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AstraZeneca Presents Tagrisso (osimertinib) Data in Patients with EGFR T790M-Mutation Positive Lung Cancer and Central Nervous System Metastases

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AstraZeneca today reported further evidence that Tagrisso (osimertinib), the potential new standard of care for adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), also shows efficacy in those patients with disease progression to central nervous system (CNS) metastases.1 The data, presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, USA, 2-6 June, are consistent with earlier clinical and preclinical findings showing the potential of osimertinib to penetrate the blood-brain barrier.2,3

In a further analysis of the Phase III AURA3 trial, osimertinib 80mg tablets once-daily demonstrated significantly longer median time without disease worsening or death (progression-free survival, PFS) than standard platinum-based doublet chemotherapy in patients with EGFR T790M mutation-positive advanced NSCLC with ≥1 measurable and/or non-measurable CNS metastases on baseline brain scan (11.7 vs 5.6 months; HR 0.32; 95% confidence interval [CI] 0.15, 0.69; p=0.004).1 Among patients who were evaluable for response, CNS objective response rate (ORR) was 70% (95% CI 51, 85) with osimertinib and 31% (95% CI 11, 59) with chemotherapy (odds ratio [OR], 5.13; 95% CI 1.44, 20.64; p=0.015). In the AURA3 trial, the adverse event (AE) profiles for osimertinib and platinum-based doublet chemotherapy were consistent with previous trials.1

Dr. Marina-Chiara Garassino, the Thoracic Oncology Unit, Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, said: “The results of osimertinib in patients with CNS metastases are consistent with what has already been reported in the overall AURA3 population. These data suggest that, like the overall EGFRm T790M mutation-positive NSCLC population, patients who have progressed to develop CNS metastases may also be able to benefit from osimertinib.”

Data were also reported from the BLOOM trial on an EGFRm T790M mutation-positive NSCLC unselected cohort of 21 patients with leptomeningeal metastases (LM) treated with osimertinib at an off-label dose of 160mg po once daily.4 The overall LM response by investigator assessment was 43%, and of the 10 patients with an ‘abnormal’ neurological assessment at baseline, seven (70%) had an improvement.4 The most common AEs were diarrhoea (n=13), nausea (n=11), paronychia (n=9) and rash (n=9). All were Grade 1/2, except one case each of diarrhoea and nausea (both Grade >3).4 Six patients had dose interruptions, four patients had an AE leading to dose reduction, and four patients had an AE leading to discontinuation. Three patients had an AE leading to death, however no deaths were considered possibly causally-related to osimertinib by the investigator.4

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “Osimertinib’s potential for blood-brain barrier penetration was recognised at an early stage of development, and it is gratifying to see those findings reflected in positive progression-free survival outcomes in patients with CNS metastases in the AURA3 trial and in responses in patients with leptomeningeal metastases in the BLOOM study.”

LM are incurable and notoriously difficult to treat, as existing therapies are often unable to effectively cross the blood-brain barrier, leaving patients with limited treatment options.5-7 The use of osimertinib for these patients is not approved and subject to further clinical research.

– 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-quarter of all cancer deaths, more than breast, prostate and colorectal cancers combined.8 Patients who have EGFR mutation-positive NSCLC, which occurs in 10-15% of NSCLC patients in the US and Europe and 30-40% of NSCLC patients in Asia, are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signalling pathways that drive the growth of tumour cells.9-12 However, tumours almost always develop resistance to treatment, leading to disease progression.13 Approximately half of patients develop resistance to approved EGFR-TKIs such as gefitinib, erlotinib and afatinib due to the secondary mutation, EGFR T790M.13,14

About Tagrisso

Tagrisso (osimertinib) 40mg and 80mg once-daily oral tablet has been approved in 50 countries, including the US, EU, Japan and China, for patients with EGFR T790M mutation-positive advanced NSCLC. Eligibility for treatment with osimertinib is dependent on confirmation that the EGFR T790M mutation is present in the tumour.

Osimertinib is a third generation, irreversible EGFR-TKI designed to inhibit both EGFR sensitising and EGFR T790M resistance mutations, with clinical activity against CNS metastases.15 Osimertinib is also being investigated in the adjuvant and metastatic 1st line settings, including in patients with and without CNS metastases, in leptomeningeal metastases, and in combination with other treatments.16-19

About the AURA3 trial

AURA3 compared the efficacy and safety of osimertinib 80mg once daily and platinum-based doublet chemotherapy in 419 patients with EGFR T790M mutation-positive, locally advanced or metastatic NSCLC whose disease had progressed on or after treatment with a previous EGFR-TKI.20 The trial was carried out in more than 130 locations worldwide, including the US, Canada, Europe, China, Japan, Korea, Taiwan and Australia.

