Investigational Drug AZD9291 Shows Clinical Responses in Patients With Advanced NSCLC Who Have Previously Failed on Established EGFR TKIs
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.
3. Szumera-Cieakiewicz A, et al. EGFR mutation testing on cytological and
histological samples in non-small cell lung cancer: a Polish, single
institution study and systematic review of European incidence. Int J Clin Exp
Pathol. 2013;6:2800-12.
4. Keedy VL, et al. American Society of Clinical Oncology provisional clinical
opinion: epidermal growth factor receptor (EGFR) Mutation testing for patients
with advanced non-small-cell lung cancer considering first-line EGFR tyrosine
kinase inhibitor therapy. J Clin Oncol. 2011;29:2121-7.
5. Ellison G, et al. EGFR mutation testing in lung cancer: a review of
available methods and their use for analysis of tumour tissue and cytology
samples. J Clin Pathol. 2013;66:79-89.
6. Sharma SV, et al. Epidermal growth factor receptor mutations in lung cancer.
Nat Rev Cancer 2007;7:169-181.
7. Mok TS, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary
Adenocarcinoma. N Engl J Med. 2009;361:947-957.
8. Rosell R, et al. Erlotinib versus standard chemotherapy as first-line
treatment for European patients with advanced EGFR mutation-positive
non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised
phase 3 trial. The Lancet Oncology. 2012;13:239-246.
9. Yu H, et al. Analysis of Tumor Specimens at the Time of Acquired Resistance
to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers. Clin Cancer
Res. 2013:19:8 2240-2247
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).
11. Pollack M. Insulin and insulin-like growth factor signalling in neoplasia.
Nature Reviews Cancer. 2008;8:915-928.
12. Reungwetwattana T, Dy GK. Targeted therapies in development for non-small
cell lung cancer. J Carcinogenesis. 2013;12:1 22-45.
SOURCE: AstraZeneca
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