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AZD9291 Shows Durable Clinical Response in Patients with Advanced EGFR Mutation Positive Non-Small Cell Lung Cancer at the ESMO 2014 Congress | Business Wire
LONDON–(BUSINESS WIRE)–Updated data from the ongoing AURA study of AZD9291 shows encouraging,
although still immature, median progression free survival of 9.6 months
(95% CI 8.3 to NC) in patients with epidermal growth factor receptor
mutation positive (EGFRm) T790M+ advanced non-small cell lung cancer
(NSCLC) who had disease progression following treatment with an EGFR
tyrosine kinase inhibitor (EGFR TKI).1 The progression free
survival (PFS) results are based on a 30% data maturity from 138
Data presented at the European Society for Medical Oncology (ESMO) 2014
Congress support and strengthen the results highlighted earlier this
year at the American Society for Clinical Oncology (ASCO) Congress.
The ongoing AURA Phase I/II study is investigating AZD9291 in patients
with advanced NSCLC.2 As of 1 August, 253 pre-treated
patients have been dosed on this study and the 80 mg once daily dose has
been selected for late stage development.1 The PFS results
were coupled with a prolonged duration of response. In patients with
EGFRm T790M+ advanced NSCLC treated at the 80 mg dose, the preliminary
median duration of response was 8.2 months.1
James Chih-Hsin Yang, MD, PhD, professor of Graduate Institute of
Oncology and Director of Cancer Research Center at National Taiwan
University College of Medicine, said: “We are optimistic and encouraged
by the rates of progression free survival and duration of response
results in patients treated with AZD9291. While the data are still
immature, they are based on robust patient numbers and this give us
confidence that this is a trend that will continue. To date, the longest
duration of response is still ongoing at more than 11 months.”
The confirmed overall response (ORR) rate for patients with EGFRm T790M+
advanced NSCLC treated at the 80 mg dose was 70 percent.1 For
the 127 evaluable patients with EGFRm T790M+ advanced NSCLC treated at
all doses, the confirmed ORR was 61 percent (78/127). As expected,
patients with EGFRm T790M- advanced NSCLC had a lower confirmed ORR (21
percent; 13/61) and a shorter median PFS (2.8 months).1
The most common adverse events (AEs) in the AURA study at the 80 mg dose
(N=90) were diarrhoea and rash, which were mostly mild (Grade 3
diarrhoea 1%; Grade 3 rash: 0%).1 Drug-related Grade 3 or
greater AEs occurred in 10 patients (11%) treated at this dose, with no
patients requiring dose reductions and one patient discontinuing
medication due to a drug-related AE.1
The most common AEs at all doses (N=253) were diarrhoea and rash, which
were mostly mild.1 Drug-related Grade 3 or greater AEs
occurred in 33 patients (13%), with 17 patients requiring dose
reductions (7%) and 7 patients (3%) discontinuing medication due to a
As of 12 September, more than 620 patients have been dosed with AZD9291
within the full clinical trial programme; pneumonitis-like events have
been reported in approximately two percent of patients (13 events).1
Of these events, seven were Grade 1 or 2; three were Grade 3 and one
Grade 5.1 Pneumonitis has been associated with both lung
cancer itself, as well as available treatments for this disease.3,4
Results were also presented at the ESMO 2014 Congress on preliminary
evidence of activity in NSCLC brain metastases5 and in first
line patients with EGFRm NSCLC,6 supporting further
investigation of AZD9291 in both of these settings.
In addition, data on the use of circulating tumour DNA (ctDNA), present
in the plasma of NSCLC patients, as a predictive biomarker for response
to AZD9291 were presented. There was a 65 percent response rate to
treatment with AZD9291 at all dose levels in patients with T790M
mutation detected using ctDNA in the AURA trial.7 ctDNA may
offer an attractive alternative for a non-invasive test to provide
tumour genotyping in patients unable to supply evaluable tumour samples
at biopsy or rebiopsy following first line EGFR-TKI failure. IRESSA®
(gefitinib) recently became the first EGFR-TKI in Europe to have a label
allowing the use of ctDNA for the assessment of EGFRm status in those
patients where a tumour sample is not evaluable.8
AstraZeneca has initiated both Phase II and Phase III studies in
patients with EGFRm T790M+ advanced NSCLC who had disease progression
following treatment with an EGFR TKI (AURA 29 and AURA 310
respectively). In addition, a Phase III study evaluating AZD9291 in
first line EGFRm advanced NSCLC is scheduled to start later this year.
