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

PR56906

CHICAGO, May 31/PRN=KYODO JBN/--

    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].

   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. Janne 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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10. Ranson M, et al. AZD9291: an irreversible, potent and selective tyrosine

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in advanced NSCLC. J Thorac Oncol. 2013;8(Suppl.2):S389 (abstract MO21.12).

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Nature Reviews Cancer. 2008;8:915-928.

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cell lung cancer. J Carcinogenesis. 2013;12:1 22-45.

SOURCE: AstraZeneca