ASTRAZENECA

AstraZeneca today reported new Phase I extended follow-up data on osimertinib in both first- and second-line treatment of patients with non-small cell lung cancer (NSCLC), at the European Lung Cancer Conference (ELCC) 2016. Late-breaker presentations reinforced the efficacy and safety profile for osimertinib previously seen in the AURA clinical trials programme.

Phase I data from the AURA trial on osimertinib investigated as first-line treatment in 60 patients (pooled 80mg and 160mg dose cohorts) with epidermal growth factor receptor (EGFR) mutation-positive advanced NSCLC showed an objective response rate (ORR, a measurement of tumour shrinkage) of 77% (95% confidence interval (CI): 64%-87%) and a progression-free survival (PFS) of 19.3 months, with 55% of patients remaining progression-free at 18 months (95% CI: 41%-67%).¹ Median duration of response (DoR) was non-calculable (NC) (95% CI: 12.5 months to NC) at the time of data cut off, with 53% of patients continuing to respond at 18 months (95% CI: 36%-67%).¹ Of the 60 first-line patients, five had tumours also harbouring the T790M mutation at diagnosis (known as de novo patients) and all five of these patients showed durable responses.¹ The most common adverse events were rash (78% overall; 2% ≥Grade 3), diarrhoea (73% overall; 3% ≥Grade 3), dry skin (58% overall; 0 ≥Grade 3) and paronychia (50% overall; 3% ≥Grade 3). All of the Grade 3 or above events in these categories occurred at the 160mg dose.¹

Klaus Edvardsen, Vice President, Clinical Oncology and Interim Head of Oncology, Global Medicines Development at AstraZeneca said: “In a Phase I study with osimertinib as first-line therapy in EGFR-mutation positive NSCLC, we are seeing consistently durable responses. In many cases, responses continue for at least 18 months including in a small group of patients with the T790M mutation detectable at diagnosis. The ongoing Phase III FLAURA trial will further characterise the potential of osimertinib 80mg in the first-line EGFRm setting.”

Updated pooled results from AURA Phase II studies in 411 pre-treated patients with EGFR T790M mutation-positive NSCLC treated with osimertinib 80mg showed a median PFS of 11 months (95% CI: 9.6-12.4 months), an ORR of 66% (95% CI: 61%-71%) and a median DoR of 12.5 months (95% CI:11.1 months to NC).² Pooled treatment-related adverse events data from the AURA Phase II studies included rash (41% overall; <1% ≥Grade 3), diarrhoea (38% overall; <1% ≥Grade 3), dry skin (30% overall; 0% ≥Grade 3) and paronychia (29% overall; 0% ≥Grade 3). Interstitial lung disease was seen in 12 patients (3% overall; 2% ≥Grade 3), hyperglycaemia in 1 patient (<1% overall; 0 ≥Grade 3) and QT prolongation in 14 patients (3% overall; 1% ≥Grade 3).²

Osimertinib recently received accelerated approval as the first indicated treatment for patients with EGFR T790M mutation-positive metastatic NSCLC in the US,³ EU⁴ and Japan.⁵ The ongoing confirmatory Phase III trial, AURA3, is assessing the efficacy and safety of osimertinib versus platinum-based doublet chemotherapy in patients with EGFR T790M mutation-positive, locally advanced, or metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI.⁶

AstraZeneca is also continuing studies in the adjuvant and locally-advanced/metastatic first-line EGFRm settings,^7,8, in patients with and without brain metastases,⁹ in leptomeningeal disease, and in combination with other compounds.^10,11

– ENDS –

NOTES TO EDITORS

About Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-third of all cancer deaths, and more than breast, prostate and colorectal cancers combined.¹² Patients who have the EGFRm form of NSCLC, which occurs in 10-15% of NSCLC patients in Europe¹³ and 30-40% of NSCLC patients in Asia,¹⁴ are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signaling pathways that drive the growth of tumour cells.¹⁵ However, tumours almost always develop resistance to treatment, leading to disease progression.¹⁶ In approximately two-thirds of patients treated with approved EGFR-TKIs such as gefitinib and erlotinib, this resistance is caused by the secondary mutation, T790M.¹⁶

About osimertinib

Osimertinib 80mg once-daily tablet is the first medicine indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC.^3,4,5 Non-clinical in vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against mutant EGFR phosphorylation across the range of clinically relevant EGFR and T790M mutant NSCLC cell lines with significantly less activity against EGFR in wild-type cell lines.¹⁷

