Epidermal growth factor receptor (EGFR)-mutant tumours define a unique subset of non-small-cell lung cancer (NSCLC). These tumours display sensitivity to small-molecule EGFR tyrosine kinase inhibitors (TKIs).
Prospective clinical trials have now validated the correlation between EGFR mutation and TKI sensitivity.
Multiple mechanisms of primary and secondary resistance of lung tumours to EGFR TKIs have been elucidated.
Unfortunately, all patients eventually develop acquired resistance. Secondary mutations in EGFR and/or amplification of the gene encoding the MET receptor tyrosine kinase account for most cases of resistance.
On the basis of promising preclinical data, many new rationally designed strategies are now being pursued in clinical trials to overcome acquired resistance.
EGFR-mutant lung cancer can serve as a model for other cancers driven by oncogenic kinases.
Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR-mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease.
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The authors would like to apologize to those whose work was not included owing to space constraints. They thank C. Lovly, K. Politi and M. R. Brewer for their insightful feedback on the manuscript, and M. R. Brewer for assistance with the crystal structure diagrams. This work was supported by US National Institutes of Health (NIH) National Cancer Institute (NCI) grants R01-CA121210, P01-CA129243 and U54-CA143798. W.P. received additional support from Vanderbilt's Specialized Program of Research Excellence in Lung Cancer grant (CA90949) and the Vanderbilt-Ingram Cancer Center (VICC) core grant (P30-CA68485).
Rights to EGFR T790M testing were licensed on behalf of William Pao and others to Molecular MD. William Pao has received research funding from Exelixis and has consulted for Molecular MD, AstraZeneca, Bristol-Myers Squibb and Symphony Evolution.
- Driver mutation
An oncogenic mutation that induces and sustains tumorigenesis.
- Oncogene addiction
The phenomenon in which cancer cells become dependent on or addicted to signalling from oncogenic mutants for survival.
- Primary resistance
The initial resistance to therapy.
The first quinazoline-based reversible small-molecule EGFR tyrosine kinase inhibitor.
An FDA-approved quinazoline-based EGFR inhibitor.
- Prospective single-arm study
A clinical trial in which a drug is administered in a prospective manner to a single group of patients (defined by certain characteristics) to see whether their condition improves. Single-arm studies are distinct from two-arm studies, in which a group of patients is randomly administered one of two possible treatments (for example, an experimental treatment versus standard treatment) to determine which treatment is better.
- Response rate
RR. The proportion of patients undergoing a documented radiographic response as determined by response evaluation criteria in solid tumours.
- Progression-free survival
PFS. The length of time during and after treatment in which a disease does not progress.
- Time to progression
TTP. Time from the beginning of treatment until treatment failure.
- Never smoker
An individual who has smoked <100 cigarettes in their lifetime.
- Former light smoker
An individual who has stopped smoking for at least 15 years previously and has a total of ≤10 pack-years of smoking.
An example of a platinum doublet for first-line treatment of NSCLC.
- Hazard ratio
HR. A measure of how often an event happens in one group compared with how often it happens in another group.
- Confidence interval
CI. A calculated value that shows the range in which a particular treatment effect is likely to be observed.
- Chimeric IgG monoclonal antibody
A recombinant antibody made from two species (in the case of cetuximab, the fusion contains human and mouse sequences).
- Acquired resistance
Resistance that develops after the initial response to therapy.
- Gatekeeper residue
A conserved residue that lies at the opening of the ATP-binding pocket in several kinases.
- Disease flare
Rapid tumour growth following withdrawal of therapy.
- Resistance mutation screen
A comprehensive cell-based screen to identify all potential mutations in a target gene that confer resistance to a given agent.
- Irreversible EGFR inhibitor
A small-molecule inhibitor that binds permanently in the ATP-binding pocket of EGFR through a covalent bond at C797.
- Chemogenomic profiling
The technique of coupling chemical compound sensitivity to genomic signatures.
- Quinazoline core
A scaffold built on the fusion of a benzene ring and a pyrimidine ring.
- Anilinopyrimidine core
A scaffold built on an anilino group and pyrimidine ring.
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Pao, W., Chmielecki, J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 10, 760–774 (2010). https://doi.org/10.1038/nrc2947
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