Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

Overcoming Resistance to EGFR-Tkis: The Potential Role of Third-Generation Inhibitors

The last decade has witnessed a silent revolution in the treatment of lung cancer: several randomized phase III studies have shown that EGFR-tyrosine kinase inhibitors (TKIs) significantly improve both response rate (RR), progression free survival (PFS) and quality of life (QoL) compared to platinum-based chemotherapy as first-line treatment of EGFR-mutated NSCLC patients [1-8]. Recently a pool...

Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors.

The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA a...

Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors.

PURPOSE To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686). EXPERIMENTAL DESIGN We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses wer...

Title: The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor

The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor.

Molecular target therapies using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, have been shown to be effective for patients with non-small cell lung cancer (NSCLC) who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the d...