Approximately 10-12% of non-small cell lung cancer (NSCLC) patients with EGFR mutations harbor in-frame mutations or insertions within exon 20 of EGFR. Unlike NSCLC patients bearing ?typical? EGFR mutations (L858R or exon 19 deletions), these patients with exon 20 mutations are highly resistant to FDA-approved first- generation tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib, with an objective response rate of approximately 4-8% and a median PFS of 2 months; by comparison, first-generation TKIs lead to an objective response rate of ~60% and a PFS of ~10 months in patients with typical EGFR mutations. The population impacted by EGFR exon 20 mutations is sizable: approximately 2,000-3,000 patients per year in the US and approximately 27,000 patients per year worldwide. Until recently, no treatment strategies had been identified that were tailored for this patient population. We recently reported the results of a detailed structure-function analysis and screening effort that led to the identification of the TKI poziotinib as a potent and clinically active inhibitor of EGFR exon 20 mutant tumors. Based on our preclinical data we have conducted a phase II trial of poziotinib. Initial results indicate high anti-tumor activity with best objective response of PR (partial response) in 55% of 44 evaluable patients. However, some patients do not initially respond to treatment (primary resistance) and, for the patients who do respond initially, acquired resistance is a clinical challenge. Our goals are to elucidate the mechanisms of primary and acquired resistance to poziotinib and other potential EGFR exon 20- targeted therapies. We find that in preclinical models, primary resistance may be associated with size and location of the specific insertion, with a greater distance of the insertion from the ?-c-helix associated with a lower sensitivity to poziotinib. Moreover, we have generated evidence from preclinical models and NSCLC patients indicating that acquired resistance may be mediated through multiple mechanisms, some EGFR-dependent (e.g. additional EGFR alterations) and others EGFR-independent (e.g. activation of alternate signal bypass pathways). We hypothesize that a) the sensitivity of different exon 20 insertions/mutations to specific TKIs will be dictated by the insertion size and location and treatment may be tailored based on this information; and b) that acquired resistance occurs through both EGFR-dependent and independent mechanisms that can be targeted. We will test these hypotheses through an integrative, multidisciplinary effort involving preclinical studies, molecular modeling, and ongoing clinical studies.
In Aim 1, we will investigate primary resistance and the structure-function relationship between specific insertions and drug response;
in Aim 2, we will investigate the mechanisms of EGFR-dependent acquired resistance, and in Aim 3 we will investigate EGFR-independent mechanisms. These studies will help guide the selection of TKIs based on a patients? mutation, and will provide a road map for the future development of improved TKIs and more effective combinations to delay or prevent the emergence of drug resistance in this group of patients for which no targeted treatments currently exist.

Public Health Relevance

Considerable progress has been made in developing effective targeted therapies for NSCLC patients harboring typical EGFR mutations (L858R and exon 19 deletions), but no advancements had been made for NSCLC patients bearing atypical EGFR exon 20 insertion mutations who are inherently resistant to the same treatment regimens. For this population, we recently identified poziotinib as a potent and clinically active compound, but critical questions remain regarding mechanisms of resistance to this agent and other tyrosine kinase inhibitors (TKIs) targeting EGFR exon 20 insertions. This project addresses a critical, unmet need to define mechanisms of resistance in this patient population and to identify therapeutic strategies to overcome resistance.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Forry, Suzanne L
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University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
United States
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