BRIEF REPORT: Modulation of biomarker expression by osimertinib: Results of the paired tumor biopsy cohorts of the AURA Phase I trial

INTRODUCTION:

Osimertinib is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for EGFR-TKI and T790M resistance mutations. To enhance understanding of osimertinib's mechanism of action, we aimed to evaluate the modulation of key molecular biomarkers post-osimertinib in paired clinical samples from the Phase I AURA trial.

METHODS:

Paired tumor biopsies were collected pre-study and following 15±7 days of osimertinib treatment (80 or 160 mg daily). Clinical efficacy outcomes were assessed according to whether or not viable paired biopsies could be collected; safety was also assessed. Immunohistochemical analyses assessed key pathway and tumor/immune-relevant markers (phospho[p]-EGFR, pS6, pAKT, PD-L1, CD8), with samples scored by image analysis or a pathologist blinded to treatment allocation.

RESULTS:

Pre-dose tumor biopsies were collected from 61 patients with EGFR T790M tumors; 29 patients had no viable post-dose biopsy due to tumor regression or insufficient tumor sample. Evaluable pre- and post-dose tumor biopsies were collected from 24 patients. Objective response rate (ORR) and median progression-free survival (mPFS) were improved in patients from whom a post-dose biopsy could not be collected (ORR 62%, mPFS 9.7 months, p = 0.027) compared to those from whom paired samples were collected (ORR 29%, mPFS 6.6 months). Osimertinib modulated key EGFR signaling pathways and led to increased immune cell infiltration.

CONCLUSIONS:

Collection of paired biopsy samples was challenging due to rapid tumor regression post-osimertinib, highlighting the difficulties of performing on-study biopsies in patients treated with highly active drugs.