Osimertinib: First Global Approval

Abstract

Osimertinib (Tagrisso(™), AZD9291) is an oral, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that is being developed by AstraZeneca for the treatment of advanced non-small cell lung cancer (NSCLC). Osimertinib has been designed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. In November 2015, the tablet formulation of osimertinib was granted accelerated approval in the USA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC (as detected by an FDA-approved test) who have progressed on or after EGFR TKI therapy. Osimertinib has also been granted accelerated assessment status for this indication in the EU, and is in phase III development for first- and second-line and adjuvant treatment of advanced EGFR mutation-positive NSCLC in several countries. Phase I trials in patients with advanced solid tumours are also being conducted. This article summarizes the milestones in the development of osimertinib leading to this first approval for NSCLC.

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

“…In AURA and AURA2, the CSF concentrations of osimertinib in two patients were 0.2 and 1 % of the predicted plasma concentrations [94]. Case reports of two patients T790M-mutated EGFR and untreated brain metastases showed that osimertinib 80 mg daily induced sustained partial responses to both CNS and systemic disease [96].…”

“…It has nearly 200-fold greater affinity for EGFR with L858R/T790M mutation than wild-type EGFR in vitro [91]. Osimertinib also inhibits HER2, HER3, HER4, ACK1 and BLK in vitro [94]. The manufacturer-recommended oral dose of osimertinib is 80 mg daily.…”

“…Intake of high fat foods prior to osimertinib administration mildly increases osimertinib plasma concentration by about 14 % [95]. After administration, maximum plasma concentration is reached in approximately 6 hours, the volume of distribution is 986 L, and the half-life is 48 hours [12,94]. Metabolism primarily occurs via oxidation in the liver through CYP3A4.…”

“…Moderate renal impairment (creatinine clearance >30 mL/min) and mild hepatic impairment do not appear to impact drug levels or toxicity. Osimertinib use in severe renal impairment (CrCl<30 mL/min) or moderate to severe hepatic impairment has not been studied [94].…”

Extending the curve: survival of EGFR-mutated lung cancer patients in the 21st century

“…In this phase 3 study performed by Soria et al, 556 patients with untreated, EGFR-mutated advanced NSCLC were randomized to receive osimertinib (80 mg once a day) or a standard TKI (gefitinib 250 mg daily; erlotinib 150 mg daily). Osimertinib represents the third generation of EGFR-tyrosine kinase inhibitors (EGFR-TKIs), and presents several advantages compared to previous-generation compounds such as erlotinib, gefitinib and afatinib (10). In vitro studies have shown that third-generation compounds are much more potent compared to their older counterparts, with high efficacy against the mutation-type spectrum of EGFR(+) lung cancer and with striking mutation specificity (11).…”