AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer

By D. Cross, S. Ashton, S. Ghiorghiu, C. Eberlein, C. Nebhan, P. Spitzler, J. Orme, M. R. Finlay, Richard A. Ward, M. Mellor and 16 more. Cancer Discovery, 2014

1,855 citations recorded by the source corpus.

First generation EGF receptor tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit in patients with advanced EGFR mutant (EGFRm+) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent and selective third generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR. This monoanilino-pyrimidine compound is structurally distinct from other third generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Pre-clinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+ and EGFRm+/T790M mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR mutant tumor xenograft and transgenic models. The treatment of two patients with advanced EGFRm T790M+ NSCLC is described as proof of principle.

Subfields: Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/6c6c7a6b2b0b0a8f2d40c3299ae95a5099f2b4d7

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Oncology

1. Jin-Yuan Shih
2. Shang-Gin Wu
3. Jie Yang
4. K. Kerr
5. M. Hellmann
6. P. Jänne
7. S. Rosenberg

In Pulmonary and Respiratory Medicine

1. Jin-Yuan Shih
2. Shang-Gin Wu
3. Marc Ladanyi
4. P. Jänne

Citations in the corpus

• AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. (2015, neutral): “Any grade 3 (14) 9 (16) 12 (13) 13 (21) 0 37 (15)”
• Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. (2016, background): “Unlike conventional EGFR-TKIs, this activity is maintained in the presence of T790M resistance mutation.(8,9) These agents were developed to have reduced activity against wild-type EGFR and reduced EGFR-mediated toxicity compared with conventional EGFR-TKIs.”
• Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer (2018, positive): “Two circulating metabolites of osimertinib, AZ5104 and AZ7550, were detected, and both had comparable potency to sensitizing EGFR mutation and T790M [89].”
• Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology (2018, background): “The detection of the EGFR T790M mutation in this setting has become clinically necessary because of the development of third-generation EGFR TKIs, such as osimertinib, which are active in the presence of this mutation.(223,224) However, although rare responses have been reported to third-generation ”
• Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity (2016, background): “Moreover, preclinical data showed that osimertinib caused durable shrinkage in an in vivo EGFRm brain metastases model at clinically relevant doses, consistent with its efficacy in extracranial preclinical models (25).”