LONDON - Sunday, September 28th 2014 [ME NewsWire]

IMPRESS Study Results also Presented at the ESMO 2014 Congress Provide Increased Understanding of Treatment Options for Patients with EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer who have Developed Acquired Resistance to First Line IRESSA

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 patients.1

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 drug-related AE.1

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 treatment gefitinib.12

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

NOTES TO EDITORS

About the AURA study

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 response.1

About AZD9291

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.

About IRESSA

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 worldwide.

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: www.astrazeneca.com.

References

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. Accessed September 2014.

3 Archontogeorgis K, et al. Lung Cancer and Interstitial Lung Diseases: A Systematic Review. Pulmonary Medicine 2012;2012:315918.

4 Qi 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 print].

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. Accessed September 2014.

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. Accessed September 2014.

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. Accessed September 2014.

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. Accessed September 2014.

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. Accessed September 2014.

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. Accessed September 2014.

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. Accessed September 2014.

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. Accessed September 2014.

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. Accessed September 2014.

16 Cross DA, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4:1046-61.

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.

Contacts

AstraZeneca

Anthonia Aboyeji, +44 (0)788 473 1627

or

Ayesha Bharmal, +44 (0)782 408 2209

or

Esra Erkal-Paler +44 (0)207 604 8030