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

ABSTRACT

Introduction: 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 EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) and got approved for first-line treatment of EGFR activation mutation-positive metastatic NSCLC in 2018. Most recently, the FDA granted approval for the adjuvant treatment of patients with early-stage mutated EGFR NSCLC after tumor resection.

Areas covered: 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.

Expert opinion: 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 EGFR 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.

KEYWORDS:

• Small molecule
• tyrosine kinase inhibitor
• 3^rd generation
• EGFR
• NSCLC

Article highlights

• Osimertinib is indicated for first- and second-line treatment of patients with advanced or metastatic EGFR mutation-positive NSCLC and as adjuvant therapy after tumor resection in patients with EGFR mutation-positive NSCLC, as detected by an FDA-approved test.

• Osimertinib targets the intracellular tyrosine kinase domain of EGFR selectively, whereby subsequent overactive downstream signals are inhibited, and proliferation, differentiation, and survival of the cancerous cells are suppressed.

• Preclinical development of osimertinib is a striking example of successful structure-based drug design. Beginning with an activity/selectivity screening of a small number of compounds and taking given parameters of previous generations into consideration, medicinal chemistry optimizations of a lead compound led to a clinical candidate with a desired activity and wild-type/mutant ratio profile.

• Osimertinib convinces with superior efficacy and slightly reduced adverse events in clinical settings compared to previous EGFR TKI generations and largely supersedes these in therapeutical practice.

• Reasons for the medication discontinuation of osimertinib due to resistances vary in front- and second-line therapy. In second-line treatments, the loss of the T790M gatekeeper mutation is often observed and usually accompanied by further bypass pathway mechanisms like KRAS mutations. In front-line settings, MET amplification is the main reason for resistance. The most frequent EGFR dependent mutation in both regimens is the somatic C797S mutation, which results in the loss of the essential covalent bond between osimertinib and EGFR.

Acknowledgments

The authors thank Kristine Schmidt for proof-reading (language) of the manuscript.

Reviewer disclosures

One referee has served as a consultant for AstraZeneca. Peer reviewers in this manuscript have no other relevant financial relationships or otherwise to disclose.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors are supported by the University of Tuebingen (Tuebingen Center for Academic Drug Discovery & Development).