ASTRAZENECA

AstraZeneca today announced updated data on AZD9291 in first-line patients with epidermal growth factor receptor mutation (EGFRm) positive advanced non-small cell lung cancer (NSCLC) and previously-treated patients with EGFRm T790M mutation-positive NSCLC. The data being presented today at the World Conference on Lung Cancer (WCLC) 2015 were from the AURA Phase I trial first-line cohort and two AURA Phase II studies.

Data demonstrated that in 60 patients who received AZD9291 once daily in the first-line setting, 72% (95% confidence interval (CI) 58% to 82%) were progression free (PFS) at 12 months. Confirmed overall response rate (ORR) was 75% (95% CI 62% to 85%). The longest duration of response (DoR) was ongoing at 18 months.¹

“While the data are still preliminary, these latest results from the AURA trial first-line cohort further reinforce the potential of AZD9291 in treatment-naïve EGFRm advanced NSCLC patients,” said Professor Suresh S. Ramalingam, presenting author of the AURA trial first-line cohort data and Chief of Thoracic Oncology and Director of Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.

Data on two AURA Phase II studies (AURA extension and AURA2) in previously treated patients with EGFRm T790M were also presented. While still preliminary, these studies showed an efficacy and tolerability profile for AZD9291 consistent with previously-reported data. In AURA extension (n=201), ORR was 61% (95% CI 54% to 68%); median DoR and median PFS were not calculable (NC). Consistent results were observed in AURA2 (n=210); ORR was 71% (95% CI 64% to 77%), median DoR was 7.8 months (95% CI 7.1 months to NC) and median PFS was 8.6 months (95% CI 8.3 months to 9.7 months).^2-3

“These data provide further evidence of the encouraging durable response with AZD9291 in treatment-naïve and pre-treated patients with advanced EGFRm NSCLC”, said Antoine Yver, Head of Oncology, Global Medicines Development at AstraZeneca. “The data support our accelerated development strategy with AZD9291, which has moved with unprecedented speed from first human studies to the US Food and Drug Administration and other regulatory submissions. With AZD9291 now under review by global regulatory authorities, we are on track to bring this innovative medicine to patients as quickly as possible to address this critical need.”

The safety profile of AZD9291 in these studies was in line with that reported earlier in the year. In the AURA first-line cohort, the most common all-cause adverse events (AE) of any grade across different dose groups included rash (grouped terms) (77% all grades, 2% Grade ≥3) and diarrhoea (73% all grades, 3% Grade ≥3). These AEs were also reported as the most common in the two AURA Phase II studies (AURA extension, rash 40% all grades, 1% Grade ≥3, diarrhoea 45% all grades, 1% Grade ≥3; AURA2, rash 42% all grades, 1% Grade ≥3, diarrhoea 39% all grades, 1% Grade ≥3).^1-3

Marketing authorisation applications for AZD9291 for the treatment of EGFRm T790M mutation-positive NSCLC have been submitted to the US Food and Drug Administration (FDA), the European Medical Agency (EMA) and other regulatory authorities. Recently, the FDA granted Priority Review to AZD9291, adding to the Breakthrough Therapy designation, Orphan Drug and Fast Track status already assigned by the regulatory body. AZD9291 has also been granted Accelerated Assessment by the EMA.

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References

¹ Ramalingam SS et al. AZD9291 in treatment-naïve EGFRm advanced NSCLC: AURA first-line cohort. Abstract 1232 [Oral Presentation]. Presented at the 16^th World Conference on Lung Cancer, 6-9 September, Denver, CO.

² Yang JC et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA study Phase II extension cohort. Abstract 943. [Oral Presentation]. Presented at the 16^th World Conference on Lung Cancer, 6-9 September, Denver, CO.

³ Mitsudomi T et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 Phase II study. Abstract 1406. [Oral Presentation]. Presented at the 16^th World Conference on Lung Cancer, 6-9 September, Denver, CO.

⁴ 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.

⁵ Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer . 2008:8;915-28.

⁶ 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.

⁷ 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.

⁸ Sharma SV, et al . Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7:169-81.

⁹ Mok TS, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med.  2009;361:947-57.

¹⁰ 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.

¹¹ 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.

About AZD9291

AZD9291 is a highly selective, irreversible inhibitor of both activating sensitising EGFRm and the resistance mutation, T790M, while sparing the activity of wild type EGFR.⁴ AZD9291 is designed to achieve minimal activity against two biological receptors, known as the insulin receptor (IR) and insulin-like growth factor receptor (IGFR), in order to minimise the potential for hyperglycaemia (high blood sugar). Hyperglycaemia can lead to patients requiring treatment with additional medications.⁵

Patients who have the EGFRm form of NSCLC, which occurs in 10-15 percent of NSCLC patients in Europe⁶ and 30-40 percent of NSCLC patients in Asia⁷ , are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signalling pathways that drive the growth of tumour cells.^8-10 However, tumours almost always develop resistance to treatment, leading to disease progression. In approximately two-thirds of patients treated with the approved EGFR-TKIs, gefitinib or erlotinib, this resistance is caused by the secondary mutation, T790M.¹¹ No targeted therapies are currently approved for the treatment of tumours with this resistance mutation.

As of June 1, 2015, of the more than 1200 patients dosed with AZD9291 across all studies, interstitial lung disease (ILD) grouped term events were reported in approximately 2.9% of patients (35 events): nine Grade 1, six Grade 2, 18 Grade ≥3, two currently ungraded. Of these, a total of four patients are reported to have died due to ILD (Grade 5).³

Osimertinib has recently been published by the World Health Organization (WHO) as the proposed International Nonproprietary Name (INN) for AZD9291, and may become formally adopted in November 2015. In the US, the American Medical Association accepted osimertinib as the United States Adopted Name (USAN).

About AstraZeneca in Oncology

Oncology is a therapeutic area in which AstraZeneca has deep-rooted heritage. It will be potentially transformational for the company’s future, becoming the sixth growth platform. Our vision is to help patients by redefining the cancer treatment paradigm and one day eliminate cancer as cause of death. By 2020, we are aiming to bring six new cancer medicines to patients.

Our broad pipeline of next-generation medicines is focused on four main disease areas - lung, ovarian, breast, and haematological cancers. These are being targeted through four key platforms – immuno-oncology, the genetic drivers of cancer and resistance, DNA damage repair and antibody drug conjugates.

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

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Key: RIA - Respiratory, Inflammation and Autoimmunity, CVMD - Cardiovascular and Metabolic Disease, ING - Infection, Neuroscience and Gastrointestinal