinical trial data for third-generation EGFR TKIs (osimertinib, rociletinib, HM61713, AZD3759).
- Analysis of mechanisms of acquired resistance to EGFR TKIs, including T790M and C797S mutations.
- Exploration of circulating tumor DNA (ctDNA) as a non-invasive tool for mutation detection and resistance monitoring.
Main Results:
- Third-generation EGFR TKIs demonstrate high efficacy and tolerability in patients with acquired resistance mutations.
- AZD3759 shows promise in treating brain metastases and leptomeningeal disease due to its blood-brain barrier penetration.
- Emerging resistance, such as EGFR C797S, necessitates further research into novel therapeutic strategies.
Conclusions:
- Third-generation EGFR TKIs represent a significant advancement in NSCLC treatment, particularly for patients with acquired resistance.
- Targeted therapies like AZD3759 offer new hope for patients with central nervous system involvement.
- Continued understanding of resistance mechanisms and utilization of ctDNA will guide the development of next-generation EGFR TKIs.
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