Osimertinib is being compared with platinum-based doublet chemotherapy in the confirmatory AURA3 Phase III study in patients with EGFR T790M mutation-positive, locally advanced or metastatic NSCLC who have progressed after EGFR-TKI therapy.⁶ It is also being investigated in the adjuvant and metastatic first-line settings,^7,8 including in patients with and without brain metastases,⁹ in leptomeningeal diseases, and in combination with other compounds.^10,11

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least 6 new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s six Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms -- immuno-oncology, the genetic drivers of cancer and resistance, DNA damage repair and antibody drug conjugates -- and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

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 diseases in three main therapy areas - respiratory, inflammation, autoimmune disease (RIA), cardiovascular and metabolic disease (CVMD) and oncology – as well as 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 Ramalingam SS, et al . Osimertinib (AZD9291) as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts. Abstract LBA1_PR [Oral Presentation]. Presented at the European Lung Cancer Conference, 13-16 April 2016, Geneva, Switzerland.

² Yang JCH, et al . Osimertinib (AZD9291) in pre-treated patients with T790M-positive advanced NSCLC: updated Phase I and pooled Phase II results. Abstract LBA2_PR [Oral Presentation]. Presented at the European Lung Cancer Conference, 13-16 April 2016, Geneva, Switzerland.

³ AstraZeneca PLC. TAGRISSO™ (AZD9291) approved by the US FDA for patients with EGFR T790M mutation-positive metastatic non-small cell lung cancer. Issued on November 13^th 2015. Available at: https://www.astrazeneca.com/our-company/media-centre/press-releases/2015/TAGRISSO-AZD9291-approved-by-the-US-FDA-for-patients-with-EGFR-T790M-mutation-positive-metastatic-non-small-cell-lung-cancer-13112015.html . Accessed April 2016.

⁴ AstraZeneca PLC. TAGRISSO™ (osimertinib) approved in EU as first-in-class treatment for patients with EGFR T790M mutation-positive metastatic non-small cell lung cancer. Issued on February 3^rd 2016. Available at: https://www.astrazeneca.com/media-centre/press-releases/2016/tagrisso-osimertinib-approved-in-eu-as-first-in-class-treatment-for-lung-cancer-03022016.html . Accessed April 2016.

⁵ AstraZeneca PLC. Tagrisso™ (osimertinib) approved in Japan for patients with EGFR T790M mutation-positive metastatic non-small cell lung cancer. Issued on March 29^th 2016. Available at: https://www.astrazeneca.com/media-centre/press-releases/2016/tagrisso-approved-in-japan-for-patients-with-egfr-t790m-mutation-positive-metastatic-non-small-cell-lung-cancer-29032016.html . Accessed April 2016.

⁶ National Institutes of Health. AZD9291 Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3). Available at: https://clinicaltrials.gov/ct2/show/NCT02151981?term=AURA3&rank=1 . Accessed April 2016.

⁷ National Institutes of Health. AZD9291 Versus Placebo in Patients With Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy (ADAURA). Available at: https://www.clinicaltrials.gov/ct2/show/NCT02511106?term=AZD9291+Versus+Placebo+in+Patients&rank=1 . Accessed April 2016.

⁸ National Institutes of Health. AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA). Available at https://clinicaltrials.gov/ct2/show/NCT02296125?term=FLAURA&rank=1 . Accessed April 2016.

⁹ National Institutes of Health. Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors, AZD3759 or AZD9291, in Patients Who Have Advanced Non-Small Cell Lung Cancer (BLOOM). Available at: https://clinicaltrials.gov/ct2/show/NCT02228369?term=AZD9291+brain+met&rank=1 . Accessed April 2016.

¹⁰ National Institutes of Health. Study of AZD9291 Plus MEDI4736 Versus AZD9291 Monotherapy in NSCLC After Previous EGFR TKI Therapy in T790M Mutation Positive Tumours (CAURAL). Available at https://clinicaltrials.gov/ct2/show/NCT02454933?term=CAURAL&rank=1 . Accessed April 2016.

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 April 2016.

¹² GLOBOCAN (2012). Estimated cancer incidence, mortality and prevalence worldwide in 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx . Accessed April 2016.

¹³ 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.

¹⁴ 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.

¹⁵ Langer CJ, et a l. Epidermal Growth Factor Receptor Inhibition in Mutation-Positive Non-Small-Cell Lung Cancer: Is Afatinib Better or Simply Newer? Journal of Clinical Oncology . 2013;31(27);3303-3305

¹⁶ Yu HA, et al . Analysis of Tumour Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancer. Clin Cancer Research :2013:19(8):2240-2246

¹⁷ Cross DAE, et al . AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer. Cancer Discov . 2014;4:1046-61.

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