AstraZeneca is also currently investigating the combination of AZD9291
with MEDI4736 (PDL-1 immunotherapy), selumetinib (small molecule MEK
inhibitor) and AZD6094 (small molecule MET inhibitor) in NSCLC.11
Antoine Yver, Head of Oncology, Global Medicines Development,
AstraZeneca, said: “The AZD9291 data at the ESMO 2014 Congress reinforce
the clinical activity results presented at ASCO for this investigative
therapy and continue to demonstrate how diagnostic-led treatments could
improve patient care. AstraZeneca is focused on developing novel
treatments that address the genetic drivers underlying lung cancer as
well as overcoming its resistance mechanisms. For over 40 years
AstraZeneca has delivered innovative drugs to improve the available
options for cancer patients, including IRESSA, the first targeted
therapy for patients with EGFRm advanced NSCLC.”
AstraZeneca also presented data from the investigational Phase III
IMPRESS study at the ESMO 2014 Congress. The study was a second line,
combination study in patients with EGFRm advanced NSCLC who have
acquired resistance to first line IRESSA.12
The IMPRESS study was designed to compare the efficacy and safety of
continuing IRESSA, combined with cisplatin and pemetrexed up to six
cycles (no pemetrexed maintenance), versus comparator placebo, combined
with cisplatin and pemetrexed up to six cycles (no pemetrexed
maintenance) following the development of resistance to first line
The study did not meet its primary endpoint of a statistically
significant improvement in PFS.12 The secondary endpoint of
overall survival (OS) is still ongoing. At the primary endpoint of PFS
analysis, the OS was immature (33% of events) and was not conclusive.
Longer OS was suggested for the placebo plus cisplatin and pemetrexed
arm, versus the IRESSA plus cisplatin and pemetrexed arm.12
Overall, IRESSA combined with cisplatin plus pemetrexed chemotherapy was
well tolerated and in line with known safety profiles.12
The IMPRESS results answer an important scientific question regarding
the effectiveness of a treatment strategy that includes IRESSA in second
line, in combination with cisplatin and pemetrexed in patients who have
acquired resistance to IRESSA.
AstraZeneca is continuing to explore several treatment strategies with
IRESSA, including the recent initiation of Phase I trials exploring the
combination of IRESSA with MEDI4736 (PDL-1 immunotherapy),13
tremelimumab (CTLA-4 immunotherapy)14 and selumetinib (small
molecule MEK inhibitor).15
The AURA 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 TKI.2 As of 1 August 2014, in the
ongoing AURA study, 253 pre-treated patients have been dosed with
AZD9291 capsule and of these, 239 have been evaluable for confirmed
AZD9291 is an investigational, highly selective, irreversible inhibitor
of both activating sensitising EGFRm and the resistance mutation, T790M,
while sparing the activity of wild type EGFR.16 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.17
Hyperglycaemia (high blood sugar) can lead to patients requiring
treatment with additional medications.17
Patients who have the EGFRm form of NSCLC, which occurs in 10-15 percent
of NSCLC patients in Europe18 and 30-40 percent of NSCLC
patients in Asia19, are particularly sensitive to treatment
with currently available EGFR TKIs, which block the cell signalling
pathways that drive the growth of tumour cells.20-22 However,
tumour cells almost always develop resistance to treatment, leading to
disease progression. In more than half of patients with EGFRm advanced
NSCLC, this resistance is caused by a secondary mutation known as T790M.23
There are currently no treatments specifically approved specifically for
EGFRm T790M+ advanced NSCLC.
AZD9291 has been granted been granted Breakthrough Therapy designation,
Orphan Drug and Fast Track status by the US Food and Drug Administration
(FDA). AstraZeneca anticipates filing for regulatory approval in the US
in the second half of 2015.
IRESSA is an EGFR TKI that blocks the signals from the EGFR, which leads
to tumour growth. EGFR is a protein found in abnormally high levels on
the surface of many types of cancer cells, particularly NSCLC cells.
IRESSA was launched in 2009 and is now approved in 89 countries
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: www.astrazeneca.com.
1 Yang, J,et al. Updated safety and
efficacy from a Phase 1 study of AZD9291 in patients (pts) with
EGFR-TKI-resistant non-small cell lung cancer (NSCLC). Presented at
European Society for Medical Oncology (ESMO) Annual Meeting, Madrid;
26-30 September 2014. Abstract available at: https://www.webges.com/cslide/library/esmo/browse/search/bjy#9f9C033w.Accessed September 2014.
2 National Institutes of Health. AZD9291 First Time In
Patients Ascending Dose Study (AURA). Available: http://www.clinicaltrials.gov/ct2/show/NCT01802632?term=AURA+AZD9291&rank=1.
