The New England Journal of Medicine recently published an article regarding phase three of a clinical trial testing osimertinib, an oral first-line treatment for patients with previously untreated epidermal growth factor receptor (EGFR) mutation-positive, advanced non-small-cell lung cancer (NSCLC).

Oncogenic EGFR mutations are correlated with NSCLCs. EGFR, a transmembrane tyrosine kinase, regulates cellular proliferation and apoptosis (1). Over activation of EGFRs increases cell proliferation and decreases apoptosis, resulting in cancer progression.

Relative to chemotherapy, treatment with first or second generation reversible EFGR tyrosine kinase inhibitors, such as gefitinib or eriotinib, extends progression-free survival (1). However, alternative trials have found that patients treated with standard EGFR-TKIs eventually acquire resistance. It has been shown that 50-60% of the gefitinib and erlotinib resistance cases were correlated with T790M EGFR mutations (2). The T790M mutation increases the EGFR’s affinity to adenosine triphosphate such that it exceeds its affinity to the TKIs (3).

Unlike the standard EGFR-TKI oral treatment options, osimertinib is an irreversible inhibitor which is not selective for the wild-type EGFR and selective for both EGFR-TKI-sensitizing mutations and EGFR-T790M-resistant mutations (1). Osimertinib targets metastatic tumors of the central nervous system, mechanism by which is crossing the blood brain barrier (1).

In the clinical trial, the subjects were 556 untreated patients with EGFR-positive mutations with either locally advanced or metastatic NSCLC. The patients were randomly assigned to be treated with either 80 mg osimertinib or standard EGFR-TKI (25 mg gefitinib or 150 mg eriotinib) daily. Progression-free survival was tested.  The median progression-free survival for osimertinib was 18.9 months and 10.2 months with standard EGFR-TKIs (1). When only looking at patients with central nervous system metastases, the median progression-free survival for patients treated with osimertinib was 15.2 months and 9.6 months for patients treated with standard EGFR-TKI (1). Adverse events of grade 3 or higher were reported in 34% and 45% of the osimertinib and standard EGFR-TKI groups respectively (1).

The study concluded that osimertinib was correlated with a decreased progression of EGFR-mutation positive advanced NSCLC and also with lower rates of serious adverse events.

References:

1. Soria, J. C., Ohe, Y., Vansteenkiste, J., et al. (2017). Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. New England Journal of Medicine.

2. Tanaka, K., Nosaki, K., Otsubo, K., et al. (2017). Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor–naïve patients with non–small cell lung cancer harboring EGFR mutations.Oncotarget, 8(40), 68123.

3. Gazdar, A. (2009). Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors.Oncogene, 28, S24-S31.