TAGRISSO (OSIMERTINIB) SHOWS CLINICAL ACTIVITY IN PATIENTS WITH LEPTOMENINGEAL DISEASE FROM LUNG CANCER

AstraZeneca today announced clinical and safety data for Tagrisso (osimertinib) in patients with leptomeningeal (LM) disease, a complication of epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC),¹ where cancer cells spread to the cerebrospinal fluid. LM is a devastating disease often associated with advanced lung cancer.

The updated BLOOM Phase I trial results, presented at the American Society of Clinical Oncology (ASCO) annual meeting, showed that irrespective of T790M status of patients, osimertinib reduced enhanced central nervous system lesions as demonstrated by the presence of cancer cells in MRI scans.¹ Osimertinib also improved neurological function and lowered overall levels of EGFR mutations (EGFRm) in cerebrospinal fluid (CSF). Data from 21 patients with pre-treated EGFRm NSCLC treated with osimertinib 160mg once daily showed intracranial radiological improvement in seven patients, neurological function improvement in five patients, and clearance of tumour cells from the CSF at two consecutive visits in two patients. None of the 21 patients treated with osimertinib received concomitant radiotherapy or intrathecal chemotherapy. Fifteen patients remained on treatment at data cut-off (10 March 2016), of whom seven had been on treatment for more than nine months.

Further data from the BLOOM study showed that osimertinibcrossed the blood-brain barrier. In six of nine patients, a greater than 50% decrease in EGFR mutation level was observed in the CSF up to cycle 9, day 1 of treatment, with a sustained reduction observed in five. These results support previously reported preclinical data demonstrating that osimertinib crosses the blood-brain barrier.²

Osimertinib is currently only approved in lung cancer patients harbouring a T790M mutation.

Martin Sandelin vid Akademiska sjukhuset i Uppsala kommenterar resultaten:

"De data som presenteras är lovande och bekräftar att osimertinib även är aktivt i CNS (centrala nervsystemet). För lungcancerpatienter med EGFR-mutation och spridning av sjukdomen till hjärna och hjärnhinnor innebär det en ny möjlighet att behandla sjukdomen målriktat. För de patienter som svarar på behandlingen innebär det att strålbehandling av CNS kan fördröjas.”

Dr James CH Yang, from the National Taiwan University Hospital and National Taiwan University Cancer Centre, Taipei, said: “Leptomeningeal disease carries a devastating prognosis, so the safety, tolerability and activity profile seen with osimertinib is encouraging. In the BLOOM study, we saw a decrease in central nervous system lesions in patients with leptomeningeal disease, with accompanying neurological improvement. The results build on previous findings with osimertinib in preclinical and clinical studies and provide evidence of the potential of osimertinib in difficult-to-treat patients who have central nervous system metastases.”

In leptomeningeal disease, cancer cells spread to the membranes surrounding the brain and spinal cord. The disease is currently treated with systemic or intrathecal chemotherapy, whole-brain radiation therapy or EGFR tyrosine kinase inhibitors (TKIs), with median overall survival of 4.5-11 months.^3,4 However, most currently-available EGFR-TKIs have limited ability to cross the blood-brain barrier to effectively treat or prevent brain metastases.^5-7

Osimertinib 160mg was associated with a manageable tolerability profile over treatment periods up to 11 months. The most common adverse events reported by patients were diarrhoea (58% overall; 5% ≥Grade 3), nausea (48% overall; 0% ≥Grade 3) and rash (43% overall; 0% ≥Grade 3). There were no reported cases of interstitial lung disease, hyperglycaemia or QT prolongation.

Osimertinibrecently received accelerated approval as the first indicated treatment for patients with EGFR T790M mutation-positive locally advanced/metastatic NSCLC in the US, EU, Japan and Israel. Osimertinib is also approved in South Korea in the same indication.

