Novel Treatment Options for T790M-Mutant Non-Small Cell Lung Cancer

Neelesh Sharma, MD, PhD
Published Online: May 8, 2014
Neelesh Sharma, MD, PhD Neelesh Sharma, MD, PhD

Assistant Professor Thoracic Oncology
University Hospitals/Case Comprehensive
Cancer Center
Case Western Reserve University


First-generation, reversible, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as erlotinib and geftinib have become the standard of care and first-line treatment option for patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. Despite initial clinical benefit, overall efficacy of these agents is limited by emergence of drug-resistance mutations, including the gatekeeper T790M mutation. Substitution of methionine for threonine at position 790 of EGFR leads to increased affinity for adenosine triphosphate (ATP), causing resistance to competitive inhibition by reversible EGFR-TKIs. Second-generation, irreversible EGFR-TKIs were developed to overcome this resistance and demonstrated significant preclinical activity in mouse models of T790M-mutant lung cancer. However, these agents had limited success in clinical trials because of concurrent inhibition of wild-type EGFR and associated toxicity that prevented achieving adequate drug levels in plasma for sufficient inhibition of EGFR T790M. CO-1686 and AZD9291 are third-generation, irreversible T790M mutant-specific EGFR-TKIs with little activity on wildtype EGFR and robust activity in T790M preclinical models. In ongoing phase I clinical trials, both agents have shown promising responses in patients with EGFR-TKI-resistant tumors carrying T790M mutation.


Developments in last decade have established a central role for epidermal growth factor receptor (EGFR) pathway in the treatment of non-small cell lung cancer (NSCLC). Initial observation that EGFR protein is highly expressed in various tumors, including lung cancer, led to the development of first-generation small molecule EGFR tyrosine kinase inhibitors (TKIs). Advances in structure-activity relationship (SAR) and molecular modeling made it easier to generate novel molecules that were complementary in shape and electrostatics to the EGFR kinase domain topography.1 A major breakthrough in this field was the discovery of 4-anilinoquinazolines (gefitinib, erlotinib, and lapatinib), which are potent and selective but reversible inhibitors of EGFR. The quinazoline ring binds in the adenine pocket with hydrogen bonds and the anilino ring binds in an adjacent, unique hydrophobic pocket, causing competitive inhibition for adenosine triphosphate (ATP) binding in the tyrosine kinase domain.2

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