The pre-clinical discovery and development of osimertinib used to treat non-small cell lung cancer.

: Osimertinib is currently the only FDA- and EMA-approved third-generation small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It was initially indicated for second-line treatment of patients with metastatic T790M mutation-positive non-small cell lung cancer (NSCLC) and got approved for first-line treatment of activation mutation-positive metastatic NSCLC in 2018. Most recently, the FDA granted approval for the adjuvant treatment of patients with early-stage mutated NSCLC after tumor resection.: This drug discovery case history focuses on the key studies that led to the preclinical discovery and development of osimertinib. The authors focus on published preclinical studies by scientists from AstraZeneca and highlight key events in the clinical development.: Although eventually compromised by the cellular plasticity of the tumor and the inevitable acquisition of drug resistance through the use of osimertinib, its key role in the treatment of NSCLC with specific mutations will be maintained in the near future. As the genome of EGFR is highly labile and since the rapid development of new mutants remains an issue, there is still room for improvement for the next generation of inhibitors.