The primary endpoint of the trial was PFS, and secondary endpoints included OS, ORR, DoR, DCR, safety and measures of health-related quality of life (HRQoL).20

About the BLOOM trial

In the BLOOM trial, patients with EGFR mutation-positive advanced NSCLC who had progressed on prior EGFR-TKI therapy and had leptomeningeal disease confirmed by positive cerebrospinal fluid cytology received osimertinib off-label dose 160mg once daily.18 Response was assessed (by investigator) in two cohorts: EGFR T790M unselected and EGFR T790M-positive (by central test). Analyses were based on cerebrospinal fluid (CSF) cytology, brain MRI imaging and neurological examination every six weeks until progression.18

About Central Nervous System (CNS) Metastases

Parenchymal brain metastases (BM) and leptomeningeal metastases (LM) are different forms of CNS metastases with a particularly devastating prognosis.21,22 While separate conditions, they may occur in parallel and are notoriously difficult to treat. BM are a common complication of advanced cancer and form when primary tumour cells disseminate through the blood stream and proliferate in the brain, whilst LM is much rarer and occurs when tumour cells spread to the meninges surrounding the brain and spinal cord.20,22,24-26

About AstraZeneca in Lung Cancer

AstraZeneca uses ground-breaking science to develop a wide range of therapies for patients with lung cancer. We are pioneering biomarker-guided therapies that aim to eliminate lung cancer by targeting molecular mutations in tumour cells and by boosting the power of the immune response against cancer. We are committed to transforming outcomes for patients with lung cancer, whose treatment options are currently limited.

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 six 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 five 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, Tumour Drivers and Resistance, DNA Damage Response 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, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three main therapy areas – Oncology, Cardiovascular & Metabolic Diseases and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. 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 and follow us on Twitter @AstraZeneca.

Intended audiences

This press release is issued from AstraZeneca Corporate Headquarters in Cambridge, UK and is intended to provide information about our global business. Please be aware that information relating to the approval status and labels of approved products may vary from country to country, and a country-specific press release on this topic may have been issued in the countries where AstraZeneca conducts business.

References

1. Garassino M , et al. CNS Response to Osimertinib in Patients with T790M-Positive Advanced Non-Small Cell Lung Cancer: Data from a Randomized Phase III Trial (AURA3) Abstract 9005 [Oral Presentation]. Presented at the annual meeting of the American Society of Clinical Oncology, 2-6 June 2017, Chicago, USA.

2. Ballard P, et al. Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clinical Cancer Research. 2016;15;22(20):5130-5140.

3. Goss G, et al. CNS Response to Osimertinib in Patients with T790M-Positive Advance NSCLC: Pooled Data from Two Phase II Trials. Presented at the World Conference on Lung Cancer (WCLC) 2016.

4. Yang J C-H, et al. Osimertinib for Patients with Leptomeningeal Metastases from EGFR-Mutant Non-Small Cell Lung Cancer: Updated Results from the BLOOM Study Abstract 2020 [Poster 262]. Presented at the annual meeting of the American Society of Clinical Oncology, 2-6 June 2017, Chicago, USA.

5. De Vries NA, et al. Restricted Brain Penetration of the Tyrosine Kinase Inhibitor Erlotinib Due to the Drug Transporters P-gp and BCRP. Invest New Drugs. 2012;30(2):443-9.

6. Zhao J, et al. Cerebrospinal Fluid Concentrations of Gefitinib in Patients with Lung Adenocarcinoma. Clin Lung Cancer. 2013;14(2):188-93.

7. European Medicines Agency CHMP assessment report for Giotrif. 2013.

8. American Cancer Society. Key Statistics for Lung Cancer. Available at https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/key-statistics.html. Accessed June 2017.

9. 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.

10. Keedy VL, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients with Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. 2011;29:2121-7.

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? J Clin Oncol. 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. Wu SG, et al. The Mechanism of Acquired Resistance to Irreversible EGFR Tyrosine Kinase Inhibitor Afatinib in Lung Adenocarcinoma Patients. Oncotarget. 2016;7(11):12404-12413.

15. 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.

16. 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 June 2017.

17. National Institutes of Health. AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic

Nonsmall Cell Lung Cancer (FLAURA). Available at https://clinicaltrials.gov/ct2/show/NCT02296125?term=FLAURA&rank=1. Accessed June 2017.

18. 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=osimertinib+leptomeningeal&rank=1. Accessed June 2017.

19. 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 June 2017.

20. 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 June 2017.

21. Preusser M, et al. Brain Metastases: Pathophysiology and Emerging Targeted Therapies. Acta Neuropathol. 2012;123:205-222.

22. Peters S, et al. The Impact of Brain Metastasis on Quality of Life, Resource Utilization and Survival in Patients with Non-Small-Cell Lung Cancer. Can Treatment Rev. 2016;45:139-162.

23. Eichler AF, et al. EGFR Mutation Status and Survival after Diagnosis of Brain Metastasis in Non-Small Cell Lung Cancer. J Clin Oncol. 2010;28:15(Suppl 1).

24. National Institutes of Health. Adult Central Nervous System Tumors Treatment–Health Professional Version (PDQ®) Metastatic Brain Tumors. http://www.cancer.gov/types/brain/hp/adult-brain-treatment-pdq. Accessed June 2017.

25. Chamberlain MC, et al. Carcinoma Meningitis Secondary to Non-small Cell Lung Cancer: Combined Modality Therapy. Arch Neurol. 1998;55:506-512.

26. Schneck MJ, et al. Leptomeningeal Carcinomatosis. Practice Essentials. Available at http://emedicine.medscape.com/article/1156338-overview. Accessed June 2017

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