Investigational Drug AZD9291 Shows Clinical Responses in Patients With Advanced NSCLC Who Have Previously Failed on Established EGFR TKIs

CHICAGO, June 3, 2014 /PRNewswire/ --

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^[1].

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)^[2]. The results were presented today 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^[3], 15 percent of NSCLC patients in the US^[4] and 30-40 percent of NSCLC patients in Asia^[5], are particularly sensitive to treatment with currently available EGFR TKIs^[6],[7],[8], 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.

Pasi A. Janne, MD, PhD, Director, Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, and Principal Investigator of the AURA study said: "As a treating oncologist, these results are promising for patients with EGFRm+ advanced NSCLC whose tumours have become resistant to treatment with established EGFR TKIs. Resistance to treatment is a major barrier to prolonged disease control. Treatments like AZD9291, which also target acquired resistance, could deliver important additional benefits to patients and redefine how we treat lung cancer."

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^[1].

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.

Susan Galbraith, SVP, Head of Oncology iMED (AZ) said: "We are particularly excited about the potential that AZD9291 has demonstrated as there is a significant unmet need for effective treatments for lung cancer patients whose tumours have become resistant to their current therapy. These results formed the basis upon which the FDA recently granted AZD9291 Breakthrough Therapy Designation, which will help us expedite its development and potentially allow patient to gain access to this treatment faster. In addition to exploring the potential for this compound in different lines of treatment, we are also actively pursuing a range of AZD9291 combinations, both with immunotherapies and small molecule compounds."

NOTES TO EDITORS 

About the AURA study 

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 non-small cell lung cancer (NSCLC) who had disease progression following treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI).

• As of 2 April 2014, 232 patients had been enrolled in the study and of these, 205 have been evaluable for response^[1].
• Amongst the 205 evaluable patients, the overall response rate (ORR) was 53 percent (unconfirmed + confirmed; 109/205; 95% CI 46%, 60%)^[1].
• A higher ORR  was seen in patients with EGFR T790M+ tumours than in patients whose tumours were negative for this mutation (T790M-):
  • In the 107 patient whose tumours were EGFR T790M+, the ORR (unconfirmed + confirmed) was 64 percent (69/107; 95% Cl 55%, 73%), compared to 22 percent (11/50; 95% Cl 12%, 36%) for those patients whose tumours were EGFR T790M-^[1].
  • In patients with EGFR T790M+ tumours, the overall disease control rate was 94 percent (101/107; 95% CI 88%, 98%) - meaning that their tumours shrank or became stable (overall disease control rate = complete response + partial response + stable disease)^[1].
  • At the time of data cut-off (2 April 2014), of the 69 patients with EGFR T790M+ tumours and a confirmed or unconfirmed objective response, 94 percent (65/69) were still receiving treatment; and the longest duration of response was approximately 7.5 months^[1].
• No dose-limiting toxicities were observed with AZD9291 treatment during the dose escalation part of the study and a maximum-tolerated dose was not defined.
• 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^[1].

About AZD9291 

AZD9291 is an investigational selective, irreversible inhibitor of both the activating sensitising EGFR mutation (EGFRm+) and the activating resistance mutation, T790M, while sparing the activity of wild type EGFR^[10]. AZD9291 is also designed to achieve minimal or no activity against two biological receptors, known as the insulin receptor and insulin-like growth factor receptor (IFGR), in order to avoid the potential for hyperglycaemia^[11]. Hyperglycaemia (high blood sugar) can lead to patients requiring treatment with additional medications^[12].

Patients who have the EGFRm+ form of NSCLC are particularly sensitive to treatment with currently available EGFR TKIs^[6],[7],[8], 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 specifically for T790M+ NSCLC.

In the ongoing Phase I study, AZD9291 has shown early evidence of activity as a once-daily monotherapy with clinical responses observed in an EGFRm+ population of patients with NSCLC who have previously failed on EGFR TKIs and also in patients with the T790M resistance mutation^[1].

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