AstraZeneca is committed to exploring the full potential of osimertinib in patients with lung cancer, including adjuvant and locally advanced/metastatic first-line EGFRm settings, in patients with and without brain metastases, and in those with leptomeningeal disease.⁸

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.⁹ Patients who have the EGFRm form of NSCLC, which occurs in 10-15% of NSCLC patients in Europe¹⁰ and 30-40% of NSCLC patients in Asia,¹¹ are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signalling pathways that drive the growth of tumour cells.¹² However, tumours almost always develop resistance to treatment, leading to disease progression.¹³ 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.¹³

About leptomeningeal disease

In leptomeningeal disease, cancer cells spread to the membranes surrounding the brain and spinal cord. It is a complication that affects 3-5% of patients with NSCLC¹⁴, and 9% of those with EGFRm NSCLC.¹⁵ Treatment is challenging due to poor penetration of the blood-brain barrier by most EGFR-TKI therapies, making it difficult for drugs to reach the brain and spinal cord. ^5-7 Average survival in patients with EGFRm NSCLC and leptomeningeal disease is 4.5 to 11 months.^3-4 In a recently reported “real-world” retrospective analysis of patients with EGFRm NSCLC treated with EGFR-TKIs, overall survival was approximately 30 months.¹⁶

About osimertinib

Osimertinib 80mg once-daily tablet is the first medicine indicated for the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC. Non-

clinical in vitro studies have demonstrated that osimertinibhas 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.¹⁸ It is also being investigated in the adjuvant and metastatic first-line settings,^19,20 including in patients with and without brain metastases, in leptomeningeal disease,⁸ and in combination treatment.²¹

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.

Om AstraZeneca

AstraZeneca är ett globalt, innovativt bioläkemedelsföretag med fokus på forskning, utveckling och marknadsföring av receptbelagda läkemedel, primärt för behandling av sjukdomar inom områdena hjärta/kärl/metabolism, andningsvägar/inflammation/autoimmunitet, cancer, infektion och neurovetenskap. AstraZeneca är verksamt i över 100 länder och våra innovativa läkemedel används av miljontals patienter världen över.

För mer information, se www.astrazeneca.se och www.astrazeneca.com eller följ oss på twitter. Https:/twitter.com/AstraZenecaSE.

För ytterligare information kontakta:

Petra Eurenius, Kommunikationschef AstraZeneca Nordic-Baltic, telefon: 0709 186562

988635.011 06.2016 SE

References

¹Yang JCH, et al. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): updated results from BLOOM, a Phase I study. Abstract 9002 [Oral Presentation]. Presented at the annual meeting of the American Society of Clinical Oncology, 3-7 June 2016, Chicago, USA

² Ballard P, et al. Preclinical activity of AZD9291 in EGFR-mutant NSCLC brain metastases. Presented at the World Congress on Lung Cancer, 6-9 September 2015. Denver, Colorado, USA.

³ Liao BC et al. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-Small-CellLungCancer Patients withLeptomeningealCarcinomatosis. JThorac Oncol. 2015 Dec;10(12):1754-61

⁴Umemura Set al. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer. 2012 Jul;77(1):134-9.

⁵ European Medicines Agency CHMP assessment report for Giotrif. 2013

⁶ De Vries NA et al. Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. InvestNewDrugs. 2012 Apr;30(2):443-9.

⁷ Zhao J et al. Cerebrospinal fluid concentrations of gefitinib in patients withlungadenocarcinoma. Clin Lung Cancer.2013Mar;14(2):188-93.

⁸ 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 May 2016.

⁹ GLOBOCAN (2012). Estimated cancer incidence, mortality and prevalence worldwide in 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed May 2016.

¹⁰ 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.

¹¹ 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.

¹² Langer CJ, et al. 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

¹³ 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

¹⁴ ChamberlainMC et al. Carcinoma meningitis secondary to non-small cell lung cancer: combined modality therapy. Arch Neurol. 1998 Apr;55(4):506-12.

¹⁵Kuiper JL et al. Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: A retrospective cohort analysis. Lung Cancer. 2015 Sep;89(3):255-61.

¹⁶ Inoue A et al. Characteristics and overall survival of EGFR mutation-positive non-small celllungcancer treated with EGFR tyrosine kinase inhibitors: a retrospective analysis for 1660 Japanese patients. Jpn J Clin Oncol. 2016 Mar 13. pii: hyw014. [Epub ahead of print]

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

¹⁸ 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 May 2016.

¹⁹ 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 May 2016.

²⁰ 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 May 2016.

²¹ 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 May 2016.