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Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer
1Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. rielyg@mskcc.org
Abstract:
Approximately 10 to 15% of patients with non-small cell lung cancer have tumors that depend on activation of the epidermal growth factor receptor (EGFR), as evidenced by mutations in EGFR. In these patients, there is often an initial dramatic response to treatment with the first-generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib. A small number of patients with EGFR mutations have primary resistance to erlotinib and gefitinib, and most patients who initially respond to treatment with erlotinib or gefitinib will develop resistance to first-generation EGFR TKIs. The problems with both primary and acquired resistance to erlotinib and gefitinib support the need for development of additional agents that inhibit EGFR signaling in such patients. This is an overview of three representative second-generation EGFR TKIs. HKI-272, a second-generation irreversible EGFR TKI that also inhibits HER2, has completed accrual of a phase II trial in both untreated patients and patients with acquired resistance to erlotinib or gefitinib. XL647 is a reversible inhibitor of EGFR, HER2, and vascular epidermal growth factor receptor. Preclinical work shows that XL647 can inhibit cell lines bearing mutated forms of EGFR that have been associated with acquired resistance. BIBW2992 is an irreversible EGFR TKI that also inhibits HER2 and vascular epidermal growth factor receptors. In vitro work shows that this compound inhibits wild-type EGFR, EGFR exon 19 deletion, EGFR L858R, and EGFR T790M, the mutation associated with acquired resistance. The preliminary results from phase I and phase II trials for BIBW-2992 and XL647 are discussed.
Insights
Second-generation EGFR TKIs offer new hope for non-small cell lung cancer patients with resistance to first-generation treatments. These agents, including HKI-272, XL647, and BIBW2992, target specific EGFR mutations and overcome resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) often harbors epidermal growth factor receptor (EGFR) mutations, driving tumor growth in 10-15% of patients.
- First-generation EGFR tyrosine kinase inhibitors (TKIs) like erlotinib and gefitinib show initial efficacy but are limited by primary and acquired resistance.
- Resistance to existing EGFR TKIs necessitates the development of novel therapeutic strategies targeting specific EGFR alterations.
Purpose of the Study:
- To provide an overview of three representative second-generation EGFR TKIs designed to overcome resistance.
- To discuss the mechanisms of action and preclinical/clinical data for HKI-272, XL647, and BIBW2992.
- To highlight the potential of these new agents in treating NSCLC patients with EGFR mutations and resistance.
Main Methods:
- Review of preclinical data and clinical trial results (Phase I/II) for HKI-272, XL647, and BIBW2992.
- In vitro studies evaluating inhibition of wild-type and mutated EGFR, including resistance-associated mutations like T790M.
- Assessment of irreversible and reversible TKI activity against EGFR, HER2, and vascular endothelial growth factor receptors.
Main Results:
- HKI-272, an irreversible EGFR/HER2 inhibitor, has completed Phase II trials in treatment-naïve and resistant NSCLC patients.
- XL647, a reversible inhibitor of EGFR/HER2/VEGFR, demonstrated preclinical activity against EGFR mutations linked to acquired resistance.
- BIBW2992, an irreversible EGFR/HER2 inhibitor, showed in vitro efficacy against wild-type EGFR and key resistance mutations (EGFR exon 19 deletion, L858R, T790M).
Conclusions:
- Second-generation EGFR TKIs represent a promising advancement in NSCLC treatment, particularly for patients with resistance to first-generation therapies.
- These agents exhibit potent activity against a spectrum of EGFR mutations, including those conferring resistance.
- Further clinical evaluation of HKI-272, XL647, and BIBW2992 is warranted to establish their role in managing EGFR-mutated NSCLC.
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