3 Archontogeorgis K, et al. Lung Cancer and
Interstitial Lung Diseases: A Systematic Review. Pulmonary Medicine 2012;2012:315918.
WX, et al. Risk of interstitial lung disease associated with
EGFR-TKIs in advanced non-small-cell lung cancer: a meta-analysis of 24
phase III clinical trials. J
Chemother. 2014 Apr 14:1973947814Y0000000189. [Epub ahead of
5 Kim DW, et al. Preclinical evidence and clinical
cases of AZD9291 activity in EGFR-mutant non-small cell lung cancer
(NSCLC) brain metastases (BM). Presented at European Society for Medical
Oncology (ESMO) Annual Meeting, Madrid; 26-30 September 2014. Abstract
available: https://www.webges.com/cslide/library/esmo/browse/search/bkN#9faC031K.
6 Ramalingam S, et al. Pre-clinical and clinical
evaluation of AZD9291, a mutation-specific inhibitor, in treatment-naïve
EGFR-mutated NSCLC. Presented at European Society for Medical Oncology
(ESMO) Annual Meeting, Madrid; 26-30 September 2014. Abstract available: https://www.webges.com/cslide/library/esmo/browse/search/bkf#9faC03fF.
7 Thress KS, et al. Levels of EGFR T790M in plasma DNA
as a predictive biomarker for response to AZD9291, a mutant-selective
EGFR kinase inhibitor. Presented at European Society for Medical
Oncology (ESMO) Annual Meeting, Madrid; 26-30 September 2014. Abstract
available at: https://www.webges.com/cslide/library/esmo/browse/search/ctV#9faC036N.
8 IRESSA Receives CHMP positive opinion to include blood
based diagnostic testing in European label. Press release to be issued
on Thursday, 25 September 2014.
9 National Institutes of Health. Phase II AZD9291 Open Label
Study in NSCLC After Previous EGFR TKI Therapy in EGFR and T790M
Mutation Positive Tumours. Available at: http://clinicaltrials.gov/ct2/show/NCT02094261?term=AURA+2&rank=1.
10 National Institutes of Health. AZD9291 Versus
Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic
Non-Small Cell Lung Cancer. Available at: http://clinicaltrials.gov/ct2/show/NCT02151981?term=AURA+3&rank=1.
11 National Institutes of Health. AZD9291 in Combination With
Ascending Doses of Novel Therapeutics. Available at: https://clinicaltrials.gov/ct2/show/NCT02143466?term=azd9291&rank=1.
12 Mok TSK, et al. Gefitinib/chemotherapy vs
chemotherapy in epidermal growth factor receptor (EGFR)
mutation-positive non-small-cell lung cancer (NSCLC) after progression
on first-line gefitinib: the Phase III, randomised IMPRESS study.
Presented at European Society for Medical Oncology (ESMO) Annual
Meeting, Madrid; 26-30 September 2014.
13 National Institutes of Health. MEDI4736 (Anti PD-L1)
Combined With Gefitinib in Subjects With Non-Small Cell Lung Cancer
(NSCLC). Available: https://clinicaltrials.gov/ct2/show/NCT02088112?term=%22gefitinib%22+and+%22combination%22+and+%22lung%22&rank=12.
14 National Institutes of Health. Tolerability and Efficacy
of Tremelimumab in Combination With Gefitinib in NSCLC Patients
(GEFTREM). Available: https://clinicaltrials.gov/ct2/show/NCT02040064?term=%22gefitinib%22+and+%22combination%22+and+%22lung%22&rank=17.
15 National Institutes of Health. Selumetinib in Combination
With Gefitinib in NSCLC Patients. Available: https://clinicaltrials.gov/ct2/show/NCT02025114?term=%22gefitinib%22+and+%22combination%22+and+%22lung%22&rank=23.
16 Cross DA, et al. AZD9291, an irreversible EGFR TKI,
overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer
17 Pollack M. Insulin and insulin-like growth factor
signalling in neoplasia. Nat Rev Cancer. 2008:8; 915-928.
18 Szumera-Ciećkiewicz 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.
19 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.
20 Sharma SV, et al. Epidermal growth factor receptor
mutations in lung cancer. Nat Rev Cancer. 2007;7:169-81.
21 Mok TS, et al. Gefitinib or Carboplatin-Paclitaxel
in Pulmonary Adenocarcinoma. N Engl J Med. 2009;361:947-57.
22 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. Lancet Oncol. 2012;13:239–46.
23 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. 2013:19:2240-7.
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