The highly selective EGFR inhibitor AZD9291 continues to show promising clinical activity in concert with tolerable toxicities in patients with advanced non-small-cell lung cancer (NSCLC) that harbour an acquired EGFR T790M resistance mutation.
Dr Pasi Jänne, Director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, presented updated results from the phase I AURA study during the Advanced NSCLC Proffered Papers session at the European Lung Cancer Conference, held April 15-18, 2015 in Geneva, Switzerland.
AZD9291, an irreversible inhibitor of EGFR and T790M mutations that also has reduced affinity for wild-type EGFR, was administered to patients with advanced NSCLC experiencing disease progression after treatment with an EGFR inhibitor.
Acquired resistance to EGFR inhibitors has been associated with a secondary EGFR mutation, EGFR T790M, in about 60% of patients.
In the AURA phase I study, 283 patients with EGFR-mutant advanced NSCLC received treatment with AZD9291 at doses ranging from 20 to 240 mg once daily. Patients with stable brain metastases were not excluded from the study. The median patient age was 60; 62% of patients were female, 61% were Asian, and 31% were Caucasian.
Prospective T790M testing was optional for 31 patients enrolled in a dose escalation cohort, but required for 252 patients in the expansion cohort; 163 patients had T790M positive tumours by central testing.
Primary and secondary endpoints met in AURA study
Responses by RECIST v1.1 criteria were observed at all dose levels; the investigator-assessed confirmed overall response rate (ORR) was 59% for patients with EGFR T790M-positive tumours and the ORR was 23% in patients with T790M-negative tumours.
When tumour response was evaluated by investigators in the cohort receiving recommended phase II 80 mg dose of AZD9291 orally, ORR was 66%. The median duration of response had not been reached at the time of analysis, with the longest duration of response being greater than 8 months in patients with EGFR T790M-positive tumours. While also immature, the median progression-free survival (PFS) in this cohort was 10.9 months. The independent centrally reviewed data showed that in patients with EGFR T790M-positive tumours receiving 80 mg daily of AZD9291, ORR was 54%, immature achieved median duration of response was 12.4 months and immature median PFS was 13.5 months.
The most common adverse events with AZD9291 treatment were primarily low-grade diarrhoea and rash that was reported by 50% and 46% of patients, respectively. Grade 3/4 investigator determined treatment related adverse events occurred in 17% of patients.
Prof. Kenneth O’Byrne of the Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia & Trinity College, Dublin, Ireland, who discussed the study results, said that currently available EGFR TKIs have two important limitations: 1. wild-type inhibition results in cutaneous toxicity and diarrhoea; 2. efficacy is limited by emergence of the EGFR T790M resistance mutation in approximately 60% of patients.
Third generation EGFR TKIs (AZD9291 and CO1686) are mutation specific inhibitors that inhibit T790M as well as the classical mutations and represent potential strategy to overcome resistance. Phase III studies of novel EGFR TKIs, with less toxicity, in first-line setting are under-investigation. However, Prof. O’Byrne questioned what next after resistance to third-generation TKIs develops and underlined the importance of tissue and liquid biopsies.
According to the investigators, the promising response rate and duration of response results from this phase I study warrant further investigation of AZD9291 and suggest that AZD9291 may have clinical benefit for patients with advanced NSCLC and acquired resistance to EGFR-TKI.
Patients tolerated the agent well and the most frequently occurring toxicities, diarrhoea and rash, were mostly mild and low-grade.
The study sponsor was AstraZeneca