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

Chicago (ots/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. Jänne, 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].

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical
business that focuses on the discovery, development and
commercialisation of prescription medicines, primarily for the
treatment of cardiovascular, metabolic, respiratory, inflammation,
autoimmune, oncology, infection and neuroscience diseases.
AstraZeneca operates in over 100 countries and its innovative
medicines are used by millions of patients worldwide. For more
information please visit: http://www.astrazeneca.com.

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1. Jänne PA, et al. Clinical activity of the mutant selective EGFR
Inhibitor AZD9291 in patients (pts) with EGFR inhibitor resistant
non-small cell lung cancer (NSCLC). Presented at the American Society
of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA; 30 May
- 3 June 2014. Abstract available at:
http://abstracts.asco.org/144/AbstView_144_129721.html. Data cited is
included in final data presentation on 31 May 2014: Session:
Targeting EGFR: The Next 10 Years; Clinical Science Symposium

2. National Institutes of Health. AZD9291 First Time In Patients
Ascending Dose Study (AURA). Available at: http://www.clinicaltrials.
gov/ct2/show/NCT01802632?term=AURA+AZD9291&rank=1. Accessed April
2014.

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9. Yu H, et al. Analysis of Tumor Specimens at the Time of
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10. Ranson M, et al. AZD9291: an irreversible, potent and
selective tyrosine kinase inhibitor (TKI) of activating (EGFRm+) and
resistance (T790M) mutations in advanced NSCLC. J Thorac Oncol.
2013;8(Suppl.2):S389 (abstract MO21.12).

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