O10.4 - AZD9291 a novel EGFR-TKI that overcomes T790M-mediated resistance in NSCLC

Abstract

ABSTRACT Background: AZD9291 is a potent, selective, irreversible EGFR-TKI, effective against the EGFR-TKI-sensitising (EGFRm+) and resistance T790M mutations. Patients (pts) with EGFRm+ NSCLC and acquired resistance to EGFR-TKIs were enrolled in a phase I trial into dose escalation and expansion cohorts. Methods: AZD9291 was administered orally, at doses of 20–240 mg once daily. Stable brain metastases were allowed. Primary objective was safety, tolerability, and efficacy (objective response rate). Prospective mandatory central T790M testing was required in the expansion cohorts and was optional for dose escalation cohorts. Results: As of 1 August 2014, 253 pts (female 62%, median age 60, Asian/Caucasian 62%/36%, immediate prior EGFR-TKI therapy 60%) were enrolled: 31 pts in the dose escalation and 222 pts in the dose expansion cohorts, of whom 138 were T790M positive by central tumour testing. Median treatment duration was 6.5 months (range 0.1–16). Adverse events (AEs) were mostly mild (CTCAE Grade 1/2), with diarrhoea (47%), rash (40%) and nausea (22%) the most commonly reported. 17 pts (7%) had dose reductions. Grade ≥3 AEs occurred in 32% of pts. There were 6 potential ILD-like reports. At the recommended Phase II dose of 80 mg QD, rash and diarrhoea occurred in 32% (Grade 3, 0%) and 33% (Grade 3, 1%) of pts, respectively. Among all evaluable pts to date, RECIST responses were observed at all dose levels. The confirmed overall response rate (ORR) in patients with centrally tested EGFR T790M positive tumours was 61% (78/127; 95% CI 52, 70%) and in pts with EGFR T790M negative tumours the confirmed ORR was 21% (13/61; 95% CI 12, 34%). In 78 pts with EGFR T790M positive tumours and confirmed response: longest duration of response to date was ongoing > 11 months and preliminary median duration of response at 80 mg was 8.2 months (95% CI 6.9, not calculable). Preliminary median progression-free survival in pts with centrally tested T790M positive NSCLC was 9.6 months (95% CI 8.3, not calculable; 30% maturity, 41/138 events). Conclusions: AZD9291 has been well tolerated at all dose levels tested. Clinical activity has been shown in pts with centrally confirmed EGFR T790M positive NSCLC.