Date: 2015-04-17
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results atELCC
Company: AstraZeneca (UK)
Product: AZD9291
Action
mechanism: kinase inhibitor/tyrosine kinase inhibitor. AZD9291 is a once daily, selective, irreversible EGFR tyrosine kinase inhibitor (TKI) designed to target both the activating sensitising mutation, EGFRm, and T790M, the genetic mutation responsible for EGFR TKI treatment resistance in up to approximately two-thirds of cases of EGFRm advanced NSCLC.
Disease: (EGFRm+), advanced non-small cell lung cancer (NSCLC)
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The Phase I study, part of larger Phase I/II trial, is an ongoing, open label, dose escalation and expansion cohort study to investigate the safety and tolerability, pharmacokinetics, response to therapy and adverse events of AZD9291 in patients with advanced NSCLC who had disease progression following treatment with an EGFR tyrosine kinase inhibitor (TKI).
Latest
news: * On April 17, 2015, AstraZeneca announced latest data from the ongoing AURA study of AZD9291 in patients with advanced epidermal growth factor receptor mutation positive (EGFRm) non-small cell lung cancer (NSCLC), who also have the T790M resistance mutation. The data demonstrated a median progression free survival (PFS) of 13.5 months (95% confidence interval (CI) 8.3 months to not calculable (NC)). These PFS findings relate to independently reviewed data from 63 patients with T790M tumours treated with AZD9291 at a dose of 80mg per day, and are based on only 38% of patients having tumour progression.The updated data also show an overall response rate with AZD9291 80mg of 54% (95% CI 41% to 67%) and a median duration of response of 12.4 months (95% CI 8.3 months to NC). The ongoing AURA Phase I/II study is investigating AZD9291 in patients with advanced NSCLC and disease progression following treatment with an EGFR TKI. As of 2 December 2014, 283 patients with EGFRm advanced NSCLC and acquired resistance to EGFR TKIs were enrolled – 31 patients in dose escalation and 252 patients in expansion cohorts. Of these patients, 163 had T790M tumours confirmed by central testing1. The updated results presented at ELCC build on previously reported data presented at the European Society for Medical Oncology 2014. In patients treated with AZD9291 80mg, the most common all-cause adverse events (AEs) of any grade were rash, 38% (0% Grade ≥3) and diarrhea, 36% (1% Grade ≥3). Investigator-determined treatment-related Grade ≥3 AEs occurred in 14% of patients. As of 19 March 2015, of more than 1000 patients across all studies dosed with AZD9291, interstitial lung disease (ILD) grouped term events were reported in approximately 2.7% of patients (27 events): 12 common terminology criteria for adverse events (CTCAE) grade 1–2; 13 grade ≥3; 2 currently ungraded. Of these, a total of 3 patients were reported to have died due to ILD (Grade 5). AstraZeneca is currently also investigating AZD9291 as first line therapy for EGFRm NSCLC patients, and in combination with MEDI4736 (anti-PDL1 immunotherapy), selumetinib (MEK inhibitor) and AZD6094 (MET inhibitor) in NSCLC. Initial data will be presented at the American Society of Clinical Oncology (ASCO) annual meeting 2015. * On May 31, 2014, AstraZeneca announced that data from the ongoing Phase I AURA study in patients with epidermal growth factor receptor mutation positive (EGFRm+), advanced non-small cell lung cancer (NSCLC), demonstrate that the overall disease control rate was 94 percent for patients with EGFR T790M+ tumours - meaning that their tumours shrank or became stable - following treatment with the investigational drug AZD9291. The results were presented as an oral presentation during the official American Society of Clinical Oncology (ASCO) Annual Conference programme. Patients who have the EGFRm+ form of NSCLC, which occurs in 10-15 percent of NSCLC patients in Europe, 15 percent of NSCLC patients in the US and 30-40 percent of NSCLC patients in Asia, are particularly sensitive to treatment with currently available EGFR TKIs, which block the cell signalling pathways that drive the growth of tumour cells. However, tumour cells almost always develop resistance to treatment, leading to disease progression. In more than half of patients with EGFRm+ NSCLC this resistance is caused by a secondary mutation known as T790M[9]. There are currently no treatments approved for T790M mutation positive (T790M+) NSCLC.
Results from the AURA study show that, amongst the 205 evaluable patients, the overall response rate (ORR) was 53 percent (unconfirmed + confirmed). The ORR was higher (64 percent confirmed and unconfirmed) in the 107 evaluable patients whose tumours were T790M+ compared to the 50 patients whose tumours were T790M- (22 percent confirmed and unconfirmed). In total, 94 percent (101/107) of patients whose tumours were T790M+ had their tumours shrink or become stable.
The most common AEs, reported in at least 10 percent of patients regardless of dose and mostly Grade 1 or 2, were: diarrhoea, rash and nausea. Grade 3/4 AEs occurred in 24 percent of patients, with four patients (2%) requiring dose reductions and 10 (4%) patients discontinuing medication. Of the six interstitial lung disease (ILD)-like cases that have been reported, all patients have responded well to treatment and all cases are being investigated further.
The development programme for AZD9291 includes AURA Phase II (the expansion portion of the current AURA Phase I/II study), AURA 2 (a separate Phase II) and a Phase III study. The Phase III study in patients with T790M+ NSCLC is planned to commence later this year.
